As you have learned, biological macromolecules are large molecules, necessary for life, that are built from smaller organic molecules. There are four major biological macromolecule classes (carbohydrates, lipids, proteins, and nucleic acids). Each is an important cell component and performs a wide array of functions. Combined, these molecules make up most of the cell’s dry mass (recall that water makes up most of its complete mass). Biological macromolecules are organic, meaning they contain carbon. In addition, they may contain hydrogen, oxygen, nitrogen, and additional minor elements.

Dehydration Synthesis

Most macromolecules are made from single subunits, or building blocks, called monomers. The monomers combine with each other using covalent bonds to form larger molecules known as polymers. In doing so, monomers release water molecules as by-products. This type of reaction is dehydration synthesis, which means “to put together while losing water.”

In a dehydration synthesis reaction (Figure 2.1.1), the hydrogen of one monomer combines with the hydroxyl group of another monomer, releasing a water molecule. At the same time, the monomers share electrons and form covalent bonds. As additional monomers join, this chain of repeating monomers forms a polymer. Different monomer types can combine in many configurations, giving rise to a diverse group of macromolecules. Even one kind of monomer can combine in a variety of ways to form several different polymers. For example, glucose monomers are the constituents of starch, glycogen, and cellulose.

Hydrolysis

Polymers break down into monomers during hydrolysis. A chemical reaction occurs when inserting a water molecule across the bond. Breaking a covalent bond with this water molecule in the compound achieves this (Figure 2.1.2). During these reactions, the polymer breaks into two components: one part gains a hydrogen atom (H+) and the other gains a hydroxyl molecule (OH–) from a split water molecule.

Dehydration and hydrolysis reactions are catalysed, or “sped up,” by specific enzymes; dehydration reactions involve the formation of new bonds, requiring energy, while hydrolysis reactions break bonds and release energy. These reactions are similar for most macromolecules, but each monomer and polymer reaction is specific for its class, for example, catalytic enzymes in the digestive system hydrolyse or break down the food we ingest into smaller molecules. This allows cells in our body to easily absorb nutrients in the intestine. A specific enzyme breaks down each macromolecule. For instance, amylase, sucrase, lactase, or maltase break down carbohydrates. Enzymes called proteases, such as pepsin and peptidase, and hydrochloric acid break down proteins. Lipases break down lipids. These broken-down macromolecules provide energy for cellular activities.

Click the drop down below to review the terms learned from this chapter.

Note: Content and images from this chapter have been adapted from Biology 2nd edition by Mary Ann Clark, Jung Choi and Matthew Douglas, used under a CC-BY license.

Most people are familiar with carbohydrates, one type of macromolecule, especially when it comes to what we eat. To lose weight, some individuals adhere to “low-carb” diets. Athletes, in contrast, often “carb-load” before important competitions to ensure that they have enough energy to compete at a high level. Carbohydrates are, in fact, an essential part of our diet. Grains, fruits, and vegetables are all-natural carbohydrate sources that provide energy to the body, particularly through glucose, a simple sugar that is a component of starch and an ingredient in many staple foods. Carbohydrates also have other important functions in humans, animals, and plants.

Molecular Structures

The stoichiometric formula (CH₂O)n, where n is the number of carbons in the molecule represents carbohydrates. In other words, the ratio of carbon to hydrogen to oxygen is 1:2:1 in carbohydrate molecules. This formula also explains the origin of the term “carbohydrate”: the components are carbon (“carbo”) and the components of water (hence, “hydrate”). Scientists classify carbohydrates into three subtypes: monosaccharides, disaccharides and polysaccharides.

Monosaccharides

Monosaccharides (mono- = “one”; sacchar- = “sweet”) are simple sugars, the most common of which is glucose. In monosaccharides, the number of carbons usually ranges from three to seven. Most monosaccharide names end with the suffix-ose. If the sugar has an aldehyde group (the functional group with the structure R-CHO), it is an aldose, and if it has a ketone group (the functional group with the structure RC(=O)R’), it is a ketose. Depending on the number of carbons in the sugar, they can be trioses (three carbons), pentoses (five carbons), and/or hexoses (six carbons). Figure 2.2.1 illustrates monosaccharides.

The chemical formula for glucose is C₆H₁₂O₆. In humans, glucose is an important source of energy. During cellular respiration, energy releases from glucose, and that energy helps make adenosine triphosphate (ATP). Plants synthesise glucose using carbon dioxide and water, and glucose in turn provides energy requirements for the plant. Humans and other animals that feed on plants often store excess glucose as catabolised (cell breakdown of larger molecules) starch.

Galactose (part of lactose, or milk sugar) and fructose (found in sucrose, in fruit) are other common monosaccharides. Although glucose, galactose, and fructose all have the same chemical formula (C₆H₁₂O₆), they differ structurally and chemically (and are isomers) because of the different arrangement of functional groups around the asymmetric carbon. All these monosaccharides have more than one asymmetric carbon (Figure 2.2.2).

What kind of sugars are these, aldose or ketose?

Glucose, galactose, and fructose are isomeric monosaccharides (hexoses), meaning they have the same chemical formula but have slightly different structures. Glucose and galactose are aldoses, and fructose is a ketose.

Monosaccharides can exist as a linear chain or as ring-shaped molecules. In aqueous solutions they are usually in ring forms (Figure 2.2.3). Glucose in a ring form can have two different hydroxyl group arrangements (OH) around the anomeric carbon (carbon 1 that becomes asymmetric in the ring formation process). If the hydroxyl group is below carbon number 1 in the sugar, it is in the alpha (α) position, and if it is above the plane, it is in the beta (β) position.

Disaccharides

Disaccharides (di- = “two”) form when two monosaccharides undergo a dehydration reaction (or a condensation reaction or dehydration synthesis). During this process, one monosaccharide’s hydroxyl group combines with another monosaccharide’s hydrogen, releasing a water molecule and forming a covalent bond. A covalent bond forms between a carbohydrate molecule and another molecule (in this case, between two monosaccharides). Scientists call this a glycosidic bond (Figure 2.2.4). Glycosidic bonds (or glycosidic linkages) can be an alpha or beta type. An alpha bond is formed when the OH group on the carbon-1 of the first glucose is below the ring plane, and a beta bond is formed when the OH group on the carbon-1 is above the ring plane.

Common disaccharides include lactose, maltose, and sucrose (Figure 2.2.5). Lactose is a disaccharide consisting of the monomers; glucose and galactose. It is naturally in milk. Maltose, or malt sugar, is a disaccharide formed by a dehydration reaction between two glucose molecules. The most common disaccharide is sucrose, or table sugar, which is comprised of glucose and fructose monomers.

Polysaccharides

A long chain of monosaccharides linked by glycosidic bonds is a polysaccharide (poly- = “many”). The chain may be branched or unbranched, and it may contain different types of monosaccharides. The molecular weight (MW) may be 100,000 Daltons or more depending on the number of joined monomers. Starch, glycogen, cellulose and chitin are primary examples of polysaccharides.

Plants store sugars in the form of starch. In plants, an amylose and amylopectin mixture (both glucose polymers) comprise these sugars. Plants can synthesise glucose, and they store the excess glucose, beyond their immediate energy needs, as starch in different plant parts, including roots and seeds. The starch in the seeds provides food for the embryo as it germinates and can also act as a food source for humans and animals. Enzymes break down the starch that humans consume, for example, an amylase present in saliva catalyses, or breaks down this starch into smaller molecules, such as maltose and glucose. The cells can then absorb the glucose.

Glucose starch comprises monomers that are joined by α 1-4 or α 1-6 glycosidic bonds. The numbers 1-4 and 1-6 refer to the carbon number of the two residues that have joined to form the bond. As Figure 2.2.6 illustrates, unbranched glucose monomer chains (only α 1-4 linkages) form the starch; whereas, amylopectin is a branched polysaccharide (α 1-6 linkages at the branch points).

Glycogen is the storage form of glucose in humans and other vertebrates and is comprised of monomers of glucose. Glycogen is the animal equivalent of starch and is a highly branched molecule usually stored in liver and muscle cells. Whenever blood glucose levels decrease, glycogen breaks down to release glucose in a process scientists call glycogenolysis.

Cellulose is the most abundant natural biopolymer. Cellulose mostly comprises a plant’s cell wall. This provides the cell structural support. Wood and paper are mostly cellulosic in nature. Glucose monomers comprise cellulose that β 1-4 glycosidic bonds link (Figure 2.2.7).

As Figure 2.2.7 shows, every other glucose monomer in cellulose is flipped over, and the monomers are packed tightly as extended long chains. This gives cellulose its rigidity and high tensile strength—which is so important to plant cells. While human digestive enzymes cannot break down the β 1-4 linkage, herbivores such as cows, koalas, and buffalos are able, with the help of the specialised microorganisms in their stomach, to digest plant material that is rich in cellulose and use it as a food source. In some of these animals, certain species of bacteria and protists reside in the rumen (part of the herbivore’s digestive system) and secrete the enzyme cellulase. The appendix of grazing animals also contains bacteria that digest cellulose, giving it an important role in ruminants’ digestive systems. Cellulases can break down cellulose into glucose monomers that animals use as an energy source. Termites are also able to break down cellulose because of the presence of other organisms in their bodies that secrete cellulases.

Carbohydrates serve various functions in different animals. Arthropods (insects, crustaceans, and others) have an outer skeleton, the exoskeleton, which protects their internal body parts (as we see in the bee in Figure 2.2.8). This exoskeleton is made of the biological macromolecule chitin, which is a nitrogen-containing polysaccharide. It is made of repeating N-acetyl-β-d-glucosamine units, which are a modified sugar. Chitin is also a major component of fungal cell walls. Fungi are neither animals nor plants and form a kingdom of their own in the domain Eukarya.

Benefits of Carbohydrates

Are carbohydrates good for you? Some people believe that carbohydrates are bad and they should avoid them. Some diets completely forbid carbohydrate consumption, claiming that a low-carbohydrate diet helps people to lose weight faster. However, carbohydrates have been an important part of the human diet for thousands of years. Artifacts from ancient civilizations show the presence of wheat, rice, and corn in our ancestors’ storage areas.

As part of a well-balanced diet, we should supplement carbohydrates with proteins, vitamins, and fats. Calorie-wise, a gram of carbohydrate provides 4.3 Kcal. For comparison, fats provide 9 Kcal/g, a less desirable ratio. Carbohydrates contain soluble and insoluble elements. The insoluble part, fibre, is mostly cellulose. Fibre has many uses. It promotes regular bowel movement by adding bulk, and it regulates the blood glucose consumption rate. Fibre also helps to remove excess cholesterol from the body. Fibre binds to the cholesterol in the small intestine, then attaches to the cholesterol and prevents the cholesterol particles from entering the bloodstream. Cholesterol then exits the body via the faeces. Fibre-rich diets also have a protective role in reducing the occurrence of colon cancer. In addition, a meal containing whole grains and vegetables gives a feeling of fullness. As an immediate source of energy, glucose breaks down during the cellular respiration process, which produces ATP, the cell’s energy currency. Without consuming carbohydrates, we reduce the availability of “instant energy”. Eliminating carbohydrates from the diet may be necessary for some people, but such a step may not be healthy for everyone.

Click the drop down below to review the terms learned from this chapter.

Note: Content and images from this chapter have been adapted from Biology 2nd edition by Mary Ann Clark, Jung Choi and Matthew Douglas, used under a CC-BY license.

Lipids include a diverse group of compounds that are largely nonpolar in nature. This is because they are hydrocarbons that include mostly nonpolar carbon–carbon or carbon–hydrogen bonds. Non-polar molecules are hydrophobic (“water fearing”), or insoluble in water. Lipids perform many different functions in a cell. Cells store energy for long-term use in the form of fats. Lipids also provide insulation from the environment for plants and animals (Figure 2.3.1). For example, they help keep aquatic birds and mammals dry when forming a protective layer over fur or feathers because of their water-repellent hydrophobic nature. Lipids are also the building blocks of many hormones and are an important constituent of all cellular membranes. Lipids include fats and oils, waxes, phospholipids and steroids.

Fats and Oils

A fat molecule consists of two main components—glycerol and fatty acids. Glycerol is an organic compound (alcohol) with three carbons, five hydrogens, and three hydroxyl (OH) groups. Fatty acids have a long chain of hydrocarbons to which a carboxyl group is attached, hence the name “fatty acid.” The number of carbons in the fatty acid may range from 4 to 36. The most common are those containing 12–18 carbons. In a fat molecule, the fatty acids attach to each of the glycerol molecule’s three carbons with an ester bond through an oxygen atom (Figure 2.3.2).

During this ester bond formation, three water molecules are released. The three fatty acids in the triacylglycerol may be similar or dissimilar. We also call fats triacylglycerols (TAGs) or triglycerides (TGs) because of their chemical structure. Some fatty acids have common names that specify their origin, for example, palmitic acid, a saturated fatty acid, is derived from the palm tree. Arachidic acid (also known as eicosanoic acid) is derived from Arachis hypogea, the scientific name for groundnuts or peanuts.

Fatty acids may be saturated or unsaturated. In a fatty acid chain, if there are only single bonds between neighbouring carbons in the hydrocarbon chain, the fatty acid is saturated. Saturated fatty acids are saturated with hydrogen. In other words, the number of hydrogen atoms attached to the carbon skeleton is maximised. Stearic acid is an example of a saturated fatty acid (Figure 2.3.3).

When the hydrocarbon chain contains a double bond, the fatty acid is unsaturated. Oleic acid is an example of an unsaturated fatty acid (Figure 2.3.4).

Most unsaturated fats are liquid at room temperature. We call these oils. If there is one double bond in the molecule, then it is a monounsaturated fat (e.g., olive oil), and if there is more than one double bond, then it is a polyunsaturated fat (e.g., canola oil).

When a fatty acid has no double bonds, it is a saturated fatty acid because it is not possible to add more hydrogen to the chain’s carbon atoms. A fat may contain similar or different fatty acids attached to glycerol. Long straight fatty acids with single bonds generally pack tightly and are solid at room temperature. Animal fats with stearic acid and palmitic acid (common in meat) and the fat with butyric acid (common in butter) are examples of saturated fats. Mammals store fats in specialised cells, or adipocytes, where fat globules occupy most of the cell’s volume. Plants store fat or oil in many seeds and use them as a source of energy during seedling development. Unsaturated fats or oils are usually of plant origin and contain cis unsaturated fatty acids. Cis and trans indicate the configuration of the molecule around the double bond. If hydrogens are present in the same plane, it is a cis fat. If the hydrogen atoms are on two different planes, it is a trans-fat. The cis double bond causes a bend or a “kink” that prevents the fatty acids from packing tightly, keeping them liquid at room temperature (Figure 2.3.5). Olive oil, corn oil, canola oil, and cod liver oil are examples of unsaturated fats. Unsaturated fats help to lower blood cholesterol levels; whereas, saturated fats contribute to plaque formation in the arteries.

Trans Fats

The food industry artificially hydrogenates oils to make them semi-solid and of a consistency desirable for many processed food products. Simply speaking, hydrogen gas is bubbled through oils to solidify them. During this hydrogenation process, double bonds of the cis– conformation in the hydrocarbon chain may convert to double bonds in the trans– conformation.

Margarine, some types of peanut butter, and shortening are examples of artificially hydrogenated trans fats. Recent studies have shown that an increase in trans fats in the human diet may lead to higher levels of low-density lipoproteins (LDL), or “bad” cholesterol, which in turn may lead to plaque deposition in the arteries, resulting in heart disease. Many fast-food restaurants have recently banned using trans fats, and food labels are required to display the trans-fat content.

Omega Fatty Acids

Essential fatty acids are those that the human body requires but does not synthesise. Consequently, they must be supplemented through ingestion via the diet. Omega-3 fatty acids (like those in Figure 2.3.6) fall into this category and are one of only two known for humans (the other is omega-6 fatty acid). These are polyunsaturated fatty acids and are omega-3 because a double bond connects the third carbon from the hydrocarbon chain’s end to its neighbouring carbon.

The farthest carbon away from the carboxyl group is numbered as the omega (ω) carbon, and if the double bond is between the third and fourth carbon from that end, it is an omega-3 fatty acid. Nutritionally important because the body does not make them, omega-3 fatty acids include alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), all of which are polyunsaturated. Salmon, trout, and tuna are good sources of omega-3 fatty acids. Research indicates that omega-3 fatty acids reduce the risk of sudden death from heart attacks, lower triglycerides in the blood, decrease blood pressure, and prevent thrombosis by inhibiting blood clotting. They also reduce inflammation and may help lower the risk of some cancers in animals.

Like carbohydrates, fats have received considerable bad publicity. It is true that eating an excess of fried foods and other “fatty” foods leads to weight gain. However, fats do have important functions. Many vitamins are fat soluble, and fats serve as a long-term storage form of fatty acids: a source of energy. They also provide insulation for the body. Therefore, we should consume “healthy” fats in moderate amounts on a regular basis.

Waxes

Wax covers some aquatic birds’ feathers and some plants’ leaf surfaces. Because of waxes’ hydrophobic nature, they prevent water from sticking on the surface (Figure 2.3.7). Long fatty acid chains esterified to long-chain alcohols comprise waxes.

Phospholipids

Phospholipids are major plasma membrane constituents that comprise cells’ outermost layer. Like fats, they are comprised of fatty acid chains attached to a glycerol or sphingosine backbone. However, instead of three fatty acids attached as in triglycerides, there are two fatty acids forming diacylglycerol, and a modified phosphate group occupies the glycerol backbone’s third carbon (Figure 2.3.8). A phosphate group alone attached to a diacylglycerol does not qualify as a phospholipid. It is phosphatidate (diacylglycerol 3-phosphate), the precursor of phospholipids. An alcohol modifies the phosphate group. Phosphatidylcholine and phosphatidylserine are two important phospholipids that are in plasma membranes.

A phospholipid is an amphipathic molecule, meaning it has a hydrophobic and a hydrophilic part. The fatty acid chains are hydrophobic and cannot interact with water; whereas, the phosphate-containing group is hydrophilic and interacts with water (Figure 2.3.9).

The head is the hydrophilic part, and the tail contains the hydrophobic fatty acids. In a membrane, a bilayer of phospholipids forms the structure’s matrix, phospholipids’ fatty acid tails face inside, away from water; whereas, the phosphate group faces the outside, aqueous side (Figure 2.3.9).

Phospholipids are responsible for the plasma membrane’s dynamic nature. If a drop of phospholipids is placed in water, it spontaneously forms a structure that scientists call a micelle, where the hydrophilic phosphate heads face the outside and the fatty acids face the structure’s interior.

Steroids

Unlike the phospholipids and fats that was discussed earlier, steroids have a fused ring structure. Although they do not resemble the other lipids, scientists group them with them because they are also hydrophobic and insoluble in water. All steroids have four linked carbon rings and several of them, like cholesterol, have a short tail (Figure 2.3.10). Many steroids also have the –OH functional group, which puts them in the alcohol classification (sterols).

Cholesterol is the most common steroid. The liver synthesises cholesterol and is the precursor to many steroid hormones such as testosterone and oestradiol, which gonads and endocrine glands secrete. It is also the precursor to Vitamin D. Cholesterol is also the precursor of bile salts, which help emulsifying fats and their subsequent absorption by cells. Although lay people often speak negatively about cholesterol, it is necessary for the body’s proper functioning. Sterols (cholesterol in animal cells, phytosterol in plants) are components of the plasma membrane of cells and are found within the phospholipid bilayer.

Click the drop down below to review the terms learned from this chapter.

Note: Content and images from this chapter have been adapted from Biology 2nd edition by Mary Ann Clark, Jung Choi and Matthew Douglas, used under a CC-BY license.

Proteins are one of the most abundant organic molecules in living systems and have the most diverse range of functions of all macromolecules. Proteins may be structural, regulatory, contractile, or protective. They may serve in transport, storage, or membranes; or they may be toxins or enzymes. Each cell in a living system may contain thousands of proteins, each with a unique function. Their structures, like their functions, vary greatly. They are all, however, amino acid polymers arranged in a linear sequence.

Types and Functions of Proteins

Enzymes, which living cells produce, are catalysts in biochemical reactions (like digestion) and are usually complex or conjugated proteins. Each enzyme is specific for the substrate (a reactant that binds to an enzyme) upon which it acts. The enzyme may help in breakdown, rearrangement, or synthesis reactions. We call enzymes that break down their substrates catabolic enzymes. Those that build more complex molecules from their substrates are anabolic enzymes, and enzymes that affect the rate of reaction are catalytic enzymes. Note that all enzymes increase the reaction rate and, therefore, are organic catalysts. An example of an enzyme is salivary amylase, which hydrolyses its substrate amylose, a component of starch.

Hormones are chemical-signalling molecules, usually small proteins or steroids, secreted by endocrine cells that act to control or regulate specific physiological processes, including growth, development, metabolism, and reproduction. For example, insulin is a protein hormone that helps regulate the blood glucose level. Table 2.4.1 lists the primary types and functions of proteins.

Protein Types and Functions

Table 2.4.1. Types of proteins and their functions.

Proteins have different shapes and molecular weights. Some proteins are globular in shape; whereas, others are fibrous in nature, for example, haemoglobin is a globular protein, but collagen, located in our skin, is a fibrous protein. Protein shape is critical to its function, and many different types of chemical bonds maintain this shape. Changes in temperature, pH, and exposure to chemicals may lead to permanent changes in the protein’s shape, leading to loss of function, or denaturation. Different arrangements of the same 20 types of amino acids comprise all proteins. Two rare new amino acids were discovered recently (selenocystein and pirrolysine), and additional new discoveries may be added to the list.

Amino Acids

Amino acids are the monomers that comprise proteins. Each amino acid has the same fundamental structure, which consists of a central carbon atom, or the alpha (α) carbon, bonded to an amino group (-NH2), a carboxyl group (-COOH), and to a hydrogen atom. Every amino acid also has another atom or group of atoms bonded to the central atom known as the R group (Figure 2.4.1).

Scientists use the name “amino acid” because these acids contain both amino group and carboxyl-acid-group in their basic structure. As we mentioned, there are 20 common amino acids present in proteins. Nine of these are essential amino acids in humans because the human body cannot produce them and we obtain them from our diet. For each amino acid, the R group (or side chain) is different (Figure 2.4.2).

Which categories of amino acid would you expect to find on a soluble protein’s surface, and which would you expect to find in the interior? What distribution of amino acids would you expect to find in a protein embedded in a lipid bilayer?

The chemical nature of the side chain determines the amino acid’s nature (that is, whether it is acidic, basic, polar, or nonpolar). For example, the amino acid glycine has a hydrogen atom as the R group. Amino acids such as valine, methionine, and alanine are nonpolar or hydrophobic in nature, while amino acids such as serine, threonine, and cysteine are polar and have hydrophilic side chains. The side chains of lysine and arginine are positively charged, and therefore these amino acids are also basic amino acids. Proline has an R group that is linked to the amino group, forming a ring-like structure. Proline is an exception to the amino acid’s standard structure since its amino group is not separate from the side chain (Figure 2.4.2).

A single upper-case letter or a three-letter abbreviation represents amino acids, for example, the letter ‘V’ or the three-letter symbol ‘val’ represent the amino acid, valine. Just as some fatty acids are essential to a diet, some amino acids also are necessary. These essential amino acids in humans include isoleucine, leucine, and cysteine. Essential amino acids refer to those necessary to build proteins in the body, but not those that the body produces. Which amino acids are essential varies from organism to organism.

The sequence and the number of amino acids ultimately determine the protein’s shape, size, and function. A covalent bond, or peptide bond, attaches to each amino acid, which a dehydration reaction forms. One amino acid’s carboxyl group and the incoming amino acid’s amino group combine, releasing a water molecule. The resulting bond is the peptide bond (Figure 2.4.3).

The products that such linkages form are peptides. As more amino acids join to this growing chain, the resulting chain is a polypeptide. Each polypeptide has a free amino group at one end. This end the N terminal, or the amino terminal, and the other end has a free carboxyl group, also the C or carboxyl terminal. While the terms polypeptide and protein are sometimes used interchangeably, a polypeptide is technically a polymer of amino acids, whereas the term protein is used for a polypeptide or polypeptides that have combined together, often have bound non-peptide prosthetic groups, have a distinct shape, and have a unique function. After protein synthesis (translation), most proteins are modified. These are known as post-translational modifications. They may undergo cleavage, phosphorylation, or may require adding other chemical groups. Only after these modifications is the protein completely functional.

Evolution Connection

The Evolutionary Significance of Cytochrome c

Cytochrome c is an important component of the electron transport chain, a part of cellular respiration, and it is normally located in the cellular organelle, the mitochondrion. This protein has a haem prosthetic group, and the haem’s central ion alternately reduces and oxidises during electron transfer. Because this essential protein’s role in producing cellular energy is crucial, it has changed very little over millions of years. Protein sequencing has shown that there is a considerable amount of cytochrome c amino acid sequence homology among different species. In other words, we can assess evolutionary kinship by measuring the similarities or differences among various species’ DNA or protein sequences.

Scientists have determined that human cytochrome c contains 104 amino acids. For each cytochrome c molecule from different organisms that scientists have sequenced to date, 37 of these amino acids appear in the same position in all cytochrome c samples. This indicates that there may have been a common ancestor. On comparing the human and chimpanzee protein sequences, scientists did not find a sequence difference. When researchers compared human and rhesus monkey sequences, the single difference was in one amino acid. In another comparison, human to yeast sequencing shows a difference in the 44th position.

Protein Structure

As was discussed earlier, a protein’s shape is critical to its function, for example, an enzyme can bind to a specific substrate at an active site. If this active site is altered because of local changes or changes in overall protein structure, the enzyme may be unable to bind to the substrate. To understand how the protein gets its final shape or conformation, we need to understand the four levels of protein structure: primary, secondary, tertiary, and quaternary.

Primary Structure

Amino acids’ unique sequence in a polypeptide chain is its primary structure. For example, the pancreatic hormone insulin has two polypeptide chains, A and B, and they are linked together by disulphide bonds. The N terminal amino acid of the A chain is glycine; whereas, the C terminal amino acid is asparagine (Figure 2.4.4). The amino acid sequences in the A and B chains are unique to insulin.

The gene encoding the protein ultimately determines the unique sequence for every protein. A change in nucleotide sequence of the gene’s coding region may lead to adding a different amino acid to the growing polypeptide chain, causing a change in protein structure and function. In sickle cell anaemia, the haemoglobin β chain (a small portion of which we show in Figure 2.4.5) has a single amino acid substitution, causing a change in protein structure and function. Specifically, valine in the β chain substitutes the amino acid glutamic. What is most remarkable to consider is that a haemoglobin molecule is comprised of two alpha and two beta chains that each consist of about 150 amino acids. The molecule, therefore, has about 600 amino acids. The structural difference between a normal haemoglobin molecule and a sickle cell molecule—which dramatically decreases life expectancy—is a single amino acid of the 600. What is even more remarkable is that three nucleotides each encode those 600 amino acids, and a single base change (point mutation), 1 in 1800 bases causes the mutation.

Because of this change of one amino acid in the chain, haemoglobin molecules form long fibres that distort the biconcave, or disc-shaped, red blood cells and causes them to assume a crescent or “sickle” shape, which clogs blood vessels (Figure 2.4.6). This can lead to myriad serious health problems such as breathlessness, dizziness, headaches and abdominal pain for those affected by this disease.

Secondary Structure

The local folding of the polypeptide in some regions gives rise to the secondary structure of the protein. The most common are the α-helix and β-pleated sheet structures (Figure 2.4.7). Both structures are held in shape by hydrogen bonds. The hydrogen bonds form between the oxygen atom in the carbonyl group in one amino acid and another amino acid that is four amino acids farther along the chain.

Every helical turn in an alpha helix has 3.6 amino acid residues. The polypeptide’s R groups (the variant groups) protrude out from the α-helix chain. In the β-pleated sheet, hydrogen bonding between atoms on the polypeptide chain’s backbone form the “pleats”. The R groups are attached to the carbons and extend above and below the pleat’s folds. The pleated segments align parallel or antiparallel to each other, and hydrogen bonds form between the partially positive hydrogen atom in the amino group and the partially negative oxygen atom in the peptide backbone’s carbonyl group. The α-helix and β-pleated sheet structures are in most globular and fibrous proteins and they play an important structural role.

Tertiary Structure

The polypeptide’s unique three-dimensional structure is its tertiary structure (Figure 2.4.8). This structure is in part due to chemical interactions at work on the polypeptide chain. Primarily, the interactions among R groups create the protein’s complex three-dimensional tertiary structure. The nature of the R groups in the amino acids involved can counteract forming the hydrogen bonds we described for standard secondary structures. For example, R groups with like charges repel each other and those with unlike charges are attracted to each other (ionic bonds). When protein folding takes place, the nonpolar amino acids’ hydrophobic R groups lie in the protein’s interior; whereas, the hydrophilic R groups lie on the outside. Scientists also call the former interaction types hydrophobic interactions. Interaction between cysteine side chains forms disulphide linkages in the presence of oxygen, the only covalent bond that forms during protein folding.

All these interactions, weak and strong, determine the protein’s final three-dimensional shape. When a protein loses its three-dimensional shape, it may no longer be functional.

Quaternary Structure

In nature, some proteins form from several polypeptides, or subunits, and the interaction of these subunits forms the quaternary structure. Weak interactions between the subunits help to stabilise the overall structure. For example, insulin (a globular protein) has a combination of hydrogen and disulphide bonds that cause it to mostly clump into a ball shape. Insulin starts out as a single polypeptide and loses some internal sequences in the presence of post-translational modification after forming the disulphide linkages that hold the remaining chains together. Silk (a fibrous protein), however, has a β-pleated sheet structure that is the result of hydrogen bonding between different chains.

Figure 2.4.9 illustrates the four levels of protein structure (primary, secondary, tertiary, and quaternary).

Denaturation and Protein Folding

Each protein has its own unique sequence and shape that chemical interactions hold together. If the protein is subject to changes in temperature, pH, or exposure to chemicals, the protein structure may change, losing its shape without losing its primary sequence in what scientists call denaturation. Denaturation is often reversible because the polypeptide’s primary structure is conserved in the process if the denaturing agent is removed, allowing the protein to resume its function. Sometimes denaturation is irreversible, leading to loss of function. One example of irreversible protein denaturation is frying an egg. The albumin protein in the liquid egg white denatures when placed in a hot pan. Not all proteins denature at high temperatures. For instance, bacteria that survive in hot springs have proteins that function at temperatures close to boiling. The stomach is also very acidic, has a low pH and denatures proteins as part of the digestion process; however, the stomach’s digestive enzymes retain their activity under these conditions.

Protein folding is critical to its function. Scientists originally thought that the proteins themselves were responsible for the folding process. Only recently researchers discovered that often they receive assistance in the folding process from protein helpers, or chaperones (or chaperonins) that associate with the target protein during the folding process. They act by preventing polypeptide aggregation that comprise the complete protein structure, and they disassociate from the protein once the target protein is folded.

Click the drop down below to review the terms learned from this chapter.

Note: Content and images from this chapter have been adapted from Biology 2nd edition by Mary Ann Clark, Jung Choi and Matthew Douglas, used under a CC-BY license.

Nucleic acids are the most important macromolecules for the continuity of life. They carry the cell’s genetic blueprint and carry instructions for its functioning.

DNA and RNA

The two main types of nucleic acids are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). DNA is the genetic material in all living organisms, ranging from single-celled bacteria to multicellular mammals. It is in the nucleus of eukaryotes and in the organelles, chloroplasts, and mitochondria. In prokaryotes, the DNA is not enclosed in a membranous envelope.

The cell’s entire genetic content is its genome, and the study of genomes is genomics. In eukaryotic cells but not in prokaryotes, DNA forms a complex with histone proteins to form chromatin, the substance of eukaryotic chromosomes. A chromosome may contain tens of thousands of genes. Many genes contain the information to make protein products. Other genes code for RNA products. DNA controls all the cellular activities by turning the genes “on” or “off.”

The other type of nucleic acid, RNA, is mostly involved in protein synthesis. The DNA molecules never leave the nucleus but instead use an intermediary to communicate with the rest of the cell. This intermediary is the messenger RNA (mRNA). Other types of RNA—like rRNA, tRNA, and microRNA—are involved in protein synthesis and its regulation.

DNA and RNA are comprised of monomers that scientists call nucleotides. The nucleotides combine with each other to form a polynucleotide, DNA or RNA. Three components comprise each nucleotide: a nitrogenous base, a pentose (five-carbon) sugar, and a phosphate group (Figure 2.5.1). Each nitrogenous base in a nucleotide is attached to a sugar molecule, which is attached to one or more phosphate groups.

The nitrogenous bases, important components of nucleotides, are organic molecules and are so named because they contain carbon and nitrogen. They are bases because they contain an amino group that has the potential of binding an extra hydrogen, and thus decreasing the hydrogen ion concentration in its environment, making it more basic. Each nucleotide in DNA contains one of four possible nitrogenous bases: adenine (A), guanine (G) cytosine (C), and thymine (T).

Scientists classify adenine and guanine as purines. The purine’s primary structure is two carbon-nitrogen rings. Scientists classify cytosine, thymine, and uracil as pyrimidines which have a single carbon-nitrogen ring as their primary structure (Figure 2.5.1). Each of these basic carbon-nitrogen rings has different functional groups attached to it. In molecular biology shorthand, we know the nitrogenous bases by their symbols A, T, G, C, and U. DNA contains A, T, G, and C; whereas, RNA contains A, U, G, and C.

The pentose sugar in DNA is deoxyribose, and in RNA, the sugar is ribose (Figure 3.5.1). The difference between the sugars is the presence of the hydroxyl group on the ribose’s second carbon and hydrogen on the deoxyribose’s second carbon. The carbon atoms of the sugar molecule are numbered as 1′, 2′, 3′, 4′, and 5′ (1′ is read as “one prime”). The phosphate residue attaches to the hydroxyl group of the 5′ carbon of one sugar and the hydroxyl group of the 3′ carbon of the sugar of the next nucleotide, which forms a 5′–3′ phosphodiester linkage. A simple dehydration reaction like the other linkages connecting monomers in macromolecules does not form the phosphodiester linkage. Its formation involves removing two phosphate groups. A polynucleotide may have thousands of such phosphodiester linkages.

DNA Double-Helix Structure

DNA has a double-helix structure (Figure 2.5.2). The sugar and phosphate lie on the outside of the helix, forming the DNA’s backbone. The nitrogenous bases are stacked in the interior, like a pair of staircase steps. Hydrogen bonds bind the pairs to each other. Every base pair in the double helix is separated from the next base pair by 0.34 nm. The helix’s two strands run in opposite directions, meaning that the 5′ carbon end of one strand will face the 3′ carbon end of its matching strand. (Scientists call this an antiparallel orientation and is important to DNA replication and in many nucleic acid interactions.)

Only certain types of base pairing are allowed. For example, a certain purine can only pair with a certain pyrimidine. This means A can pair with T, and G can pair with C, as Figure 2.5.3 shows. This is the base complementary rule. In other words, the DNA strands are complementary to each other. If the sequence of one strand is AATTGGCC, the complementary strand would have the sequence TTAACCGG. During DNA replication, each strand copies itself, resulting in a daughter DNA double helix containing one parental DNA strand and a newly synthesised strand.

A mutation occurs, and adenine replaces cytosine. What impact do you think this will have on the DNA structure?

RNA

Ribonucleic acid, or RNA, is mainly involved in the process of protein synthesis under the direction of DNA. RNA is usually single-stranded and is comprised of ribonucleotides that are linked by phosphodiester bonds. A ribonucleotide in the RNA chain contains ribose (the pentose sugar), one of the four nitrogenous bases (A, U, G, and C), and the phosphate group.

There are four major types of RNA: messenger RNA (mRNA), ribosomal RNA (rRNA), transfer RNA (tRNA), and microRNA (miRNA). The first, mRNA, carries the message from DNA, which controls all the cellular activities in a cell. If a cell requires synthesising a certain protein, the gene for this product turns “on” and the messenger RNA synthesises in the nucleus. The RNA base sequence is complementary to the DNA’s coding sequence from which it has been copied. However, in RNA, the base T is absent and U is present instead. If the DNA strand has a sequence AATTGCGC, the sequence of the complementary RNA is UUAACGCG. In the cytoplasm, the mRNA interacts with ribosomes and other cellular machinery (Figure 2.5.4).

The mRNA is read in sets of three bases known as codons. Each codon codes for a single amino acid. In this way, the mRNA is read and the protein product is made. Ribosomal RNA (rRNA) is a major constituent of ribosomes on which the mRNA binds. The rRNA ensures the proper alignment of the mRNA and the Ribosomes. The ribosome’s rRNA also has an enzymatic activity (peptidyl transferase) and catalyses peptide bond formation between two aligned amino acids. Transfer RNA (tRNA) is one of the smallest of the four types of RNA, usually 70–90 nucleotides long. It carries the correct amino acid to the protein synthesis site. It is the base pairing between the tRNA and mRNA that allows for the correct amino acid to insert itself in the polypeptide chain. MicroRNAs are the smallest RNA molecules and their role involves regulating gene expression by interfering with the expression of certain mRNA messages. Table 2.5.1 summarises DNA and RNA features.

Table 2.5.1 DNA and RNA Features

Even though the RNA is single stranded, most RNA types show extensive intramolecular base pairing between complementary sequences, creating a predictable three-dimensional structure essential for their function.

As you have learned, information flow in an organism takes place from DNA to RNA to protein. DNA dictates the structure of mRNA in a process scientists call transcription, and RNA dictates the protein’s structure in a process scientists call translation. This is the Central Dogma of Life, which holds true for all organisms; however, exceptions to the rule occur in connection with viral infections.

Click the drop down below to review the terms learned from this chapter.

Note: Content and images from this chapter have been adapted from Biology 2nd edition by Mary Ann Clark, Jung Choi and Matthew Douglas, used under a CC-BY license.

Despite differences in structure and function, all living cells in multicellular organisms have a surrounding cell membrane. As the outer layer of your skin separates your body from its environment, the cell membrane (also known as the plasma membrane) separates the inner contents of a cell from its exterior environment. This cell membrane provides a protective barrier around the cell and regulates which materials can pass in or out.

Structure and Composition of the Cell Membrane

The cell membrane is an extremely pliable structure composed primarily of back-to-back phospholipids (a “bilayer”). Cholesterol is also present, which contributes to the fluidity of the membrane, and there are various proteins embedded within the membrane that have a variety of functions.

A single phospholipid molecule has a phosphate group on one end, called the “head,” and two side-by-side chains of fatty acids that make up the lipid tails (Figure 2.6.1). The phosphate group is negatively charged, making the head polar and hydrophilic—or “water loving.” A hydrophilic molecule (or region of a molecule) is one that is attracted to water. The phosphate heads are thus attracted to the water molecules of both the extracellular and intracellular environments. The lipid tails, on the other hand, are uncharged, or nonpolar, and are hydrophobic—or “water fearing.” A hydrophobic molecule (or region of a molecule) repels and is repelled by water. Some lipid tails consist of saturated fatty acids and some contain unsaturated fatty acids. This combination adds to the fluidity of the tails that are constantly in motion. Phospholipids are thus amphipathic molecules. An amphipathic molecule is one that contains both a hydrophilic and a hydrophobic region. In fact, soap works to remove oil and grease stains because it has amphipathic properties. The hydrophilic portion can dissolve in water while the hydrophobic portion can trap grease in micelles that then can be washed away.

The cell membrane consists of two adjacent layers of phospholipids. The lipid tails of one layer face the lipid tails of the other layer, meeting at the interface of the two layers. The phospholipid heads face outward, one layer exposed to the interior of the cell and one layer exposed to the exterior (Figure 2.6.2). Because the phosphate groups are polar and hydrophilic, they are attracted to water in the intracellular fluid. Intracellular fluid (ICF) is the fluid interior of the cell. The phosphate groups are also attracted to the extracellular fluid. Extracellular fluid (ECF) is the fluid environment outside the enclosure of the cell membrane. Interstitial fluid (IF) is the term given to extracellular fluid not contained within blood vessels. Because the lipid tails are hydrophobic, they meet in the inner region of the membrane, excluding watery intracellular and extracellular fluid from this space. The cell membrane has many proteins, as well as other lipids (such as cholesterol), that are associated with the phospholipid bilayer. An important feature of the membrane is that it remains fluid; the lipids and proteins in the cell membrane are not rigidly locked in place.

Membrane Proteins

The lipid bilayer forms the basis of the cell membrane, but it is peppered throughout with various proteins. Two different types of proteins that are commonly associated with the cell membrane are the integral proteins and peripheral protein (Figure 2.6.3). As its name suggests, an integral protein is a protein that is embedded in the membrane. A channel protein is an example of an integral protein that selectively allows particular materials, such as certain ions, to pass into or out of the cell.

Another important group of integral proteins are cell recognition proteins, which serve to mark a cell’s identity so that it can be recognised by other cells. A receptor is a type of recognition protein that can selectively bind a specific molecule outside the cell, and this binding induces a chemical reaction within the cell. A ligand is the specific molecule that binds to and activates a receptor. Some integral proteins serve dual roles as both a receptor and an ion channel. One example of a receptor-ligand interaction is the receptors on nerve cells that bind neurotransmitters, such as dopamine. When a dopamine molecule binds to a dopamine receptor protein, a channel within the transmembrane protein opens to allow certain ions to flow into the cell.

Some integral membrane proteins are glycoproteins. A glycoprotein is a protein that has carbohydrate molecules attached, which extend into the extracellular matrix. The attached carbohydrate tags on glycoproteins aid in cell recognition. The carbohydrates that extend from membrane proteins and even from some membrane lipids collectively form the glycocalyx. The glycocalyx is a fuzzy-appearing coating around the cell formed from glycoproteins and other carbohydrates attached to the cell membrane. The glycocalyx can have various roles. For example, it may have molecules that allow the cell to bind to another cell, it may contain receptors for hormones, or it might have enzymes to break down nutrients. The glycocalyces found in a person’s body are products of that person’s genetic makeup. They give each of the individual’s trillions of cells the “identity” of belonging in the person’s body. This identity is the primary way that a person’s immune defence cells “know” not to attack the person’s own body cells, but it also is the reason organs donated by another person might be rejected.

Peripheral proteins are typically found on the inner or outer surface of the lipid bilayer but can also be attached to the internal or external surface of an integral protein. These proteins typically perform a specific function for the cell. Some peripheral proteins on the surface of intestinal cells, for example, act as digestive enzymes to break down nutrients to sizes that can pass through the cells and into the bloodstream.

Transport Across the Cell

One of the great wonders of the cell membrane is its ability to regulate the concentration of substances inside the cell. These substances include ions such as Ca²⁺, Na⁺, K⁺ and Cl^–; nutrients including sugars, fatty acids, and amino acids; and waste products, particularly carbon dioxide (CO₂), which must leave the cell.

The membrane’s lipid bilayer structure provides the first level of control. The phospholipids are tightly packed together, and the membrane has a hydrophobic interior. This structure causes the membrane to be selectively permeable. A membrane that has selective permeability allows only substances meeting certain criteria to pass through it unaided. In the case of the cell membrane, only relatively small, nonpolar materials can move through the lipid bilayer (remember, the lipid tails of the membrane are nonpolar). Some examples of these are other lipids, oxygen and carbon dioxide gases, and alcohol. However, water-soluble materials—like glucose, amino acids, and electrolytes—need some assistance to cross the membrane because they are repelled by the hydrophobic tails of the phospholipid bilayer. All substances that move through the membrane do so by one of two general methods, which are categorised based on whether or not energy is required. Passive transport is the movement of substances across the membrane without the expenditure of cellular energy. In contrast, active transport is the movement of substances across the membrane using energy from adenosine triphosphate (ATP).

Passive Transport

In order to understand how substances move passively across a cell membrane, it is necessary to understand concentration gradients and diffusion. A concentration gradient is the difference in concentration of a substance across a space. Molecules (or ions) will spread/diffuse from where they are more concentrated to where they are less concentrated until they are equally distributed in that space. (When molecules move in this way, they are said to move down their concentration gradient.) Diffusion is the movement of particles from an area of higher concentration to an area of lower concentration. A couple of common examples will help to illustrate this concept. Imagine being inside a closed bathroom. If a bottle of perfume were sprayed, the scent molecules would naturally diffuse from the spot where they left the bottle to all corners of the bathroom, and this diffusion would go on until no more concentration gradient remains. Another example is a spoonful of sugar placed in a cup of tea. Eventually the sugar will diffuse throughout the tea until no concentration gradient remains. In both cases, if the room is warmer or the tea hotter, diffusion occurs even faster as the molecules are bumping into each other and spreading out faster than at cooler temperatures. Having an internal body temperature around 37^oC (98.6° F) thus also aids in diffusion of particles within the body.

Whenever a substance exists in greater concentration on one side of a semipermeable membrane, such as the cell membranes, any substance that can move down its concentration gradient across the membrane will do so. Consider substances that can easily diffuse through the lipid bilayer of the cell membrane, such as the gases oxygen (O₂) and CO₂. O₂ generally diffuses into cells because it is more concentrated outside of them, and CO₂ typically diffuses out of cells because it is more concentrated inside of them. Neither of these examples requires any energy on the part of the cell, and therefore they use passive transport to move across the membrane.

Before moving on, you need to review the gases that can diffuse across a cell membrane. Because cells rapidly use up oxygen during metabolism, there is typically a lower concentration of O₂ inside the cell than outside. As a result, oxygen will diffuse from the interstitial fluid directly through the lipid bilayer of the membrane and into the cytoplasm within the cell. On the other hand, because cells produce CO₂ as a by-product of metabolism, CO₂ concentrations rise within the cytoplasm; therefore, CO₂ will move from the cell through the lipid bilayer and into the interstitial fluid, where its concentration is lower. This mechanism of molecules moving across a cell membrane from the side where they are more concentrated to the side where they are less concentrated is a form of passive transport called simple diffusion (Figure 2.6.4).

Large polar or ionic molecules, which are hydrophilic, cannot easily cross the phospholipid bilayer. Very small polar molecules, such as water, can cross via simple diffusion due to their small size. Charged atoms or molecules of any size cannot cross the cell membrane via simple diffusion as the charges are repelled by the hydrophobic tails in the interior of the phospholipid bilayer. Solutes dissolved in water on either side of the cell membrane will tend to diffuse down their concentration gradients, but because most substances cannot pass freely through the lipid bilayer of the cell membrane, their movement is restricted to protein channels and specialised transport mechanisms in the membrane. Facilitated diffusion is the diffusion process used for those substances that cannot cross the lipid bilayer due to their size, charge, and/or polarity (Figure 2.6.5). A common example of facilitated diffusion is the movement of glucose into the cell, where it is used to make ATP. Although glucose can be more concentrated outside of a cell, it cannot cross the lipid bilayer via simple diffusion because it is both large and polar. To resolve this, a specialised carrier protein called the glucose transporter will transfer glucose molecules into the cell to facilitate its inward diffusion.

As an example, even though sodium ions (Na⁺) are highly concentrated outside of cells, these electrolytes are charged and cannot pass through the nonpolar lipid bilayer of the membrane. Their diffusion is facilitated by membrane proteins that form sodium channels (or “pores”), so that Na⁺ ions can move down their concentration gradient from outside the cells to inside the cells. There are many other solutes that must undergo facilitated diffusion to move into a cell, such as amino acids, or to move out of a cell, such as wastes. Because facilitated diffusion is a passive process, it does not require energy expenditure by the cell.

Water also can move freely across the cell membrane of all cells, either through protein channels or by slipping between the lipid tails of the membrane itself. Osmosis is the diffusion of water through a semipermeable membrane (Figure 2.6.6).

The movement of water molecules is not itself regulated by cells, so it is important that cells are exposed to an environment in which the concentration of solutes outside of the cells (in the extracellular fluid) is equal to the concentration of solutes inside the cells (in the cytoplasm). Two solutions that have the same concentration of solutes are said to be isotonic (equal tension). When cells and their extracellular environments are isotonic, the concentration of water molecules is the same outside and inside the cells, and the cells maintain their normal shape (and function).

Osmosis occurs when there is an imbalance of solutes outside of a cell versus inside the cell. A solution that has a higher concentration of solutes than another solution is said to be hypertonic, and water molecules tend to diffuse into a hypertonic solution (Figure 2.6.7). Cells in a hypertonic solution will shrivel as water leaves the cell via osmosis. In contrast, a solution that has a lower concentration of solutes than another solution is said to be hypotonic, and water molecules tend to diffuse out of a hypotonic solution. Cells in a hypotonic solution will take on too much water and swell, with the risk of eventually bursting. A critical aspect of homeostasis in living things is to create an internal environment in which all of the body’s cells are in an isotonic solution. Various organ systems, particularly the kidneys, work to maintain this homeostasis.

Another mechanism besides diffusion to passively transport materials between compartments is filtration. Unlike diffusion of a substance from where it is more concentrated to less concentrated, filtration uses a hydrostatic pressure gradient that pushes the fluid—and the solutes within it—from a higher pressure area to a lower pressure area. Filtration is an extremely important process in the body. For example, the circulatory system uses filtration to move plasma and substances across the endothelial lining of capillaries and into surrounding tissues, supplying cells with the nutrients. Filtration pressure in the kidneys provides the mechanism to remove wastes from the bloodstream.

Active Transport

For all the transport methods described above, the cell expends no energy. Membrane proteins that aid in the passive transport of substances do so without the use of ATP. During active transport, ATP is required to move a substance across a membrane, often with the help of protein carriers, and usually against its concentration gradient.

One of the most common types of active transport involves proteins that serve as pumps. The word “pump” probably conjures up thoughts of using energy to pump up the tire of a bicycle or a basketball. Similarly, energy from ATP is required for these membrane proteins to transport substances—molecules or ions—across the membrane, usually against their concentration gradients (from an area of low concentration to an area of high concentration).

The sodium-potassium pump, which is also called Na⁺/K⁺ ATPase, transports sodium out of a cell while moving potassium into the cell. The Na⁺/K⁺ pump is an important ion pump found in the membranes of many types of cells. These pumps are particularly abundant in nerve cells, which are constantly pumping out sodium ions and pulling in potassium ions to maintain an electrical gradient across their cell membranes. An electrical gradient is a difference in electrical charge across a space. In the case of nerve cells, for example, the electrical gradient exists between the inside and outside of the cell, with the inside being negatively-charged (at around -70 mV) relative to the outside. The negative electrical gradient is maintained because each Na⁺/K⁺ pump moves three Na⁺ ions out of the cell and two K⁺ ions into the cell for each ATP molecule that is used (Figure 2.6.8). This process is so important for nerve cells that it accounts for the majority of their ATP usage.

Active transport pumps can also work together with other active or passive transport systems to move substances across the membrane. For example, the sodium-potassium pump maintains a high concentration of sodium ions outside of the cell. Therefore, if the cell needs sodium ions, all it has to do is open a passive sodium channel, as the concentration gradient of the sodium ions will drive them to diffuse into the cell. In this way, the action of an active transport pump (the sodium-potassium pump) powers the passive transport of sodium ions by creating a concentration gradient. When active transport powers the transport of another substance in this way, it is called secondary active transport.

Symporters are secondary active transporters that move two substances in the same direction. For example, the sodium-glucose symporter uses sodium ions to “pull” glucose molecules into the cell. Because cells store glucose for energy, glucose is typically at a higher concentration inside of the cell than outside. However, due to the action of the sodium-potassium pump, sodium ions will easily diffuse into the cell when the symporter is opened. The flood of sodium ions through the symporter provides the energy that allows glucose to move through the symporter and into the cell, against its concentration gradient.

Conversely, antiporters are secondary active transport systems that transport substances in opposite directions. For example, the sodium-hydrogen ion antiporter uses the energy from the inward flood of sodium ions to move hydrogen ions (H⁺) out of the cell. The sodium-hydrogen antiporter is used to maintain the pH of the cell’s interior.

Other forms of active transport do not involve membrane carriers. Endocytosis (bringing “into the cell”) is the process of a cell ingesting material by enveloping it in a portion of its cell membrane, and then pinching off that portion of membrane (Figure 2.6.9). Once pinched off, the portion of membrane and its contents becomes an independent, intracellular vesicle. A vesicle is a membranous sac—a spherical and hollow organelle bounded by a lipid bilayer membrane. Endocytosis often brings materials into the cell that must be broken down or digested. Phagocytosis (“cell eating”) is the endocytosis of large particles. Many immune cells engage in phagocytosis of invading pathogens. Like little Pac-men, their job is to patrol body tissues for unwanted matter, such as invading bacterial cells, phagocytose them, and digest them. In contrast to phagocytosis, pinocytosis (“cell drinking”) brings fluid containing dissolved substances into a cell through membrane vesicles.

Phagocytosis and pinocytosis take in large portions of extracellular material, and they are typically not highly selective in the substances they bring in. Cells regulate the endocytosis of specific substances via receptor-mediated endocytosis. Receptor-mediated endocytosis is endocytosis by a portion of the cell membrane that contains many receptors that are specific for a certain substance. Once the surface receptors have bound enough of the specific substance (the receptor’s ligand), the cell will endocytose the part of the cell membrane containing the receptor-ligand complexes. Iron, a required component of haemoglobin, is endocytosed by red blood cells in this way. Iron is bound to a protein called transferrin in the blood. Specific transferrin receptors on red blood cell surfaces bind the iron-transferrin molecules, and the cell endocytoses the receptor-ligand complexes.

In contrast with endocytosis, exocytosis (taking “out of the cell”) is the process of a cell exporting material using vesicular transport (Figure 2.6.10). Many cells manufacture substances that must be secreted, like a factory manufacturing a product for export. These substances are typically packaged into membrane-bound vesicles within the cell. When the vesicle membrane fuses with the cell membrane, the vesicle releases its contents into the interstitial fluid. The vesicle membrane then becomes part of the cell membrane. Cells of the stomach and pancreas produce and secrete digestive enzymes through exocytosis (Figure 2.6.11). Endocrine cells produce and secrete hormones that are sent throughout the body, and certain immune cells produce and secrete large amounts of histamine, a chemical important for immune responses.

Diseases of the Cell: Cystic Fibrosis

Over 3,000 Australians are living with cystic fibrosis (CF), with an estimated 1 out of every 2,500 babies being born with CF every week. In the United States, approximately 1,000 new cases are reported each year, with an approximate 30,000 people affected by CF. The genetic disease is most well-known for its damage to the lungs, causing breathing difficulties and chronic lung infections, but it also affects the liver, pancreas, and intestines. Only about 50 years ago, the prognosis for children born with CF was very grim—a life expectancy rarely over 10 years. Today, with advances in medical treatment, many CF patients live into their 30s.

The symptoms of CF result from a malfunctioning membrane ion channel called the cystic fibrosis transmembrane conductance regulator, or CFTR. In healthy people, the CFTR protein is an integral membrane protein that transports Cl^– ions out of the cell. In a person who has CF, the gene for the CFTR is mutated, thus, the cell manufactures a defective channel protein that typically is not incorporated into the membrane but is instead degraded by the cell.

The CFTR requires ATP in order to function, making its Cl^– transport a form of active transport. This characteristic puzzled researchers for a long time because the Cl^– ions are actually flowing down their concentration gradient when transported out of cells. Active transport generally pumps ions against their concentration gradient, but the CFTR presents an exception to this rule.

In normal lung tissue, the movement of Cl^– out of the cell maintains a Cl^–-rich, negatively charged environment immediately outside of the cell. This is particularly important in the epithelial lining of the respiratory system. Respiratory epithelial cells secrete mucus, which serves to trap dust, bacteria, and other debris. A cilium (plural = cilia) is one of the hair-like appendages found on certain cells. Cilia on the epithelial cells move the mucus and its trapped particles up the airways away from the lungs and toward the outside. In order to be effectively moved upward, the mucus cannot be too viscous; rather it must have a thin, watery consistency. The transport of Cl^– and the maintenance of an electronegative environment outside of the cell attract positive ions such as Na⁺ to the extracellular space. The accumulation of both Cl^– and Na⁺ ions in the extracellular space creates solute-rich mucus, which has a low concentration of water molecules. As a result, through osmosis, water moves from cells and extracellular matrix into the mucus, “thinning” it out. This is how, in a normal respiratory system, the mucus is kept sufficiently watered-down to be propelled out of the respiratory system.

If the CFTR channel is absent, Cl– ions are not transported out of the cell in adequate numbers, thus preventing them from drawing positive ions. The absence of ions in the secreted mucus results in the lack of a normal water concentration gradient. Thus, there is no osmotic pressure pulling water into the mucus. The resulting mucus is thick and sticky, and the ciliated epithelia cannot effectively remove it from the respiratory system. Passageways in the lungs become blocked with mucus, along with the debris it carries. Bacterial infections occur more easily because bacterial cells are not effectively carried away from the lungs.

Click the drop down below to review the terms learned from this chapter.

Now that you have learned that the cell membrane surrounds all cells, you can dive inside of a prototypical human cell to learn about its internal components and their functions. All living cells in multicellular organisms contain an internal cytoplasmic compartment, and a nucleus within the cytoplasm. Cytosol, the jelly-like substance within the cell, provides the fluid medium necessary for biochemical reactions. Eukaryotic cells, including all animal cells, also contain various cellular organelles. An organelle (“little organ”) is one of several different types of membrane-enclosed bodies in the cell, each performing a unique function. Just as the various bodily organs work together in harmony to perform all of a human’s functions, the many different cellular organelles work together to keep the cell healthy and performing all of its important functions. The organelles and cytosol, taken together, compose the cell’s cytoplasm. The nucleus is a cell’s central organelle, which contains the cell’s DNA (Figure 2.7.1).

Organelles of the Endomembrane System

A set of three major organelles together form a system within the cell called the endomembrane system. These organelles work together to perform various cellular jobs, including the task of producing, packaging, and exporting certain cellular products. The organelles of the endomembrane system include the endoplasmic reticulum, Golgi apparatus, and vesicles.

Endoplasmic Reticulum

The endoplasmic reticulum (ER) is a system of channels that is continuous with the nuclear membrane (or “envelope”) covering the nucleus and composed of the same lipid bilayer material. The ER can be thought of as a series of winding thoroughfares like the waterway canals in Venice. The ER provides passages throughout much of the cell that function in transporting, synthesising, and storing materials. The winding structure of the ER results in a large membranous surface area that supports its many functions (Figure 2.7.2).

Endoplasmic reticulum can exist in two forms: rough ER and smooth ER. These two types of ER perform some very different functions and can be found in very different amounts depending on the type of cell. Rough ER (RER) is so-called because its membrane is dotted with embedded granules—organelles called ribosomes, giving the RER a bumpy appearance. A ribosome is an organelle that serves as the site of protein synthesis. It is composed of two ribosomal RNA subunits that wrap around mRNA to start the process of translation, followed by protein synthesis. Smooth ER (SER) lacks these ribosomes.

One of the main functions of the smooth ER is in the synthesis of lipids. The smooth ER synthesises phospholipids, the main component of biological membranes, as well as steroid hormones. For this reason, cells that produce large quantities of such hormones, such as those of the female ovaries and male testes, contain large amounts of smooth ER. In addition to lipid synthesis, the smooth ER also sequesters (i.e., stores) and regulates the concentration of cellular Ca²⁺, a function extremely important in cells of the nervous system where Ca²⁺  is the trigger for neurotransmitter release. The smooth ER additionally metabolises some carbohydrates and performs a detoxification role, breaking down certain toxins.

In contrast with the smooth ER, the primary job of the rough ER is the synthesis and modification of proteins destined for the cell membrane or for export from the cell. For this protein synthesis, many ribosomes attach to the ER (giving it the studded appearance of rough ER). Typically, a protein is synthesised within the ribosome and released inside the channel of the rough ER, where sugars can be added to it (by a process called glycosylation) before it is transported within a vesicle to the next stage in the packaging and shipping process: the Golgi apparatus.

The Golgi Apparatus

The Golgi apparatus is responsible for sorting, modifying, and shipping off the products that come from the rough ER, much like a post-office. The Golgi apparatus looks like stacked flattened discs, almost like stacks of oddly shaped pancakes. Like the ER, these discs are membranous. The Golgi apparatus has two distinct sides, each with a different role. One side of the apparatus receives products in vesicles. These products are sorted through the apparatus, and then they are released from the opposite side after being repackaged into new vesicles. If the product is to be exported from the cell, the vesicle migrates to the cell surface and fuses to the cell membrane, and the cargo is secreted (Figure 2.7.3).

Lysosomes

Some of the protein products packaged by the Golgi include digestive enzymes that are meant to remain inside the cell for use in breaking down certain materials. The enzyme-containing vesicles released by the Golgi may form new lysosomes, or fuse with existing, lysosomes. A lysosome is an organelle that contains enzymes that break down and digest unneeded cellular components, such as a damaged organelle. (A lysosome is like a wrecking crew that takes down old and unsound buildings in a neighbourhood.) Autophagy (“self-eating”) is the process of a cell digesting its own structures. Lysosomes are also important for breaking down foreign material, for example, when certain immune defence cells (white blood cells) phagocytose bacteria, the bacterial cell is transported into a lysosome and digested by the enzymes inside. As one might imagine, such phagocytic defence cells contain large numbers of lysosomes.

Under certain circumstances, lysosomes perform a more grand and dire function. In the case of damaged or unhealthy cells, lysosomes can be triggered to open up and release their digestive enzymes into the cytoplasm of the cell, killing the cell. This “self-destruct” mechanism is called autolysis, and makes the process of cell death controlled (a mechanism called “apoptosis”).

Organelles for the Energy Production and Detoxification

In addition to the jobs performed by the endomembrane system, the cell has many other important functions. Just as you must consume nutrients to provide yourself with energy, so must each of your cells take in nutrients, some of which convert to chemical energy that can be used to power biochemical reactions. Another important function of the cell is detoxification. Humans take in all sorts of toxins from the environment and also produce harmful chemicals as by-products of cellular processes. Cells called hepatocytes in the liver detoxify many of these toxins.

Mitochondria

A mitochondrion (plural = mitochondria) is a membranous, bean-shaped organelle that is the “energy transformer” of the cell. Mitochondria consist of an outer lipid bilayer membrane as well as an additional inner lipid bilayer membrane (Figure 2.7.4). The inner membrane is highly folded into winding structures with a great deal of surface area, called cristae. It is along this inner membrane that a series of proteins, enzymes, and other molecules perform the biochemical reactions of cellular respiration. These reactions convert energy stored in nutrient molecules (such as glucose) into adenosine triphosphate (ATP), which provides usable cellular energy to the cell. Cells use ATP constantly, and so the mitochondria are constantly at work. Oxygen molecules are required during cellular respiration, which is why you must constantly breathe it in. One of the organ systems in the body that uses huge amounts of ATP is the muscular system because ATP is required to sustain muscle contraction. As a result, muscle cells are packed full of mitochondria. Nerve cells also need large quantities of ATP to run their sodium-potassium pumps. Therefore, an individual neuron will be loaded with over a thousand mitochondria. On the other hand, a bone cell, which is not nearly as metabolically active, might only have a couple hundred mitochondria.

Peroxisomes

Like lysosomes, a peroxisome is a membrane-bound cellular organelle that contains mostly enzymes (Figure 2.7.5). Peroxisomes perform a couple of different functions, including lipid metabolism and chemical detoxification. In contrast to the digestive enzymes found in lysosomes, the enzymes within peroxisomes serve to transfer hydrogen atoms from various molecules to oxygen, producing hydrogen peroxide (H2O2). In this way, peroxisomes neutralise poisons such as alcohol. In order to appreciate the importance of peroxisomes, it is necessary to understand the concept of reactive oxygen species.

Reactive oxygen species (ROS) such as peroxides and free radicals are the highly reactive products of many normal cellular processes, including the mitochondrial reactions that produce ATP and oxygen metabolism. Examples of ROS include the hydroxyl radical OH, H2O2, and superoxide (O2−). Some ROS are important for certain cellular functions, such as cell signalling processes and immune responses against foreign substances. Free radicals are reactive because they contain free unpaired electrons; they can easily oxidise other molecules throughout the cell, causing cellular damage and even cell death. Free radicals are thought to play a role in many destructive processes in the body, from cancer to coronary artery disease.

Peroxisomes, on the other hand, oversee reactions that neutralise free radicals. Peroxisomes produce large amounts of the toxic H2O2 in the process, but peroxisomes contain enzymes that convert H2O2 into water and oxygen. These by-products are safely released into the cytoplasm. Like miniature sewage treatment plants, peroxisomes neutralise harmful toxins so that they do not wreak havoc in the cells. The liver is the organ primarily responsible for detoxifying the blood before it travels throughout the body, and liver cells contain an exceptionally high number of peroxisomes.

Defence mechanisms such as detoxification within the peroxisome and certain cellular antioxidants serve to neutralise many of these molecules. Some vitamins and other substances, found primarily in fruits and vegetables, have antioxidant properties. Antioxidants work by being oxidised themselves, halting the destructive reaction cascades initiated by the free radicals. Sometimes though, ROS accumulate beyond the capacity of such defences.

Oxidative stress is the term used to describe damage to cellular components caused by ROS. Due to their characteristic unpaired electrons, ROS can set off chain reactions where they remove electrons from other molecules, which then become oxidised and reactive, and do the same to other molecules, causing a chain reaction. ROS can cause permanent damage to cellular lipids, proteins, carbohydrates, and nucleic acids. Damaged DNA can lead to genetic mutations and even cancer. A mutation is a change in the nucleotide sequence in a gene within a cell’s DNA, potentially altering the protein coded by that gene. Other diseases believed to be triggered or exacerbated by ROS include Alzheimer’s disease, cardiovascular diseases, diabetes, Parkinson’s disease, arthritis, Huntington’s disease and schizophrenia, among many others. It is noteworthy that these diseases are largely age-related. Many scientists believe that oxidative stress is a major contributor to the ageing process.

Ageing and the Cell: The Free Radical Theory

The free radical theory on ageing was originally proposed in the 1950s, and still remains under debate. Generally speaking, the free radical theory of ageing suggests that accumulated cellular damage from oxidative stress contributes to the physiological and anatomical effects of ageing. There are two significantly different versions of this theory: one states that the ageing process itself is a result of oxidative damage, and the other states that oxidative damage causes age-related disease and disorders. The latter version of the theory is more widely accepted than the former. However, many lines of evidence suggest that oxidative damage does contribute to the ageing process. Research has shown that reducing oxidative damage can result in a longer lifespan in certain organisms such as yeast, worms, and fruit flies. Conversely, increasing oxidative damage can shorten the lifespan of mice and worms. Interestingly, a manipulation called calorie-restriction (moderately restricting the caloric intake) has been shown to increase life span in some laboratory animals. It is believed that this increase is at least in part due to a reduction of oxidative stress. However, a long-term study of primates with calorie-restriction showed no increase in their lifespan. A great deal of additional research will be required to better understand the link between reactive oxygen species and ageing.

The Cytoskeleton

Much like the bony skeleton structurally supports the human body, the cytoskeleton helps the cells to maintain their structural integrity. The cytoskeleton is a group of fibrous proteins that provide structural support for cells, but this is only one of the functions of the cytoskeleton. Cytoskeletal components are also critical for cell motility, cell reproduction, and transportation of substances within the cell.

The cytoskeleton forms a complex thread-like network throughout the cell consisting of three different kinds of protein-based filaments: microfilaments, intermediate filaments, and microtubules (Figure 2.7.6). The thickest of the three is the microtubule, a structural filament composed of subunits of a protein called tubulin. Microtubules maintain cell shape and structure, help resist compression of the cell, and play a role in positioning the organelles within the cell. Microtubules also make up two types of cellular appendages important for motion: cilia and flagella. Cilia are found on many cells of the body, including the epithelial cells that line the airways of the respiratory system. Cilia move rhythmically; they beat constantly, moving waste materials such as dust, mucus, and bacteria upward through the airways, away from the lungs and toward the mouth. Beating cilia on cells in the female fallopian tubes move egg cells from the ovary towards the uterus. A flagellum (plural = flagella) is an appendage larger than a cilium and specialised for cell locomotion. The only flagellated cell in humans is the sperm cell that must propel itself towards female egg cells.

A very important function of microtubules is to set the paths (somewhat like railroad tracks) along which the genetic material can be pulled (a process requiring ATP) during cell division, so that each new daughter cell receives the appropriate set of chromosomes. Two short, identical microtubule structures called centrioles are found near the nucleus of cells. A centriole can serve as the cellular origin point for microtubules extending outward as cilia or flagella or can assist with the separation of DNA during cell division. Microtubules grow out from the centrioles by adding more tubulin subunits, like adding additional links to a chain.

In contrast with microtubules, the microfilament is a thinner type of cytoskeletal filament (see Figure 2.7.6b). Actin, a protein that forms chains, is the primary component of these microfilaments. Actin fibres, twisted chains of actin filaments, constitute a large component of muscle tissue and, along with the protein myosin, are responsible for muscle contraction. Like microtubules, actin filaments are long chains of single subunits (called actin subunits). In muscle cells, these long actin strands, called thin filaments, are “pulled” by thick filaments of the myosin protein to contract the cell.

Actin also has an important role during cell division. When a cell is about to split in half during cell division, actin filaments work with myosin to create a cleavage furrow that eventually splits the cell down the middle, forming two new cells from the original cell.

The final cytoskeletal filament is the intermediate filament. As its name would suggest, an intermediate filament is a filament intermediate in thickness between the microtubules and microfilaments (see Figure 2.7.6c). Intermediate filaments are made up of long fibrous subunits of a protein called keratin that are wound together like the threads that compose a rope. Intermediate filaments, in concert with the microtubules, are important for maintaining cell shape and structure. Unlike the microtubules, which resist compression, intermediate filaments resist tension—the forces that pull apart cells. There are many cases in which cells are prone to tension, such as when epithelial cells of the skin are compressed, tugging them in different directions. Intermediate filaments help anchor organelles together within a cell and link cells to other cells by forming special cell-to-cell junctions.

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The nucleus is the largest and most prominent of a cell’s organelles (Figure 2.8.1). The nucleus is generally considered the control centre of the cell because it stores all of the genetic instructions for manufacturing proteins. Interestingly, some cells in the body, such as muscle cells, contain more than one nucleus (Figure 2.8.2), which is known as multinucleated. Other cells, such as mammalian red blood cells (RBCs), do not contain nuclei at all. RBCs eject their nuclei as they mature, making space for the large numbers of haemoglobin molecules that carry oxygen throughout the body (Figure 2.8.3). Without nuclei, the life span of RBCs is short, and so the body must produce new ones constantly.

Inside the nucleus lies the blueprint that dictates everything a cell will do and all the products it will make. This information is stored within DNA. The nucleus sends “commands” to the cell via molecular messengers that translate the information from DNA. Each cell in your body (with the exception of germ cells) contains the complete set of your DNA. When a cell divides, the DNA must be duplicated so that each new cell receives a full complement of DNA. The following section will explore the structure of the nucleus and its contents, as well as the process of DNA replication.

Organisation of the Nucleus and its DNA

Like most other cellular organelles, the nucleus is surrounded by a membrane called the nuclear envelope. This membranous covering consists of two adjacent lipid bilayers with a thin fluid space in between them. Spanning these two bilayers are nuclear pores. A nuclear pore is a tiny passageway for the passage of proteins, RNA, and solutes between the nucleus and the cytoplasm. Proteins called pore complexes lining the nuclear pores regulate the passage of materials into and out of the nucleus.

Inside the nuclear envelope is a gel-like nucleoplasm with solutes that include the building blocks of nucleic acids. There also can be a dark-staining mass often visible under a simple light microscope, called a nucleolus (plural = nucleoli). The nucleolus is a region of the nucleus that is responsible for manufacturing the RNA necessary for construction of ribosomes. Once synthesised, newly made ribosomal subunits exit the cell’s nucleus through the nuclear pores.

The genetic instructions that are used to build and maintain an organism are arranged in an orderly manner in strands of DNA. Within the nucleus are threads of chromatin composed of DNA and associated proteins (Figure 2.8.4). Along the chromatin threads, the DNA is wrapped around a set of histone proteins. A nucleosome is a single, wrapped DNA-histone complex. Multiple nucleosomes along the entire molecule of DNA appear like a beaded necklace, in which the string is the DNA and the beads are the associated histones. When a cell is in the process of division, the chromatin condenses into chromosomes, so that the DNA can be safely transported to the “daughter cells.” The chromosome is composed of DNA and proteins; it is the condensed form of chromatin. It is estimated that humans have almost 22,000 genes distributed on 46 chromosomes.

DNA Replication

In order for an organism to grow, develop, and maintain its health, cells must reproduce themselves by dividing to produce two new daughter cells, each with the full complement of DNA as found in the original cell. Billions of new cells are produced in an adult human every day. Only very few cell types in the body do not divide, including nerve cells, skeletal muscle fibres and cardiac muscle cells. The division time of different cell types varies. Epithelial cells of the skin and gastrointestinal lining, for instance, divide very frequently to replace those that are constantly being rubbed off the surface by friction.

A DNA molecule is made of two strands that “complement” each other in the sense that the molecules that compose the strands fit together and bind to each other, creating a double-stranded molecule that looks much like a long, twisted ladder. Each side rail of the DNA ladder is composed of alternating sugar and phosphate groups (Figure 2.8.5). The two sides of the ladder are not identical, but are complementary. These two backbones are bonded to each other across pairs of protruding bases, each bonded pair forming one “rung,” or cross member. The four DNA bases are adenine (A), thymine (T), cytosine (C), and guanine (G). Because of their shape and charge, the two bases that compose a pair always bond together. Adenine always binds with thymine, and cytosine always binds with guanine. The particular sequence of bases along the DNA molecule determines the genetic code. Therefore, if the two complementary strands of DNA were pulled apart, you could infer the order of the bases in one strand from the bases in the other, complementary strand. For example, if one strand has a region with the sequence AGTGCCT, then the sequence of the complementary strand would be TCACGGA.

DNA replication is the copying of DNA that occurs before cell division can take place. After a great deal of debate and experimentation, the general method of DNA replication was deduced in 1958 by two scientists in California, Matthew Meselson and Franklin Stahl. This method is illustrated in Figure 2.8.6 and described below.

Stage 1: Initiation. The two complementary strands are separated, much like unzipping a zipper. Special enzymes, including helicase, untwist and separate the two strands of DNA.

Stage 2: Elongation. Each strand becomes a template along which a new complementary strand is built. DNA polymerase brings in the correct bases to complement the template strand, synthesising a new strand base by base. A DNA polymerase is an enzyme that adds free nucleotides to the end of a chain of DNA, making a new double strand. This growing strand continues to be built until it has fully complemented the template strand.

Stage 3: Termination. Once the two original strands are bound to their own, finished, complementary strands, DNA replication is stopped and the two new identical DNA molecules are complete.

Each new DNA molecule contains one strand from the original molecule and one newly synthesised strand. The term for this mode of replication is “semiconservative,” because half of the original DNA molecule is conserved in each new DNA molecule. This process continues until the cell’s entire genome, the entire complement of an organism’s DNA, is replicated. As you might imagine, it is very important that DNA replication take place precisely so that new cells in the body contain the exact same genetic material as their parent cells. Mistakes made during DNA replication, such as the accidental addition of an inappropriate nucleotide, have the potential to render a gene dysfunctional or useless. Fortunately, there are mechanisms in place to minimise such mistakes. A DNA proofreading process enlists the help of special enzymes that scan the newly synthesised molecule for mistakes and corrects them. Once the process of DNA replication is complete, the cell is ready to divide. You will explore the process of cell division later in the chapter.

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It was mentioned earlier that DNA provides a “blueprint” for the cell structure and physiology. This refers to the fact that DNA contains the information necessary for the cell to build one very important type of molecule: the protein. Most structural components of the cell are made up, at least in part, by proteins and virtually all the functions that a cell carries out are completed with the help of proteins. One of the most important classes of proteins is enzymes, which help speed up necessary biochemical reactions that take place inside the cell. Some of these critical biochemical reactions include building larger molecules from smaller components (such as occurs during DNA replication or synthesis of microtubules) and breaking down larger molecules into smaller components (such as when harvesting chemical energy from nutrient molecules). Whatever the cellular process may be, it is almost sure to involve proteins. Just as the cell’s genome describes its full complement of DNA, a cell’s proteome is its full complement of proteins. Protein synthesis begins with genes. A gene is a functional segment of DNA that provides the genetic information necessary to build a protein. Each particular gene provides the code necessary to construct a particular protein. Gene expression, which transforms the information coded in a gene to a final gene product, ultimately dictates the structure and function of a cell by determining which proteins are made.

The interpretation of genes works in the following way. Recall that proteins are polymers, or chains, of many amino acid building blocks. The sequence of bases in a gene (that is, its sequence of A, T, C, G nucleotides) translates to an amino acid sequence. A triplet is a section of three DNA bases in a row that codes for a specific amino acid. Similar to the way in which the three-letter code d-o-g signals the image of a dog, the three-letter DNA base code signals the use of a particular amino acid. For example, the DNA triplet CAC (cytosine, adenine, and cytosine) specifies the amino acid valine. Therefore, a gene, which is composed of multiple triplets in a unique sequence, provides the code to build an entire protein, with multiple amino acids in the proper sequence (Figure 2.9.1). The mechanism by which cells turn the DNA code into a protein product is a two-step process, with an RNA molecule as the intermediate.

From DNA to RNA: Transcription

DNA is housed within the nucleus, and protein synthesis takes place in the cytoplasm, thus there must be some sort of intermediate messenger that leaves the nucleus and manages protein synthesis. This intermediate messenger is messenger RNA (mRNA), a single-stranded nucleic acid that carries a copy of the genetic code for a single gene out of the nucleus and into the cytoplasm where it is used to produce proteins.

There are several different types of RNA, each having different functions in the cell. The structure of RNA is similar to DNA with a few small exceptions. For one thing, unlike DNA, most types of RNA, including mRNA, are single-stranded and contain no complementary strand. Second, the ribose sugar in RNA contains an additional oxygen atom compared with DNA. Finally, instead of the base thymine, RNA contains the base uracil. This means that adenine will always pair up with uracil during the protein synthesis process.

Gene expression begins with the process called transcription, which is the synthesis of a strand of mRNA that is complementary to the gene of interest. This process is called transcription because the mRNA is like a transcript, or copy, of the gene’s DNA code. Transcription begins in a fashion somewhat like DNA replication, in that a region of DNA unwinds and the two strands separate, however, only that small portion of the DNA will be split apart. The triplets within the gene on this section of the DNA molecule are used as the template to transcribe the complementary strand of RNA (Figure 2.9.2). A codon is a three-base sequence of mRNA, so-called because they directly encode amino acids. Like DNA replication, there are three stages to transcription: initiation, elongation, and termination.

Stage 1: Initiation. A region at the beginning of the gene called a promoter—a particular sequence of nucleotides—triggers the start of transcription.

Stage 2: Elongation. Transcription starts when RNA polymerase unwinds the DNA segment. One strand, referred to as the coding strand, becomes the template with the genes to be coded. The polymerase then aligns the correct nucleic acid (A, C, G, or U) with its complementary base on the coding strand of DNA. RNA polymerase is an enzyme that adds new nucleotides to a growing strand of RNA. This process builds a strand of mRNA.

Stage 3: Termination. When the polymerase has reached the end of the gene, one of three specific triplets (UAA, UAG, or UGA) codes a “stop” signal, which triggers the enzymes to terminate transcription and release the mRNA transcript.

Before the mRNA molecule leaves the nucleus and proceeds to protein synthesis, it is modified in several ways. For this reason, it is often called a pre-mRNA at this stage. For example, your DNA, and thus complementary mRNA, contains long regions called non-coding regions that do not code for amino acids. Their function is still a mystery, but the process called splicing removes these non-coding regions from the pre-mRNA transcript (Figure 2.9.3). A spliceosome—a structure composed of various proteins and other molecules—attaches to the mRNA and “splices” or cuts out the non-coding regions. The removed segment of the transcript is called an intron. The remaining exons are pasted together. An exon is a segment of RNA that remains after splicing. Interestingly, some introns that are removed from mRNA are not always non-coding. When different coding regions of mRNA are spliced out, different variations of the protein will eventually result, with differences in structure and function. This process results in a much larger variety of possible proteins and protein functions. When the mRNA transcript is ready, it travels out of the nucleus and into the cytoplasm.

From RNA to Protein: Translation

Like translating a book from one language into another, the codons on a strand of mRNA must be translated into the amino acid alphabet of proteins. Translation is the process of synthesising a chain of amino acids called a polypeptide. Translation requires two major aids: first, a “translator,” the molecule that will conduct the translation, and second, a substrate on which the mRNA strand is translated into a new protein, like the translator’s “desk.” Both of these requirements are fulfilled by other types of RNA. The substrate on which translation takes place is the ribosome.

Remember that many of a cell’s ribosomes are found associated with the rough ER, and carry out the synthesis of proteins destined for the Golgi apparatus. Ribosomal RNA (rRNA) is a type of RNA that, together with proteins, composes the structure of the ribosome. Ribosomes exist in the cytoplasm as two distinct components, a small and a large subunit. When an mRNA molecule is ready to be translated, the two subunits come together and attach to the mRNA. The ribosome provides a substrate for translation, bringing together and aligning the mRNA molecule with the molecular “translators” that must decipher its code.

The other major requirement for protein synthesis is the translator molecules that physically “read” the mRNA codons. Transfer RNA (tRNA) is a type of RNA that ferries the appropriate corresponding amino acids to the ribosome, and attaches each new amino acid to the last, building the polypeptide chain one-by-one. Thus, tRNA transfers specific amino acids from the cytoplasm to a growing polypeptide. The tRNA molecules must be able to recognise the codons on mRNA and match them with the correct amino acid. The tRNA is modified for this function. On one end of its structure is a binding site for a specific amino acid. On the other end is a base sequence that matches the codon specifying its particular amino acid. This sequence of three bases on the tRNA molecule is called an anticodon. For example, a tRNA responsible for shuttling the amino acid glycine contains a binding site for glycine on one end. On the other end it contains an anticodon that complements the glycine codon (GGA is a codon for glycine, and so the tRNAs anticodon would read CCU). Equipped with its particular cargo and matching anticodon, a tRNA molecule can read its recognised mRNA codon and bring the corresponding amino acid to the growing chain (Figure 2.9.4).

Much like the processes of DNA replication and transcription, translation consists of three main stages: initiation, elongation, and termination. Initiation takes place with the binding of a ribosome to an mRNA transcript. The elongation stage involves the recognition of a tRNA anticodon with the next mRNA codon in the sequence. Once the anticodon and codon sequences are bound (remember, they are complementary base pairs), the tRNA presents its amino acid cargo and the growing polypeptide strand is attached to this next amino acid. This attachment takes place with the assistance of various enzymes and requires energy. The tRNA molecule then releases the mRNA strand, the mRNA strand shifts one codon over in the ribosome, and the next appropriate tRNA arrives with its matching anticodon. This process continues until the final codon on the mRNA is reached which provides a “stop” message that signals termination of translation and triggers the release of the complete, newly synthesised protein. Thus, a gene within the DNA molecule is transcribed into mRNA, which is then translated into a protein product (Figure 2.9.5).

Commonly, an mRNA transcription will be translated simultaneously by several adjacent ribosomes. This increases the efficiency of protein synthesis. A single ribosome might translate an mRNA molecule in approximately one minute; so multiple ribosomes aboard a single transcript could produce multiple times the number of the same protein in the same minute. A polyribosome is a string of ribosomes translating a single mRNA strand.

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So far in this chapter, you have read numerous times of the importance and prevalence of cell division. While there are a few cells in the body that do not undergo cell division (such as gametes, red blood cells, most neurons, and some muscle cells), most somatic cells divide regularly. A somatic cell is a general term for a body cell, and all human cells, except for the cells that produce eggs and sperm (which are referred to as germ cells), are somatic cells. Somatic cells contain two copies of each of their chromosomes (one copy received from each parent). A homologous pair of chromosomes is the two copies of a single chromosome found in each somatic cell. The human is a diploid organism, having 23 homologous pairs of chromosomes in each of the somatic cells. The condition of having pairs of chromosomes is known as diploidy.

Cells in the body replace themselves over the lifetime of a person. For example, the cells lining the gastrointestinal tract must be frequently replaced when constantly “worn off” by the movement of food through the gut. But what triggers a cell to divide, and how does it prepare for and complete cell division? The cell cycle is the sequence of events in the life of the cell from the moment it is created at the end of a previous cycle of cell division until it then divides itself, generating two new cells.

The Cell Cycle

One “turn” or cycle of the cell cycle consists of two general phases: interphase, followed by mitosis and cytokinesis. Interphase is the period of the cell cycle during which the cell is not dividing. The majority of cells are in interphase most of the time. Mitosis is the division of genetic material, during which the cell nucleus breaks down and two new, fully functional, nuclei are formed. Cytokinesis divides the cytoplasm into two distinctive cells.

Interphase

A cell grows and carries out all normal metabolic functions and processes in a period called G1 (Figure 2.10.1). G1 phase (gap 1 phase) is the first gap, or growth phase in the cell cycle. For cells that will divide again, G1 is followed by replication of the DNA, during the S phase. The S phase (synthesis phase) is period during which a cell replicates its DNA.

After the synthesis phase, the cell proceeds through the G2 phase. The G2 phase is a second gap phase, during which the cell continues to grow and makes the necessary preparations for mitosis. Between G1, S, and G2 phases, cells will vary the most in their duration of the G1 phase. It is here that a cell might spend a couple of hours, or many days. The S phase typically lasts between 8-10 hours and the G2 phase approximately 5 hours. In contrast to these phases, the G0 phase is a resting phase of the cell cycle. Cells that have temporarily stopped dividing and are resting (a common condition) and cells that have permanently ceased dividing (like nerve cells) are said to be in G0.

The Structure of Chromosomes

Billions of cells in the human body divide every day. During the synthesis phase (S, for DNA synthesis) of interphase, the amount of DNA within the cell precisely doubles. Therefore, after DNA replication but before cell division, each cell contains two copies of each chromosome. Each copy of the chromosome is referred to as a sister chromatid and is physically bound to the other copy. The centromere is the structure that attaches one sister chromatid to another. Because a human cell has 46 chromosomes, during this phase, there are 92 chromatids (46 × 2) in the cell. Make sure not to confuse the concept of a pair of chromatids (one chromosome and its exact copy attached during mitosis) and a homologous pair of chromosomes (two paired chromosomes which were inherited separately, one from each parent) (Figure 2.10.2).

Mitosis and Cytokinesis

The mitotic phase of the cell typically takes between 1 and 2 hours. During this phase, a cell undergoes two major processes. First, it completes mitosis, during which the contents of the nucleus are equitably pulled apart and distributed between its two halves. Cytokinesis then occurs, dividing the cytoplasm and cell body into two new cells. Mitosis is divided into four major stages that take place after interphase (Figure 2.10.3) and in the following order: prophase, metaphase, anaphase, and telophase. The process is then followed by cytokinesis.

Prophase is the first phase of mitosis, during which the loosely packed chromatin coils and condenses into visible chromosomes. During prophase, each chromosome becomes visible with its identical partner attached, forming the familiar X-shape of sister chromatids. The nucleolus disappears early during this phase, and the nuclear envelope also disintegrates.

A major occurrence during prophase concerns a very important structure that contains the origin site for microtubule growth. Recall the cellular structures called centrioles that serve as origin points from which microtubules extend. These tiny structures also play a very important role during mitosis. A centrosome is a pair of centrioles together. The cell contains two centrosomes side-by-side, which begin to move apart during prophase. As the centrosomes migrate to two different sides of the cell, microtubules begin to extend from each like long fingers from two hands extending toward each other. The mitotic spindle is the structure composed of the centrosomes and their emerging microtubules.

Near the end of prophase there is an invasion of the nuclear area by microtubules from the mitotic spindle. The nuclear membrane has disintegrated, and the microtubules attach themselves to the centromeres that adjoin pairs of sister chromatids. The kinetochore is a protein structure on the centromere that is the point of attachment between the mitotic spindle and the sister chromatids. This stage is referred to as late prophase or “prometaphase” to indicate the transition between prophase and metaphase.

Metaphase is the second stage of mitosis. During this stage, the sister chromatids, with their attached microtubules, line up along a linear plane in the middle of the cell. A metaphase plate forms between the centrosomes that are now located at either end of the cell. The metaphase plate is the name for the plane through the centre of the spindle on which the sister chromatids are positioned. The microtubules are now poised to pull apart the sister chromatids and bring one from each pair to each side of the cell.

Anaphase is the third stage of mitosis. Anaphase takes place over a few minutes, when the pairs of sister chromatids are separated from one another, forming individual chromosomes once again. These chromosomes are pulled to opposite ends of the cell by their kinetochores, as the microtubules shorten. Each end of the cell receives one partner from each pair of sister chromatids, ensuring that the two new daughter cells will contain identical genetic material.

Telophase is the final stage of mitosis. Telophase is characterised by the formation of two new daughter nuclei at either end of the dividing cell. These newly formed nuclei surround the genetic material, which uncoils such that the chromosomes return to loosely packed chromatin. Nucleoli also reappear within the new nuclei, and the mitotic spindle breaks apart, each new cell receiving its own complement of DNA, organelles, membranes, and centrioles. At this point, the cell is already beginning to split in half as cytokinesis begins.

The cleavage furrow is a contractile band made up of microfilaments that forms around the midline of the cell during cytokinesis. (Recall that microfilaments consist of actin.) This contractile band squeezes the two cells apart until they finally separate. Two new cells are now formed. One of these cells (the “stem cell”) enters its own cell cycle; able to grow and divide again at some future time. The other cell transforms into the functional cell of the tissue, typically replacing an “old” cell there.

Imagine a cell that completed mitosis but never underwent cytokinesis. In some cases, a cell may divide its genetic material and grow in size, but fail to undergo cytokinesis. This results in larger cells with more than one nucleus. Usually this is an unwanted aberration and can be a sign of cancerous cells.

Cell Cycle Control

A very elaborate and precise system of regulation controls direct the way cells proceed from one phase to the next in the cell cycle and begin mitosis. The control system involves molecules within the cell as well as external triggers. These internal and external control triggers provide “stop” and “advance” signals for the cell. Precise regulation of the cell cycle is critical for maintaining the health of an organism, and loss of cell cycle control can lead to cancer.

Mechanisms of Cell Cycle Control

As the cell proceeds through its cycle, each phase involves certain processes that must be completed before the cell should advance to the next phase. A checkpoint is a point in the cell cycle at which the cycle can be signalled to move forward or stopped. At each of these checkpoints, different varieties of molecules provide the stop or go signals, depending on certain conditions within the cell. A cyclin is one of the primary classes of cell cycle control molecules (Figure 2.10.4). A cyclin-dependent kinase (CDK) is one of a group of molecules that work together with cyclins to determine progression past cell checkpoints. By interacting with many additional molecules, these triggers push the cell cycle forward unless prevented from doing so by “stop” signals, if for some reason the cell is not ready. At the G1 checkpoint, the cell must be ready for DNA synthesis to occur. At the G2 checkpoint the cell must be fully prepared for mitosis. Even during mitosis, a crucial stop and go checkpoint in metaphase ensures that the cell is fully prepared to complete cell division. The metaphase checkpoint ensures that all sister chromatids are properly attached to their respective microtubules and lined up at the metaphase plate before the signal is given to separate them during anaphase.

The Cell Cycle Out of Control: Implications

Most people understand that cancer or tumours are caused by abnormal cells that multiply continuously. If the abnormal cells continue to divide unstopped, they can damage the tissues around them, spread to other parts of the body, and eventually result in death. In healthy cells, the tight regulation mechanisms of the cell cycle prevent this from happening, while failures of cell cycle control can cause unwanted and excessive cell division. Failures of control may be caused by inherited genetic abnormalities that compromise the function of certain “stop” and “go” signals. Environmental insult that damages DNA can also cause dysfunction in those signals. Often, a combination of both genetic predisposition and environmental factors lead to cancer.

The process of a cell escaping its normal control system and becoming cancerous may actually happen throughout the body quite frequently. Fortunately, certain cells of the immune system are capable of recognising cells that have become cancerous and destroying them. However, in certain cases the cancerous cells remain undetected and continue to proliferate. If the resulting tumour does not pose a threat to surrounding tissues, it is said to be benign and can usually be easily removed. If capable of damage, the tumour is considered malignant and the patient is diagnosed with cancer.

Homeostatic Imbalances

Cancer Arises from Homeostatic Imbalances

Cancer is an extremely complex condition, capable of arising from a wide variety of genetic and environmental causes. Typically, mutations or aberrations in a cell’s DNA that compromise normal cell cycle control systems lead to cancerous tumours. Cell cycle control is an example of a homeostatic mechanism that maintains proper cell function and health. While progressing through the phases of the cell cycle, a large variety of intracellular molecules provide stop and go signals to regulate movement forward to the next phase. These signals are maintained in an intricate balance so that the cell only proceeds to the next phase when it is ready. This homeostatic control of the cell cycle can be thought of like a car’s cruise control. Cruise control will continually apply just the right amount of acceleration to maintain a desired speed, unless the driver hits the brakes, in which case the car will slow down. Similarly, the cell includes molecular messengers, such as cyclins, that push the cell forward in its cycle.

In addition to cyclins, a class of proteins that are encoded by genes called proto-oncogenes provide important signals that regulate the cell cycle and move it forward. Examples of proto-oncogene products include cell-surface receptors for growth factors, or cell-signalling molecules, two classes of molecules that can promote DNA replication and cell division. In contrast, a second class of genes known as tumours suppressor genes sends stop signals during a cell cycle. For example, certain protein products of tumours suppressor genes signal potential problems with the DNA and thus stop the cell from dividing, while other proteins signal the cell to die if it is damaged beyond repair. Some tumours suppressor proteins also signal a sufficient surrounding cellular density, which indicates that the cell need not presently divide. The latter function is uniquely important in preventing tumours growth: normal cells exhibit a phenomenon called “contact inhibition;” thus, extensive cellular contact with neighbouring cells causes a signal that stops further cell division.

These two contrasting classes of genes, proto-oncogenes and tumour suppressor genes, are like the accelerator and brake pedal of the cell’s own “cruise control system,” respectively. Under normal conditions, these stop and go signals are maintained in a homeostatic balance. Generally speaking, there are two ways that the cell’s cruise control can lose control: a malfunctioning (overactive) accelerator, or a malfunctioning (underactive) brake. When compromised through a mutation, or otherwise altered, proto-oncogenes can be converted to oncogenes, which produce oncoproteins that push a cell forward in its cycle and stimulate cell division even when it is undesirable to do so. For example, a cell that should be programmed to self-destruct (a process called apoptosis) due to extensive DNA damage might instead be triggered to proliferate by an oncoprotein. On the other hand, a dysfunctional tumours suppressor gene may fail to provide the cell with a necessary stop signal, also resulting in unwanted cell division and proliferation.

A delicate homeostatic balance between the many proto-oncogenes and tumours suppressor genes delicately controls the cell cycle and ensures that only healthy cells replicate. Therefore, a disruption of this homeostatic balance can cause aberrant cell division and cancerous growths.

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How does a complex organism such as a human develop from a single cell—a fertilised egg—into the vast array of cell types such as nerve cells, muscle cells, and epithelial cells that characterise the adult? Throughout development and adulthood, the process of cellular differentiation leads cells to assume their final morphology and physiology. Differentiation is the process by which unspecialised cells become specialised to carry out distinct functions.

Stem Cells

A stem cell is an unspecialised cell that can divide without limit as needed and can, under specific conditions, differentiate into specialised cells. Stem cells are divided into several categories according to their potential to differentiate.

The first embryonic cells that arise from the division of the zygote are the ultimate stem cells; these stems cells are described as totipotent because they have the potential to differentiate into any of the cells needed to enable an organism to grow and develop.

The embryonic cells that develop from totipotent stem cells and are precursors to the fundamental tissue layers of the embryo are classified as pluripotent. A pluripotent stem cell is one that has the potential to differentiate into any type of human tissue but cannot support the full development of an organism. These cells then become slightly more specialised and are referred to as multipotent cells.

A multipotent stem cell has the potential to differentiate into different types of cells within a given cell lineage or small number of lineages, such as a red blood cell or white blood cell.

Finally, multipotent cells can become further specialised oligopotent cells. An oligopotent stem cell is limited to becoming one of a few different cell types. In contrast, a unipotent cell is fully specialised and can only reproduce to generate more of its own specific cell type.

Stem cells are unique in that they can also continually divide and regenerate new stem cells instead of further specialising. There are different stem cells present at different stages of a human’s life. They include the embryonic stem cells of the embryo, foetal stem cells of the foetus, and adult stem cells in the adult. One type of adult stem cell is the epithelial stem cell, which gives rise to the keratinocytes in the multiple layers of epithelial cells in the epidermis of skin. Adult bone marrow has three distinct types of stem cells: hematopoietic stem cells, which give rise to red blood cells, white blood cells and platelets (Figure 2.11.1); endothelial stem cells, which give rise to the endothelial cell types that line blood and lymph vessels; and mesenchymal stem cells, which give rise to the different types of muscle cells.

Differentiation

When a cell differentiates (becomes more specialised), it may undertake major changes in its size, shape, metabolic activity, and overall function. Because all cells in the body, beginning with the fertilised egg, contain the same DNA, how do the different cell types come to be so different? The answer is analogous to a movie script. The different actors in a movie all read from the same script, however, they are each only reading their own part of the script. Similarly, all cells contain the same full complement of DNA, but each type of cell only “reads” the portions of DNA that are relevant to its own function. In biology, this is referred to as the unique genetic expression of each cell.

In order for a cell to differentiate into its specialised form and function, it need only manipulate those genes (and thus those proteins) that will be expressed, and not those that will remain silent. The primary mechanism by which genes are turned “on” or “off” is through transcription factors. A transcription factor is one of a class of proteins that bind to specific genes on the DNA molecule and either promote or inhibit their transcription (Figure 2.11.2).

Everyday Connection

Stem Cell Research

Stem cell research aims to find ways to use stem cells to regenerate and repair cellular damage. Over time, most adult cells undergo the wear and tear of ageing and lose their ability to divide and repair themselves. Stem cells do not display a particular morphology or function. Adult stem cells, which exist as a small subset of cells in most tissues, keep dividing and can differentiate into a number of specialised cells generally formed by that tissue. These cells enable the body to renew and repair body tissues.

The mechanisms that induce a non-differentiated cell to become a specialised cell are poorly understood. In a laboratory setting, it is possible to induce stem cells to differentiate into specialised cells by changing the physical and chemical conditions of growth. Several sources of stem cells are used experimentally and are classified according to their origin and potential for differentiation. Human embryonic stem cells (hESCs) are extracted from embryos and are pluripotent. The adult stem cells that are present in many organs and differentiated tissues, such as bone marrow and skin, are multipotent, being limited in differentiation to the types of cells found in those tissues. The stem cells isolated from umbilical cord blood are also multipotent, as are cells from deciduous teeth (baby teeth). Researchers have recently developed induced pluripotent stem cells (iPSCs) from mouse and human adult stem cells. These cells are genetically reprogrammed multipotent adult cells that function like embryonic stem cells; they are capable of generating cells characteristic of all three germ layers.

Because of their capacity to divide and differentiate into specialised cells, stem cells offer a potential treatment for diseases such as diabetes and heart disease (Figure 2.11.3). Cell-based therapy refers to treatment in which stem cells induced to differentiate in a growth dish are injected into a patient to repair damaged or destroyed cells or tissues. Many obstacles must be overcome for the application of cell-based therapy. Although embryonic stem cells have a nearly unlimited range of differentiation potential, they are seen as foreign by the patient’s immune system and may trigger rejection. Also, the destruction of embryos to isolate embryonic stem cells raises considerable ethical and legal questions.

In contrast, adult stem cells isolated from a patient are not seen as foreign by the body, but they have a limited range of differentiation. Some individuals bank the cord blood or deciduous teeth of their child, storing away those sources of stem cells for future use, should their child need it. Induced pluripotent stem cells are considered a promising advance in the field because using them avoids the legal, ethical and immunological pitfalls of embryonic stem cells.

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The term tissue is used to describe a group of cells found together in the body. The cells within a tissue share a common embryonic origin. Microscopic observation reveals that the cells in a tissue share morphological features and are arranged in an orderly pattern that achieves the tissue’s functions. From the evolutionary perspective, tissues appear in more complex organisms. For example, multicellular protists, ancient eukaryotes, do not have cells organised into tissues.

Although there are many types of cells in the human body, they are organised into four broad categories of tissues: epithelial, connective, muscle, and nervous. Each of these categories is characterised by specific functions that contribute to the overall health and maintenance of the body. A disruption of the structure is a sign of injury or disease. Such changes can be detected through histology, the microscopic study of tissue appearance, organisation, and function.

The Four Types of Tissues

Epithelial tissue, also referred to as epithelium, refers to the sheets of cells that cover exterior surfaces of the body, lines internal cavities and passageways, and forms certain glands. Connective tissue, as its name implies, binds the cells and organs of the body together and functions in the protection, support, and integration of all parts of the body. Muscle tissue is excitable, responding to stimulation and contracting to provide movement, and occurs as three major types: skeletal (voluntary) muscle, smooth muscle, and cardiac muscle in the heart. Nervous tissue is also excitable, allowing the propagation of electrochemical signals in the form of nerve impulses that communicate between different regions of the body (Figure 3.1.1).

The next level of organisation is the organ, where several types of tissues come together to form a working unit. Just as knowing the structure and function of cells helps you in your study of tissues, knowledge of tissues will help you understand how organs function. The epithelial and connective tissues are discussed in detail in this chapter. Muscle and nervous tissues will be discussed only briefly in this chapter.

Embryonic Origin of Tissues

The zygote, or fertilised egg, is a single cell formed by the fusion of an egg and sperm. After fertilisation the zygote gives rise to rapid mitotic cycles, generating many cells to form the embryo. The first embryonic cells generated can differentiate into any type of cell in the body and, as such, are called totipotent, meaning each has the capacity to divide, differentiate, and develop into a new organism. As cell proliferation progresses, three major cell lineages are established within the embryo. Each of these lineages of embryonic cells forms the distinct germ layers from which all the tissues and organs of the human body eventually form. Each germ layer is identified by its relative position: ectoderm (ecto- = “outer”), mesoderm (meso- = “middle”), and endoderm (endo- = “inner”). Figure 3.1.2 shows the types of tissues and organs associated with the each of the three germ layers. Note that epithelial tissue originates in all three layers, whereas nervous tissue derives primarily from the ectoderm and muscle tissue from mesoderm.

Tissue Membranes

A tissue membrane is a thin layer or sheet of cells that covers the outside of the body (for example, skin), the organs (for example, pericardium), internal passageways that lead to the exterior of the body (for example, abdominal mesenteries), and the lining of the moveable joint cavities. There are two basic types of tissue membranes: connective tissue and epithelial membranes (Figure 3.1.3).

Connective Tissue Membranes

The connective tissue membrane is formed solely from connective tissue. These membranes encapsulate organs, such as the kidneys, and line our movable joints. A synovial membrane is a type of connective tissue membrane that lines the cavity of a freely movable joint. For example, synovial membranes surround the joints of the shoulder, elbow, and knee. Fibroblasts in the inner layer of the synovial membrane release hyaluronan into the joint cavity. The hyaluronan effectively traps available water to form the synovial fluid, a natural lubricant that enables the bones of a joint to move freely against one another without much friction. This synovial fluid readily exchanges water and nutrients with blood, as do all body fluids.

Epithelial Membranes

The epithelial membrane is composed of epithelium attached to a layer of connective tissue, for example, your skin. The mucous membrane is also a composite of connective and epithelial tissues. Sometimes called mucosae, these epithelial membranes line the body cavities and hollow passageways that open to the external environment, and include the digestive, respiratory, excretory, and reproductive tracts. Mucous, produced by the epithelial exocrine glands, covers the epithelial layer. The underlying connective tissue, called the lamina propria (literally “own layer”), help support the fragile epithelial layer.

A serous membrane is an epithelial membrane composed of mesodermally derived epithelium called the mesothelium that is supported by connective tissue. These membranes line the coelomic cavities of the body, that is, those cavities that do not open to the outside, and they cover the organs located within those cavities. They are essentially membranous bags, with mesothelium lining the inside and connective tissue on the outside. Serous fluid secreted by the cells of the thin squamous mesothelium lubricates the membrane and reduces abrasion and friction between organs. Serous membranes are identified according locations. Three serous membranes line the thoracic cavity; the two pleura that cover the lungs and the pericardium that covers the heart. A fourth, the peritoneum, is the serous membrane in the abdominal cavity that covers abdominal organs and forms double sheets of mesenteries that suspend many of the digestive organs.

The skin is an epithelial membrane also called the cutaneous membrane. It is a stratified squamous epithelial membrane resting on top of connective tissue. The apical surface of this membrane is exposed to the external environment and is covered with dead, keratinised cells that help protect the body from desiccation and pathogens.

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Most epithelial tissues are essentially large sheets of cells covering all the surfaces of the body exposed to the outside world and lining the outside of organs. Epithelium also forms much of the glandular tissue of the body. Skin is not the only area of the body exposed to the outside. Other areas include the airways, the digestive tract, as well as the urinary and reproductive systems, all of which are lined by an epithelium. Hollow organs and body cavities that do not connect to the exterior of the body, which includes, blood vessels and serous membranes, are lined by endothelium (plural = endothelia), which is a type of epithelium.

Epithelial cells derive from all three major embryonic layers. The epithelia lining the skin, parts of the mouth and nose, and the anus develop from the ectoderm. Cells lining the airways and most of the digestive system originate in the endoderm. The epithelium that lines vessels in the lymphatic and cardiovascular system derives from the mesoderm and is called an endothelium.

All epithelia share some important structural and functional features. This tissue is highly cellular, with little or no extracellular material present between cells. Adjoining cells form a specialised intercellular connection between their cell membranes called a cell junction. The epithelial cells exhibit polarity with differences in structure and function between the exposed or apical facing surface of the cell and the basal surface close to the underlying body structures. The basal lamina, a mixture of glycoproteins and collagen, provides an attachment site for the epithelium, separating it from underlying connective tissue. The basal lamina attaches to a reticular lamina, which is secreted by the underlying connective tissue, forming a basement membrane that helps hold it all together.

Epithelial tissues are nearly completely avascular. For instance, no blood vessels cross the basement membrane to enter the tissue, and nutrients must come by diffusion or absorption from underlying tissues or the surface. Many epithelial tissues are capable of rapidly replacing damaged and dead cells. Sloughing off damaged or dead cells is a characteristic of surface epithelium and allows our airways and digestive tracts to rapidly replace damaged cells with new cells.

Generalised Functions of Epithelial Tissue

Epithelial tissues provide the body’s first line of protection from physical, chemical, and biological wear and tear. The cells of an epithelium act as gatekeepers of the body controlling permeability and allowing selective transfer of materials across a physical barrier. All substances that enter the body must cross an epithelium. Some epithelia often include structural features that allow the selective transport of molecules and ions across their cell membranes.

Many epithelial cells are capable of secretion and release mucous and specific chemical compounds onto their apical surfaces. The epithelium of the small intestine releases digestive enzymes, for example. Cells lining the respiratory tract secrete mucous that traps incoming microorganisms and particles. A glandular epithelium contains many secretory cells.

The Epithelial Cell

Epithelial cells are typically characterised by the polarised distribution of organelles and membrane-bound proteins between their basal and apical surfaces. Particular structures found in some epithelial cells are an adaptation to specific functions. Certain organelles are segregated to the basal sides, whereas other organelles and extensions, such as cilia, when present, are on the apical surface.

Cilia are microscopic extensions of the apical cell membrane that are supported by microtubules. They beat in unison and move fluids as well as trapped particles. Ciliated epithelium lines the ventricles of the brain where it helps circulate the cerebrospinal fluid. The ciliated epithelium of your airway forms a mucociliary escalator that sweeps particles of dust and pathogens trapped in the secreted mucous toward the throat. It is called an escalator because it continuously pushes mucous with trapped particles upward. In contrast, nasal cilia sweep the mucous blanket down towards your throat. In both cases, the transported materials are usually swallowed, and end up in the acidic environment of your stomach.

Cell to Cell Junctions

Cells of epithelia are closely connected and are not separated by intracellular material. Three basic types of connections allow varying degrees of interaction between the cells: tight junctions, anchoring junctions, and gap junctions (Figure 3.2.1).

At one end of the spectrum is the tight junction, which separates the cells into apical and basal compartments. An anchoring junction includes several types of cell junctions that help stabilise epithelial tissues. Anchoring junctions are common on the lateral and basal surfaces of cells where they provide strong and flexible connections. There are three types of anchoring junctions: desmosomes, hemidesmosomes, and adherens. Desmosomes occur in patches on the membranes of cells. The patches are structural proteins on the inner surface of the cell’s membrane. The adhesion molecule, cadherin, is embedded in these patches and projects through the cell membrane to link with the cadherin molecules of adjacent cells. These connections are especially important in holding cells together. Hemidesmosomes, which look like half a desmosome, link cells to the extracellular matrix, for example, the basal lamina. While similar in appearance to desmosomes, they include the adhesion proteins called integrins rather than cadherins. Adherens junctions use either cadherins or integrins depending on whether they are linking to other cells or matrix. The junctions are characterised by the presence of the contractile protein actin located on the cytoplasmic surface of the cell membrane. The actin can connect isolated patches or form a belt-like structure inside the cell. These junctions influence the shape and folding of the epithelial tissue.

In contrast with the tight and anchoring junctions, a gap junction forms an intercellular passageway between the membranes of adjacent cells to facilitate the movement of small molecules and ions between the cytoplasm of adjacent cells. These junctions allow electrical and metabolic coupling of adjacent cells, which coordinates function in large groups of cells.

Classification of Epithelial Tissues

Epithelial tissues are classified according to the shape of the cells and number of the cell layers formed (Figure 3.2.2). Cell shapes can be squamous (flattened and thin), cuboidal (boxy, as wide as it is tall), or columnar (rectangular, taller than it is wide). Similarly, the number of cell layers in the tissue can be one—where every cell rests on the basal lamina—which is a simple epithelium, or more than one, which is a stratified epithelium and only the basal layer of cells rests on the basal lamina. Pseudostratified (pseudo- = “false”) describes tissue with a single layer of irregularly shaped cells that give the appearance of more than one layer. Transitional describes a form of specialised stratified epithelium in which the shape of the cells can vary.

Simple Epithelium

The shape of the cells in the single cell layer of simple epithelium reflects the functioning of those cells. The cells in simple squamous epithelium have the appearance of thin scales. Squamous cell nuclei tend to be flat, horizontal, and elliptical, mirroring the form of the cell. The endothelium is the epithelial tissue that lines vessels of the lymphatic and cardiovascular system, and it is made up of a single layer of squamous cells. Simple squamous epithelium, because of the thinness of the cell, is present where rapid passage of chemical compounds is observed. The alveoli of lungs where gases diffuse, segments of kidney tubules, and the lining of capillaries are also made of simple squamous epithelial tissue. The mesothelium is a simple squamous epithelium that forms the surface layer of the serous membrane that lines body cavities and internal organs. Its primary function is to provide a smooth and protective surface. Mesothelial cells are squamous epithelial cells that secrete a fluid that lubricates the mesothelium.

In simple cuboidal epithelium, the nucleus of the box-like cells appears round and is generally located near the centre of the cell. These epithelia are active in the secretion and absorptions of molecules. Simple cuboidal epithelia are observed in the lining of the kidney tubules and in the ducts of glands.

In simple columnar epithelium, the nucleus of the tall column-like cells tends to be elongated and located in the basal end of the cells. Like the cuboidal epithelia, this epithelium is active in the absorption and secretion of molecules. Simple columnar epithelium forms the lining of some sections of the digestive system and parts of the female reproductive tract. Ciliated columnar epithelium is composed of simple columnar epithelial cells with cilia on their apical surfaces. These epithelial cells are found in the lining of the fallopian tubes and parts of the respiratory system, where the beating of the cilia helps remove particulate matter.

Pseudostratified columnar epithelium is a type of epithelium that appears to be stratified but instead consists of a single layer of irregularly shaped and differently sized columnar cells. In pseudostratified epithelium, nuclei of neighbouring cells appear at different levels rather than clustered in the basal end. The arrangement gives the appearance of stratification; but in fact, all the cells are in contact with the basal lamina, although some do not reach the apical surface. Pseudostratified columnar epithelium is found in the respiratory tract, where some of these cells have cilia.

Both simple and pseudostratified columnar epithelia are heterogeneous epithelia because they include additional types of cells interspersed among the epithelial cells. For example, a goblet cell is a mucous-secreting unicellular “gland” interspersed between the columnar epithelial cells of mucous membranes (Figure 3.2.3).

Stratified Epithelium

A stratified epithelium consists of several stacked layers of cells. This epithelium protects against physical and chemical wear and tear. The stratified epithelium is named by the shape of the most apical layer of cells, closest to the free space. Stratified squamous epithelium is the most common type of stratified epithelium in the human body. The apical cells are squamous, whereas the basal layer contains either columnar or cuboidal cells. The top layer may be covered with dead cells filled with keratin. Mammalian skin is an example of this dry, keratinised, stratified squamous epithelium. The lining of the mouth cavity is an example of an unkeratinised, stratified squamous epithelium. Stratified cuboidal epithelium and stratified columnar epithelium can also be found in certain glands and ducts but are uncommon in the human body.

Another kind of stratified epithelium is transitional epithelium, so-called because of the gradual changes in the shapes of the apical cells as the bladder fills with urine. It is found only in the urinary system, specifically the ureters and urinary bladder. When the bladder is empty, this epithelium is convoluted and has cuboidal apical cells with convex, umbrella shaped, apical surfaces. As the bladder fills with urine, this epithelium loses its convolutions and the apical cells transition from cuboidal to squamous. It appears thicker and more multi-layered when the bladder is empty, and more stretched out and less stratified when the bladder is full and distended. Figure 3.2.4 summarises the different categories of epithelial cell tissue cells.

Glandular Epithelium

A gland is a structure made up of one or more cells modified to synthesise and secrete chemical substances. Most glands consist of groups of epithelial cells. A gland can be classified as an endocrine gland, a ductless gland that releases secretions directly into surrounding tissues and fluids (endo- = “inside”), or an exocrine gland whose secretions leave through a duct that opens directly, or indirectly, to the external environment (exo- = “outside”).

Endocrine Glands

The secretions of endocrine glands are called hormones. Hormones are released into the interstitial fluid, diffused into the bloodstream, and delivered to targets, in other words, cells that have receptors to bind the hormones. The endocrine system is part of a major regulatory system coordinating the regulation and integration of body responses. A few examples of endocrine glands include the anterior pituitary, thymus, adrenal cortex, and gonads.

Exocrine Glands

Exocrine glands release their contents through a duct that leads to the epithelial surface. Mucous, sweat, saliva, and breast milk are all examples of secretions from exocrine glands. They are all discharged through tubular ducts. Secretions into the lumen of the gastrointestinal tract, technically outside of the body, are of the exocrine category.

Glandular Structure

Exocrine glands are classified as either unicellular or multicellular. The unicellular glands are scattered single cells, such as goblet cells, found in the mucous membranes of the small and large intestine.

The multicellular exocrine glands known as serous glands develop from simple epithelium to form a secretory surface that secretes directly into an inner cavity. These glands line the internal cavities of the abdomen and chest and release their secretions directly into the cavities. Other multicellular exocrine glands release their contents through a tubular duct. The duct is single in a simple gland but in compound glands is divided into one or more branches (Figure 3.2.5). In tubular glands, the ducts can be straight or coiled, whereas tubes that form pockets are alveolar (acinar), such as the exocrine portion of the pancreas. Combinations of tubes and pockets are known as tubuloalveolar (tubuloacinar) compound glands. In a branched gland, a duct is connected to more than one secretory group of cells.

Methods and Types of Secretion

Exocrine glands can be classified by their mode of secretion and the nature of the substances released, as well as by the structure of the glands and shape of ducts (Figure 3.2.6). Merocrine secretion is the most common type of exocrine secretion. The secretions are enclosed in vesicles that move to the apical surface of the cell where the contents are released by exocytosis. For example, watery mucous containing the glycoprotein mucin, a lubricant that offers some pathogen protection is a merocrine secretion. The eccrine glands that produce and secrete sweat are another example.

Apocrine secretion accumulates near the apical portion of the cell. That portion of the cell and its secretory contents pinch off from the cell and are released. The sweat glands of the armpit are classified as apocrine glands. Both merocrine and apocrine glands continue to produce and secrete their contents with little damage caused to the cell because the nucleus and Golgi regions remain intact after secretion.

In contrast, the process of holocrine secretion involves the rupture and destruction of the entire gland cell. The cell accumulates its secretory products and releases them only when it bursts. New gland cells differentiate from cells in the surrounding tissue to replace those lost by secretion. The sebaceous glands that produce the oils on the skin and hair are holocrine glands/cells (Figure 3.2.7).

Glands are also named after the products they produce. The serous gland produces watery, blood-plasma-like secretions rich in enzymes such as alpha amylase, whereas the mucous gland releases watery to viscous products rich in the glycoprotein mucin. Both serous and mucous glands are common in the salivary glands of the mouth. Mixed exocrine glands contain both serous and mucous glands and release both types of secretions.

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As may be obvious from its name, one of the major functions of connective tissue is to connect tissues and organs. Unlike epithelial tissue, which is composed of cells closely packed with little or no extracellular space in between, connective tissue cells are dispersed in a matrix. The matrix usually includes a large amount of extracellular material produced by the connective tissue cells that are embedded within it. The matrix plays a major role in the functioning of this tissue. The major component of the matrix is a ground substance often crisscrossed by protein fibres. This ground substance is usually a fluid, but it can also be mineralised and solid, as in bones. Connective tissues come in a vast variety of forms, yet they typically have in common three characteristic components: cells, large amounts of amorphous ground substance, and protein fibres. The amount and structure of each component correlates with the function of the tissue, from the rigid ground substance in bones supporting the body to the inclusion of specialised cells; for example, a phagocytic cell that engulfs pathogens and rids tissue of cellular debris.

Functions of Connective Tissues

Connective tissues perform many functions in the body, but most importantly, they support and connect other tissues; from the connective tissue sheath that surrounds muscle cells, to the tendons that attach muscles to bones, and to the skeleton that supports the positions of the body. Protection is another major function of connective tissue, in the form of fibrous capsules and bones that protect delicate organs and, of course, the skeletal system. Specialised cells in connective tissue defend the body from microorganisms that enter the body. Transport of fluid, nutrients, waste, and chemical messengers is ensured by specialised fluid connective tissues, such as blood and lymph. Adipose cells store surplus energy in the form of fat and contribute to the thermal insulation of the body.

Embryonic Connective Tissue

All connective tissues derive from the mesodermal layer of the embryo. The first connective tissue to develop in the embryo is mesenchyme, the stem cell line from which all connective tissues are later derived. Clusters of mesenchymal cells are scattered throughout adult tissue and supply the cells needed for replacement and repair after a connective tissue injury. A second type of embryonic connective tissue forms in the umbilical cord, called mucous connective tissue or Wharton’s jelly. This tissue is no longer present after birth, leaving only scattered mesenchymal cells throughout the body.

Classification of Connective Tissues

The three broad categories of connective tissue are classified according to the characteristics of their ground substance and the types of fibres found within the matrix (Table 3.3.1). Connective tissue proper includes loose connective tissue and dense connective tissue. Both tissues have a variety of cell types and protein fibres suspended in a viscous ground substance. Dense connective tissue is reinforced by bundles of fibres that provide tensile strength, elasticity, and protection. In loose connective tissue, the fibres are loosely organised, leaving large spaces in between. Supportive connective tissue—bone and cartilage—provide structure and strength to the body and protect soft tissues. A few distinct cell types and densely packed fibres in a matrix characterise these tissues. In bone, the matrix is rigid and described as calcified because of the deposited calcium salts. In fluid connective tissue, in other words, lymph and blood, various specialised cells circulate in a watery fluid containing salts, nutrients, and dissolved proteins.

Table 3.3.1. Connective Tissue Examples

Connective Tissue Proper

Fibroblasts are present in all connective tissue proper (Figure 3.3.1). Fibrocytes, adipocytes, and mesenchymal cells are fixed cells, which means they remain within the connective tissue. Other cells move in and out of the connective tissue in response to chemical signals. Macrophages, mast cells, lymphocytes, plasma cells, and phagocytic cells are found in connective tissue proper but are actually part of the immune system protecting the body.

Cell Types

The most abundant cell in connective tissue proper is the fibroblast. Polysaccharides and proteins secreted by fibroblasts combine with extra-cellular fluids to produce a viscous ground substance that, with embedded fibrous proteins, forms the extra-cellular matrix. As you might expect, a fibrocyte, a less active form of fibroblast, is the second most common cell type in connective tissue proper.

Adipocytes are cells that store lipids as droplets that fill most of the cytoplasm. There are two basic types of adipocytes: white and brown. The brown adipocytes store lipids as many droplets, and have high metabolic activity. In contrast, white fat adipocytes store lipids as a single large drop and are metabolically less active. Their effectiveness at storing large amounts of fat is witnessed in obese individuals. The number and type of adipocytes depends on the tissue and location, and vary among individuals in the population.

The mesenchymal cell is a multipotent adult stem cell. These cells can differentiate into any type of connective tissue cells needed for repair and healing of damaged tissue.

The macrophage cell is a large cell derived from a monocyte, a type of blood cell, which enters the connective tissue matrix from the blood vessels. The macrophage cells are an essential component of the immune system, which is the body’s defence against potential pathogens and degraded host cells. When stimulated, macrophages release cytokines, small proteins that act as chemical messengers. Cytokines recruit other cells of the immune system to infected sites and stimulate their activities. Roaming, or free, macrophages move rapidly by amoeboid movement, engulfing infectious agents and cellular debris. In contrast, fixed macrophages are permanent residents of their tissues.

The mast cell, found in connective tissue proper, has many cytoplasmic granules. These granules contain the chemical signals histamine and heparin. When irritated or damaged, mast cells release histamine, an inflammatory mediator, which causes vasodilation and increased blood flow at a site of injury or infection, along with itching, swelling, and redness you recognise as an allergic response. Like blood cells, mast cells are derived from hematopoietic stem cells and are part of the immune system.

Connective Tissue Fibres and Ground Substance

Three main types of fibres are secreted by fibroblasts: collagen fibres, elastic fibres, and reticular fibres. Collagen fibres is made from fibrous protein subunits linked together to form a long and straight fibres. Collagen fibres, while flexible, have great tensile strength, resist stretching, and give ligaments and tendons their characteristic resilience and strength. These fibres hold connective tissues together, even during the movement of the body.

Elastic fibres contain the protein elastin along with lesser amounts of other proteins and glycoproteins. The main property of elastin is that after being stretched or compressed, it will return to its original shape. Elastic fibres are prominent in elastic tissues found in skin and the elastic ligaments of the vertebral column.

Reticular fibres are also formed from the same protein subunits as collagen fibres; however, these fibres remain narrow and are arrayed in a branching network. They are found throughout the body, but are most abundant in the reticular tissue of soft organs, such as liver and spleen, where they anchor and provide structural support to the parenchyma (the functional cells, blood vessels, and nerves of the organ).

All these fibres types are embedded in ground substance. Secreted by fibroblasts, ground substance is made of polysaccharides, specifically hyaluronic acid, and proteins. These combine to form a proteoglycan with a protein core and polysaccharide branches. The proteoglycan attracts and traps available moisture forming the clear, viscous, colourless matrix you now know as ground substance.

Loose Connective Tissue

Loose connective tissue is found between many organs where it acts both to absorb shock and bind tissues together. It allows water, salts, and various nutrients to diffuse through to adjacent or imbedded cells and tissues.

Adipose tissue consists mostly of fat storage cells, with little extracellular matrix (Figure 3.3.2). Many capillaries allow rapid storage and mobilisation of lipid molecules. White adipose tissue is most abundant. It can appear yellow and owes its colour to carotene and related pigments from plant food. White fat contributes mostly to lipid storage and can serve as insulation from cold temperatures and mechanical injuries. White adipose tissue can be found protecting the kidneys and cushioning the back of the eye. Brown adipose tissue is more common in infants, hence the term “baby fat.” In adults, there is a reduced amount of brown fat and it is found mainly in the neck and clavicular regions of the body. The many mitochondria in the cytoplasm of brown adipose tissue help explain its efficiency at metabolising stored fat. Brown adipose tissue is thermogenic, meaning that as it breaks down fats, it releases metabolic heat, rather than producing adenosine triphosphate (ATP), a key molecule used in metabolism.

Areolar tissue shows little specialisation. It contains all the cell types and fibres previously described and is distributed in a random, web-like fashion. It fills the spaces between muscle fibres, surrounds blood and lymph vessels, and supports organs in the abdominal cavity. Areolar tissue underlies most epithelia and represents the connective tissue component of epithelial membranes, which are described further in a later section.

Reticular tissue is a mesh-like, supportive framework for soft organs such as lymphatic tissue, the spleen, and the liver (Figure 3.3.3). Reticular cells produce the reticular fibres that form the network onto which other cells attach. It derives its name from the Latin reticulus, which means “little net.”

Dense Connective Tissue

Dense connective tissue contains more collagen fibres than does loose connective tissue. Consequently, it displays greater resistance to stretching. There are two major categories of dense connective tissue: regular and irregular. Dense regular connective tissue fibres are parallel to each other, enhancing tensile strength and resistance to stretching in the direction of the fibre’s orientation. Ligaments and tendons are made of dense regular connective tissue, but in ligaments not all fibres are parallel. Dense regular elastic tissue contains elastin fibres in addition to collagen fibres, which allows the ligament to return to its original length after stretching. The ligaments in the vocal folds and between the vertebrae in the vertebral column are elastic.

In dense irregular connective tissue, the direction of fibres is random. This arrangement gives the tissue greater strength in all directions and less strength in one particular direction. In some tissues, fibres crisscross and form a mesh. In other tissues, stretching in several directions is achieved by alternating layers where fibres run in the same orientation in each layer, and it is the layers themselves that are stacked at an angle. The dermis of the skin is an example of dense irregular connective tissue rich in collagen fibres. Dense irregular elastic tissues give arterial walls the strength and the ability to regain original shape after stretching (Figure 3.3.4).

Disorders of the Connective Tissue: Tendinitis

Your opponent stands ready as you prepare to hit the serve, but you are confident that you will smash the ball past your opponent. As you toss the ball high in the air, a burning pain shoots across your wrist and you drop the tennis racket. That dull ache in the wrist that you ignored through the summer is now an unbearable pain. The game is over for now.

After examining your swollen wrist, the doctor in the emergency room announces that you have developed wrist tendinitis. She recommends icing the tender area, taking non-steroidal anti-inflammatory medication to ease the pain and to reduce swelling, and complete rest for a few weeks. She interrupts your protests that you cannot stop playing. She issues a stern warning about the risk of aggravating the condition and the possibility of surgery. She consoles you by mentioning that well known tennis players such as Venus and Serena Williams and Rafael Nadal have also suffered from tendinitis related injuries.

What is tendinitis and how did it happen? Tendinitis is the inflammation of a tendon, the thick band of fibrous connective tissue that attaches a muscle to a bone. The condition causes pain and tenderness in the area around a joint. On rare occasions, a sudden serious injury will cause tendinitis. Most often, the condition results from repetitive motions over time that strain the tendons needed to perform the tasks.

Persons whose jobs and hobbies involve performing the same movements over and over again are often at the greatest risk of tendinitis. You hear of tennis and golfer’s elbow, jumper’s knee, and swimmer’s shoulder. In all cases, overuse of the joint causes a microtrauma that initiates the inflammatory response. Tendinitis is routinely diagnosed through a clinical examination. In case of severe pain, X-rays can be examined to rule out the possibility of a bone injury. Severe cases of tendinitis can even tear loose a tendon. Surgical repair of a tendon is painful. Connective tissue in the tendon does not have abundant blood supply and heals slowly.

While older adults are at risk for tendinitis because the elasticity of tendon tissue decreases with age, active people of all ages can develop tendinitis. Young athletes, dancers, and computer operators; anyone who performs the same movements constantly is at risk for tendinitis. Although repetitive motions are unavoidable in many activities and may lead to tendinitis, precautions can be taken that can lessen the probability of developing tendinitis. For active individuals, stretches before exercising and cross training or changing exercises are recommended. For the passionate athlete, it may be time to take some lessons to improve technique. All of the preventive measures aim to increase the strength of the tendon and decrease the stress put on it. With proper rest and managed care, you will be back on the court to hit that slice-spin serve over the net.

Supportive Connective Tissues

Two major forms of supportive connective tissue, cartilage and bone, allow the body to maintain its posture and protect internal organs.

Cartilage

The distinctive appearance of cartilage is due to polysaccharides called chondroitin sulphates, which bind with ground substance proteins to form proteoglycans. Embedded within the cartilage matrix are chondrocytes, or cartilage cells, and the space they occupy are called lacunae (singular = lacuna). A layer of dense irregular connective tissue, the perichondrium, encapsulates the cartilage. Cartilaginous tissue is avascular, thus all nutrients need to diffuse through the matrix to reach the chondrocytes. This is a factor contributing to the very slow healing of cartilaginous tissues.

The three main types of cartilage tissue are hyaline cartilage, fibrocartilage, and elastic cartilage (Figure 3.3.5). Hyaline cartilage, the most common type of cartilage in the body, consists of short and dispersed collagen fibres and contains large amounts of proteoglycans. Under the microscope, tissue samples appear clear. The surface of hyaline cartilage is smooth. Both strong and flexible, it is found in the rib cage and nose and covers bones where they meet to form moveable joints. It makes up a template of the embryonic skeleton before bone formation. A plate of hyaline cartilage at the ends of bone allows continued growth until adulthood. Fibrocartilage is tough because it has thick bundles of collagen fibres dispersed through its matrix. The knee and jaw joints and the intervertebral discs are examples of fibrocartilage. Elastic cartilage contains elastic fibres as well as collagen and proteoglycans. This tissue gives rigid support as well as elasticity. Tug gently at your ear lobes and notice that the lobes return to their initial shape. The external ear contains elastic cartilage.

Bone

Bone is the hardest connective tissue. It provides protection to internal organs and supports the body. Bone’s rigid extracellular matrix contains mostly collagen fibres embedded in a mineralised ground substance containing hydroxyapatite, a form of calcium phosphate. Both components of the matrix, organic and inorganic, contribute to the unusual properties of bone. Without collagen, bones would be brittle and shatter easily. Without mineral crystals, bones would flex and provide little support. Osteocytes, bone cells like chondrocytes, are located within lacunae. The histology of transverse tissue from long bone shows a typical arrangement of osteocytes in concentric circles around a central canal. Bone is a highly vascularised tissue. Unlike cartilage, bone tissue can recover from injuries in a relatively short time.

Cancellous bone looks like a sponge under the microscope and contains empty spaces between trabeculae, or arches of bone proper. It is lighter than compact bone and found in the interior of some bones and at the end of long bones. Compact bone is solid and has greater structural strength.

Fluid Connective Tissue

Blood and lymph are fluid connective tissues. Cells circulate in a liquid extracellular matrix. The formed elements circulating in blood are all derived from hematopoietic stem cells located in bone marrow (Figure 3.3.6). Erythrocytes, red blood cells, transport oxygen and some carbon dioxide. Leukocytes, white blood cells, are responsible for defending against potentially harmful microorganisms or molecules. Platelets are cell fragments involved in blood clotting. Some white blood cells can cross the endothelial layer that lines blood vessels and enter adjacent tissues. Nutrients, salts, and wastes are dissolved in the liquid matrix and transported through the body.

Lymph contains a liquid matrix and white blood cells. Lymphatic capillaries are extremely permeable, allowing larger molecules and excess fluid from interstitial spaces to enter the lymphatic vessels. Lymph drains into blood vessels, delivering molecules to the blood that could not otherwise directly enter the bloodstream. In this way, specialised lymphatic capillaries transport absorbed fats away from the intestine and deliver these molecules to the blood.

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Muscle tissue is characterised by properties that allow movement. Muscle cells are excitable; they respond to a stimulus. They are contractile, meaning they can shorten and generate a pulling force. When attached between two movable objects, in other words, bones, contractions of the muscles cause the bones to move. Some muscle movement is voluntary, which means it is under conscious control. For example, a person decides to open a book and read a chapter on anatomy. Other movements are involuntary, meaning they are not under conscious control, such as the contraction of your pupil in bright light. Muscle tissue is classified into three types according to structure and function: skeletal, cardiac, and smooth (Table 3.4.1).

Table 3.4.1. Comparison of structure and properties of muscle tissue types

Skeletal muscle is attached to bones and its contraction makes possible locomotion, facial expressions, posture, and other voluntary movements of the body. Forty percent of your body mass is made up of skeletal muscle. Skeletal muscles generate heat as a by-product of their contraction and thus participate in thermal homeostasis. Shivering is an involuntary contraction of skeletal muscles in response to perceived lower than normal body temperature. The muscle cell, or myocyte, develops from myoblasts derived from the mesoderm. Myocytes and their numbers remain relatively constant throughout life. Skeletal muscle tissue is arranged in bundles surrounded by connective tissue. Under the light microscope, muscle cells appear striated with many nuclei squeezed along the membranes. The striation is due to the regular alternation of the contractile proteins, actin and myosin, along with the structural proteins that couple the contractile proteins to connective tissues. The cells are multinucleated as a result of the fusion of the many myoblasts that fuse to form each long muscle fibre.

Cardiac muscle forms the contractile walls of the heart. The cells of cardiac muscle, known as cardiomyocytes, also appear striated under the microscope. Unlike skeletal muscle fibres, cardiomyocytes are single cells typically with a single centrally located nucleus. A principal characteristic of cardiomyocytes is that they contract on their own intrinsic rhythms without any external stimulation. Cardiomyocyte attach to one another with specialised cell junctions called intercalated discs. Intercalated discs have both anchoring junctions and gap junctions. Attached cells form long, branching cardiac muscle fibres that are, essentially, a mechanical and electrochemical syncytium allowing the cells to synchronise their actions. The cardiac muscle pumps blood through the body and is under involuntary control. The attachment junctions hold adjacent cells together across the dynamic pressures changes of the cardiac cycle.

Smooth muscle tissue contraction is responsible for involuntary movements in the internal organs. It forms the contractile component of the digestive, urinary, and reproductive systems as well as the airways and arteries. Each cell is spindle shaped with a single nucleus and no visible striations (Figure 3.4.1).

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Nervous tissue is characterised as being excitable and capable of sending and receiving electrochemical signals that provide the body with information. Two main classes of cells make up nervous tissue: the neuron and neuroglia (Figure 3.5.1). Neurons propagate information via electrochemical impulses, called action potentials, which are biochemically linked to the release of chemical signals. Neuroglia play an essential role in supporting neurons and modulating their information propagation.

Neurons display distinctive morphology, well suited to their role as conducting cells, with three main parts. The cell body includes most of the cytoplasm, the organelles, and the nucleus. Dendrites branch off the cell body and appear as thin extensions. A long “tail,” the axon, extends from the neuron body and can be wrapped in an insulating layer known as myelin, which is formed by accessory cells. The synapse is the gap between nerve cells, or between a nerve cell and its target, for example, a muscle or a gland, across which the impulse is transmitted by chemical compounds known as neurotransmitters. Neurons categorised as multipolar neurons have several dendrites and a single prominent axon. Bipolar neurons possess a single dendrite and axon with the cell body, while unipolar neurons have only a single process extending out from the cell body, which divides into a functional dendrite and into a functional axon. When a neuron is sufficiently stimulated, it generates an action potential that propagates down the axon towards the synapse. If enough neurotransmitters are released at the synapse to stimulate the next neuron or target, a response is generated.

The second class of neural cells comprises the neuroglia or glial cells, which have been characterised as having a simple support role. The word “glia” comes from the Greek word for glue. Recent research is shedding light on the more complex role of neuroglia in the function of the brain and nervous system. Astrocyte cells, named for their distinctive star shape, are abundant in the central nervous system. The astrocytes have many functions, including regulation of ion concentration in the intercellular space, uptake and/or breakdown of some neurotransmitters, and formation of the blood-brain barrier, the membrane that separates the circulatory system from the brain. Microglia protect the nervous system against infection but are not nervous tissue because they are related to macrophages. Oligodendrocyte cells produce myelin in the central nervous system (brain and spinal cord) while the Schwann cell produces myelin in the peripheral nervous system (Figure 3.5.2).

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Tissues of all types are vulnerable to injury and, inevitably, ageing. In the former case, understanding how tissues respond to damage can guide strategies to aid repair. In the latter case, understanding the impact of ageing can help in the search for ways to diminish its effects.

Tissue Injury and Repair

Inflammation is the standard, initial response of the body to injury. Whether biological, chemical, physical, or radiation burns, all injuries lead to the same sequence of physiological events. Inflammation limits the extent of injury, partially or fully eliminates the cause of injury, and initiates repair and regeneration of damaged tissue. Necrosis, or accidental cell death, causes inflammation. Apoptosis is programmed cell death, a normal step-by-step process that destroys cells no longer needed by the body. By mechanisms still under investigation, apoptosis does not initiate the inflammatory response. Acute inflammation resolves over time by the healing of tissue. If inflammation persists, it becomes chronic and leads to diseased conditions. Arthritis and tuberculosis are examples of chronic inflammation. The suffix “-itis” denotes inflammation of a specific organ or type, for example, peritonitis is the inflammation of the peritoneum, and meningitis refers to the inflammation of the meninges, the tough membranes that surround the central nervous system

The four cardinal signs of inflammation—redness, swelling, pain and local heat—were first recorded in antiquity. Cornelius Celsus is credited with documenting these signs during the days of the Roman Empire, as early as the first century AD. A fifth sign, loss of function, may also accompany inflammation.

Upon tissue injury, damaged cells release inflammatory chemical signals that evoke local vasodilation, the widening of the blood vessels. Increased blood flow results in apparent redness and heat. In response to injury, mast cells present in tissue degranulate, releasing the potent vasodilator histamine. Increased blood flow and inflammatory mediators recruit white blood cells to the site of inflammation. The endothelium lining the local blood vessel becomes “leaky” under the influence of histamine and other inflammatory mediators allowing neutrophils, macrophages, and fluid to move from the blood into the interstitial tissue spaces. The excess liquid in tissue causes swelling, more properly called oedema. The swollen tissues squeezing pain receptors cause the sensation of pain. Prostaglandins released from injured cells also activate pain neurons. Non-steroidal anti-inflammatory drugs (NSAIDs) reduce pain because they inhibit the synthesis of prostaglandins. High levels of NSAIDs reduce inflammation. Antihistamines decrease allergies by blocking histamine receptors and as a result the histamine response.

After containment of an injury, the tissue repair phase starts with removal of toxins and waste products. Clotting (coagulation) reduces blood loss from damaged blood vessels and forms a network of fibrin proteins that trap blood cells and bind the edges of the wound together. A scab forms when the clot dries, reducing the risk of infection. Sometimes a mixture of dead leukocytes and fluid called pus accumulates in the wound. As healing progresses, fibroblasts from the surrounding connective tissues replace the collagen and extracellular material lost by the injury. Angiogenesis, the growth of new blood vessels, results in vascularisation of the new tissue known as granulation tissue. The clot retracts pulling the edges of the wound together, and it slowly dissolves as the tissue is repaired. When a large amount of granulation tissue forms and capillaries disappear, a pale scar is often visible in the healed area. A primary union describes the healing of a wound where the edges are close together. When there is a gaping wound, it takes longer to refill the area with cells and collagen. The process called secondary union occurs as the edges of the wound are pulled together by what is called wound contraction. When a wound is more than one quarter of an inch deep, sutures (stitches) are recommended to promote a primary union and avoid the formation of a disfiguring scar. Regeneration is the addition of new cells of the same type as the ones that were injured (Figure 3.6.1).

Tissue and Ageing

According to poet Ralph Waldo Emerson, “The surest poison is time.” In fact, biology confirms that many functions of the body decline with age. All the cells, tissues, and organs are affected by senescence, with noticeable variability between individuals owing to different genetic makeup and lifestyles. The outward signs of ageing are easily recognisable. The skin and other tissues become thinner and drier, reducing their elasticity, contributing to wrinkles and high blood pressure. Hair turns grey because follicles produce less melanin, the brown pigment of hair and the iris of the eye. The face looks flabby because elastic and collagen fibres decrease in connective tissue and muscle tone is lost. Glasses and hearing aids may become parts of life as the senses slowly deteriorate, all due to reduced elasticity. Overall height decreases as the bones lose calcium and other minerals. With age, fluid decreases in the fibrous cartilage disks intercalated between the vertebrae in the spine. Joints lose cartilage and stiffen. Many tissues, including those in muscles, lose mass through a process called atrophy. Lumps and rigidity become more widespread. As a consequence, the passageways, blood vessels, and airways become more rigid. The brain and spinal cord lose mass. Nerves do not transmit impulses with the same speed and frequency as in the past. Some loss of thought clarity and memory can accompany ageing. More severe problems are not necessarily associated with the ageing process and may be symptoms of underlying illness.

As exterior signs of ageing increase, so do the interior signs, which are not as noticeable. The incidence of heart diseases, respiratory syndromes, and type 2 diabetes increases with age, though these are not necessarily age-dependent effects. Wound healing is slower in the elderly, accompanied by a higher frequency of infection as the capacity of the immune system to fend off pathogen declines.

Ageing is also apparent at the cellular level because all cells experience changes with ageing. Telomeres, regions of the chromosomes necessary for cell division, shorten each time cells divide. As they do, cells are less able to divide and regenerate. Because of alterations in cell membranes, transport of oxygen and nutrients into the cell and removal of carbon dioxide and waste products from the cell are not as efficient in the elderly. Cells may begin to function abnormally, which may lead to diseases associated with ageing, including arthritis, memory issues, and some cancers.

The progressive impact of ageing on the body varies considerably among individuals, with some studies indicating that exercise and healthy lifestyle choices may slow down the deterioration of the body that comes with old age.

Homeostatic Imbalances

Tissues and Cancer

Cancer is a generic term for many diseases in which cells escape regulatory signals. Uncontrolled growth, invasion into adjacent tissues, and colonisation of other organs, if not treated early enough, are its hallmarks. Health suffers when tumours “rob” blood supply from the “normal” organs.

A mutation is defined as a permanent change in the DNA of a cell. Epigenetic modifications, changes that do not affect the code of the DNA but alter how the DNA is decoded, are also known to generate abnormal cells. Alterations in the genetic material may be caused by environmental agents, infectious agents, or errors in the replication of DNA that accumulate with age. Many mutations do not cause any noticeable change in the functions of a cell. However, if the modification affects key proteins that have an impact on the cell’s ability to proliferate in an orderly fashion, the cell starts to divide abnormally. As changes in cells accumulate, they lose their ability to form regular tissues. A tumour, a mass of cells displaying abnormal architecture, forms in the tissue. Many tumours are benign, meaning they do not metastasise nor cause disease. A tumour becomes malignant, or cancerous, when it breaches the confines of its tissue, promotes angiogenesis, attracts the growth of capillaries, and metastasises to other organs (Figure 3.6.2). The specific names of cancers reflect the tissue of origin. Cancers derived from epithelial cells are referred to as carcinomas. Cancer in myeloid tissue or blood cells form myelomas. Leukemias are cancers of white blood cells, whereas sarcomas derive from connective tissue. Cells in tumours differ both in structure and function. Some cells, called cancer stem cells, appear to be a subtype of cell responsible for uncontrolled growth. Recent research shows that contrary to what was previously assumed, tumours are not disorganised masses of cells, but have their own structures.

Cancer treatments vary depending on the disease’s type and stage. Traditional approaches, including surgery, radiation, chemotherapy, and hormonal therapy, aim to remove or kill rapidly dividing cancer cells, but these strategies have their limitations. Depending on a tumour’s location, for example, cancer surgeons may be unable to remove it. Radiation and chemotherapy are difficult, and it is often impossible to target only the cancer cells. The treatments inevitably destroy healthy tissue as well. To address this, researchers are working on pharmaceuticals that can target specific proteins implicated in cancer-associated molecular pathways.

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Although you may not typically think of the skin as an organ, it is in fact made of tissues that work together as a single structure to perform unique and critical functions. The skin and its accessory structures make up the integumentary system, which provides the body with overall protection. The skin is made of multiple layers of cells and tissues, which are held to underlying structures by connective tissue (Figure 4.1.1). The deeper layer of skin is well vascularised (has numerous blood vessels). It also has numerous sensory, and autonomic and sympathetic nerve fibres ensuring communication to and from the brain.

The Epidermis

The epidermis is composed of keratinised, stratified squamous epithelium. It is made of four or five layers of epithelial cells, depending on its location in the body. It does not have any blood vessels within it (i.e., it is avascular). Skin that has four layers of cells is referred to as “thin skin.” From deep to superficial, these layers are the stratum basale, stratum spinosum, stratum granulosum, and stratum corneum. Most of the skin can be classified as thin skin. “Thick skin” is found only on the palms of the hands and the soles of the feet. It has a fifth layer, called the stratum lucidum, located between the stratum corneum and the stratum granulosum (Figure 4.1.2).

The cells in all of the layers except the stratum basale are called keratinocytes. A keratinocyte is a cell that manufactures and stores the protein keratin. Keratin is an intracellular fibrous protein that gives hair, nails, and skin their hardness and water-resistant properties. The keratinocytes in the stratum corneum are dead and regularly slough away, being replaced by cells from the deeper layers (Figure 4.1.3).

Stratum Basale

The stratum basale (also called the stratum germinativum) is the deepest epidermal layer and attaches the epidermis to the basal lamina, below which lie the layers of the dermis. The cells in the stratum basale bond to the dermis via intertwining collagen fibres, referred to as the basement membrane. A finger-like projection, or fold, known as the dermal papilla (plural = dermal papillae) is found in the superficial portion of the dermis. Dermal papillae increase the strength of the connection between the epidermis and dermis; the greater the folding, the stronger the connections made (Figure 4.1.4).

The stratum basale is a single layer of cells primarily made of basal cells. A basal cell is a cuboidal-shaped stem cell that is a precursor of the keratinocytes of the epidermis. All of the keratinocytes are produced from this single layer of cells, which are constantly going through mitosis to produce new cells. As new cells are formed, the existing cells are pushed superficially away from the stratum basale. Two other cell types are found dispersed among the basal cells in the stratum basale. The first is a Merkel cell, which functions as a receptor and is responsible for stimulating sensory nerves that the brain perceives as touch. These cells are especially abundant on the surfaces of the hands and feet. The second is a melanocyte, a cell that produces the pigment melanin. Melanin gives hair and skin its colour, and also helps protect the living cells of the epidermis from ultraviolet (UV) radiation damage.

In a growing foetus, fingerprints form where the cells of the stratum basale meet the papillae of the underlying dermal layer (papillary layer), resulting in the formation of the ridges on your fingers that you recognise as fingerprints. Fingerprints are unique to each individual and are used for forensic analyses because the patterns do not change with the growth and ageing processes.

Stratum Spinosum

As the name suggests, the stratum spinosum is spiny in appearance due to the protruding cell processes that join the cells via a structure called a desmosome. The desmosomes interlock with each other and strengthen the bond between the cells. It is interesting to note that the “spiny” nature of this layer is an artifact of the staining process. Unstained epidermis samples do not exhibit this characteristic appearance. The stratum spinosum is composed of eight to 10 layers of keratinocytes, formed as a result of cell division in the stratum basale (Figure 4.1.5). Interspersed among the keratinocytes of this layer is a type of dendritic cell called the Langerhans cell, which functions as a macrophage by engulfing bacteria, foreign particles, and damaged cells that occur in this layer.

The keratinocytes in the stratum spinosum begin the synthesis of keratin and release a water-repelling glycolipid that helps prevent water loss from the body, making the skin relatively waterproof. As new keratinocytes are produced atop the stratum basale, the keratinocytes of the stratum spinosum are pushed into the stratum granulosum.

Stratum Granulosum

The stratum granulosum has a grainy appearance due to further changes to the keratinocytes as they are pushed from the stratum spinosum. The cells (three to five layers deep) become flatter, their cell membranes thicken, and they generate large amounts of the proteins keratin, which is fibrous, and keratohyalin, which accumulates as lamellar granules within the cells (see Figure 4.1.4 and Figure 4.1.5). These two proteins make up the bulk of the keratinocyte mass in the stratum granulosum and give the layer its grainy appearance. The nuclei and other cell organelles disintegrate as the cells die, leaving behind the keratin, keratohyalin, and cell membranes that will form the stratum lucidum, the stratum corneum, and the accessory structures of hair and nails.

Stratum Lucidum

The stratum lucidum is a smooth, seemingly translucent layer of the epidermis located just above the stratum granulosum and below the stratum corneum. This thin layer of cells is found only in the thick skin of the palms, soles, and digits. The keratinocytes that compose the stratum lucidum are dead and flattened (see Figure 4.1.4 and Figure 4.1.5). These cells are densely packed with eleidin, a clear protein rich in lipids, derived from keratohyalin, which gives these cells their transparent (i.e., lucid) appearance and provides a barrier to water.

Stratum Corneum

The stratum corneum is the most superficial layer of the epidermis and is the layer exposed to the outside environment (see Figure 4.1.4 and Figure 4.1.5). The increased keratinisation (also called cornification) of the cells in this layer gives it its name. There are usually 15 to 30 layers of cells in the stratum corneum. This dry, dead layer helps prevent the penetration of microbes and the dehydration of underlying tissues and provides a mechanical protection against abrasion for the more delicate, underlying layers. Cells in this layer are shed periodically and are replaced by cells pushed up from the stratum granulosum (or stratum lucidum in the case of the palms and soles of feet). The entire layer is replaced during a period of about 4 weeks. Cosmetic procedures, such as microdermabrasion, help remove some of the dry, upper layer and aim to keep the skin looking “fresh” and healthy.

Dermis

The dermis might be considered the “core” of the integumentary system (derma- = “skin”), as distinct from the epidermis (epi- = “upon” or “over”) and hypodermis (hypo- = “below”). It contains blood and lymph vessels, nerves, and other structures, such as hair follicles and sweat glands. The dermis is made of two layers of connective tissue that compose an interconnected mesh of elastin and collagenous fibres, produced by fibroblasts (Figure 4.1.6).

Papillary Layer

The papillary layer is made of loose, areolar connective tissue, which means the collagen and elastin fibres of this layer form a loose mesh. This superficial layer of the dermis projects into the stratum basale of the epidermis to form finger-like dermal papillae (see Figure 4.1.6). Within the papillary layer are fibroblasts, a small number of fat cells (adipocytes), and an abundance of small blood vessels. In addition, the papillary layer contains phagocytes, defensive cells that help fight bacteria or other infections that have breached the skin. This layer also contains lymphatic capillaries, nerve fibres, and touch receptors called the Meissner corpuscles.

Reticular Layer

Underlying the papillary layer is the much thicker reticular layer, composed of dense, irregular connective tissue. This layer is well vascularised and has a rich sensory and sympathetic nerve supply. The reticular layer appears reticulated (net-like) due to a tight meshwork of fibres. Elastin fibres provide some elasticity to the skin, enabling movement. Collagen fibres provide structure and tensile strength, with strands of collagen extending into both the papillary layer and the hypodermis. In addition, collagen binds water to keep the skin hydrated. Collagen injections and Retin-A creams help restore skin turgor by either introducing collagen externally or stimulating blood flow and repair of the dermis, respectively.

Hypodermis

The hypodermis (also called the subcutaneous layer or superficial fascia) is a layer directly below the dermis and serves to connect the skin to the underlying fascia (fibrous tissue) of the bones and muscles. It is not strictly a part of the skin, although the border between the hypodermis and dermis can be difficult to distinguish. The hypodermis consists of well-vascularised, loose, areolar connective tissue and adipose tissue, which functions as a mode of fat storage and provides insulation and cushioning for the integument.

Everyday Connection

Lipid Storage

The hypodermis is home to most of the fat that concerns people when they are trying to keep their weight under control. Adipose tissue present in the hypodermis consists of fat-storing cells called adipocytes. This stored fat can serve as an energy reserve, insulate the body to prevent heat loss, and act as a cushion to protect underlying structures from trauma.

Where the fat is deposited and accumulates within the hypodermis depends on hormones (testosterone, oestrogen, insulin, glucagon, leptin and others), as well as genetic factors. Fat distribution changes as our bodies mature and age. Men tend to accumulate fat in different areas (neck, arms, lower back, and abdomen) than do women (breasts, hips, thighs, and buttocks). The body mass index (BMI) is often used as a measure of fat, although this measure is, in fact, derived from a mathematical formula that compares body weight (mass) to height. Therefore, its accuracy as a health indicator can be called into question in individuals who are extremely physically fit.

In many animals, there is a pattern of storing excess calories as fat to be used in times when food is not readily available. In much of the developed world, insufficient exercise coupled with the ready availability and consumption of high-calorie foods have resulted in unwanted accumulations of adipose tissue in many people. Although periodic accumulation of excess fat may have provided an evolutionary advantage to our ancestors, who experienced unpredictable bouts of famine, it is now becoming chronic and considered a major health threat. Recent studies indicate that a distressing percentage of our population is overweight and/or clinically obese. Not only is this a problem for the individuals affected, but it also has a severe impact on our healthcare system. Changes in lifestyle, specifically in diet and exercise, are the best ways to control body fat accumulation, especially when it reaches levels that increase the risk of heart disease and diabetes.

Pigmentation

The colour of skin is influenced by a number of pigments, including melanin, carotene and haemoglobin. Recall that melanin is produced by cells called melanocytes, which are found scattered throughout the stratum basale of the epidermis. The melanin is transferred into the keratinocytes via a cellular vesicle called a melanosome (Figure 4.1.7).

Melanin occurs in two primary forms. Eumelanin exists as black and brown, whereas pheomelanin provides a red colour. Dark-skinned individuals produce more melanin than those with pale skin. Exposure to the UV rays of the sun or a tanning salon causes melanin to be manufactured and built up in keratinocytes, as sun exposure stimulates keratinocytes to secrete chemicals that stimulate melanocytes. The accumulation of melanin in keratinocytes results in the darkening of the skin, or a tan. This increased melanin accumulation protects the DNA of epidermal cells from UV ray damage and the breakdown of folic acid, a nutrient necessary for our health and well-being. In contrast, too much melanin can interfere with the production of vitamin D, an important nutrient involved in calcium absorption. Thus, the amount of melanin present in our skin is dependent on a balance between available sunlight and folic acid destruction, and protection from UV radiation and vitamin D production.

It requires about 10 days after initial sun exposure for melanin synthesis to peak, which is why pale-skinned individuals tend to suffer sunburns of the epidermis initially. Dark-skinned individuals can also get sunburned but are more protected than are pale-skinned individuals. Melanosomes are temporary structures that are eventually destroyed by fusion with lysosomes; this fact, along with melanin-filled keratinocytes in the stratum corneum sloughing off, makes tanning impermanent.

Too much sun exposure can eventually lead to wrinkling due to the destruction of the cellular structure of the skin, and in severe cases, can cause sufficient DNA damage to result in skin cancer. When there is an irregular accumulation of melanocytes in the skin, freckles appear. Moles are larger masses of melanocytes, and although most are benign, they should be monitored for changes that might indicate the presence of cancer (Figure 4.1.8).

Disorders of the Integumentary System

The first thing a clinician sees is the skin, and so the examination of the skin should be part of any thorough physical examination. Most skin disorders are relatively benign, but a few, including melanomas, can be fatal if untreated. A couple of the more noticeable disorders, albinism and vitiligo, affect the appearance of the skin and its accessory organs. Although neither is fatal, it would be hard to claim that they are benign, at least to the individuals so afflicted.

Albinism is a genetic disorder that affects (completely or partially) the colouring of skin, hair, and eyes. The defect is primarily due to the inability of melanocytes to produce melanin. Individuals with albinism tend to appear white or very pale due to the lack of melanin in their skin and hair. Recall that melanin helps protect the skin from the harmful effects of UV radiation. Individuals with albinism tend to need more protection from UV radiation, as they are more prone to sunburns and skin cancer. They also tend to be more sensitive to light and have vision problems due to the lack of pigmentation on the retinal wall. Treatment of this disorder usually involves addressing the symptoms, such as limiting UV light exposure to the skin and eyes. In vitiligo, the melanocytes in certain areas lose their ability to produce melanin, possibly due to an autoimmune reaction. This leads to a loss of colour in patches (Figure 4.1.9). Neither albinism nor vitiligo directly affects the lifespan of an individual.

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Accessory structures of the skin include hair, nails, sweat glands, and sebaceous glands. These structures embryologically originate from the epidermis and can extend down through the dermis into the hypodermis.

Hair

Hair is a keratinous filament growing out of the epidermis. It is primarily made of dead, keratinised cells. Strands of hair originate in an epidermal penetration of the dermis called the hair follicle. The hair shaft is the part of the hair not anchored to the follicle, and much of this is exposed at the skin’s surface. The rest of the hair, which is anchored in the follicle, lies below the surface of the skin and is referred to as the hair root. The hair root ends deep in the dermis at the hair bulb and includes a layer of mitotically active basal cells called the hair matrix. The hair bulb surrounds the hair papilla, which is made of connective tissue and contains blood capillaries and nerve endings from the dermis (Figure 4.2.1).

Just as the basal layer of the epidermis forms the layers of epidermis that get pushed to the surface as the dead skin on the surface sheds, the basal cells of the hair bulb divide and push cells outward in the hair root and shaft as the hair grows. The medulla forms the central core of the hair, which is surrounded by the cortex, a layer of compressed, keratinised cells that is covered by an outer layer of very hard, keratinised cells known as the cuticle. These layers are depicted in a longitudinal cross-section of the hair follicle (Figure 4.2.2), although not all hair has a medullary layer. Hair texture (straight, curly) is determined by the shape and structure of the cortex, and to the extent that it is present, the medulla. The shape and structure of these layers are, in turn, determined by the shape of the hair follicle. Hair growth begins with the production of keratinocytes by the basal cells of the hair bulb. As new cells are deposited at the hair bulb, the hair shaft is pushed through the follicle toward the surface. Keratinisation is completed as the cells are pushed to the skin surface to form the shaft of hair that is externally visible. The external hair is completely dead and composed entirely of keratin. For this reason, our hair does not have sensation. Furthermore, you can cut your hair or shave without damaging the hair structure because the cut is superficial. Most chemical hair removers also act superficially; however, electrolysis and yanking both attempt to destroy the hair bulb so hair cannot grow.

The wall of the hair follicle is made of three concentric layers of cells. The cells of the internal root sheath surround the root of the growing hair and extend just up to the hair shaft. They are derived from the basal cells of the hair matrix. The external root sheath, which is an extension of the epidermis, encloses the hair root. It is made of basal cells at the base of the hair root and tends to be more keratinous in the upper regions. The glassy membrane is a thick, clear connective tissue sheath covering the hair root, connecting it to the tissue of the dermis.

Hair serves a variety of functions, including protection, sensory input, thermoregulation and communication, for example, hair on the head protects the skull from the sun. The hair in the nose and ears, and around the eyes (eyelashes) defends the body by trapping and excluding dust particles that may contain allergens and microbes. Hair of the eyebrows prevents sweat and other particles from dripping into and bothering the eyes. Hair also has a sensory function due to sensory innervation by a hair root plexus surrounding the base of each hair follicle. Hair is extremely sensitive to air movement or other disturbances in the environment, much more so than the skin surface. This feature is also useful for the detection of the presence of insects or other potentially damaging substances on the skin surface. Each hair root is connected to a smooth muscle called the arrector pili that contracts in response to nerve signals from the sympathetic nervous system, making the external hair shaft “stand up.” The primary purpose for this is to trap a layer of air to add insulation. This is visible in humans as goose bumps and even more obvious in animals, such as when a frightened cat raises its fur. Of course, this is much more obvious in organisms with a heavier coat than most humans, such as dogs and cats.

Hair Growth

Hair grows and is eventually shed and replaced by new hair. This occurs in three phases. The first is the anagen phase, during which cells divide rapidly at the root of the hair, pushing the hair shaft up and out. The length of this phase is measured in years, typically from 2 to 7 years. The catagen phase lasts only 2 to 3 weeks and marks a transition from the hair follicle’s active growth. Finally, during the telogen phase, the hair follicle is at rest and no new growth occurs. At the end of this phase, which lasts about 2 to 4 months, another anagen phase begins. The basal cells in the hair matrix then produce a new hair follicle, which pushes the old hair out as the growth cycle repeats itself. Hair typically grows at the rate of 0.3 mm per day during the anagen phase. On average, 50 hairs are lost and replaced per day. Hair loss occurs if there is more hair shed than what is replaced and can happen due to hormonal or dietary changes. Hair loss can also result from the ageing process, or the influence of hormones.

Hair Colour

Similar to the skin, hair gets its colour from the pigment melanin, produced by melanocytes in the hair papilla. Different hair colour results from differences in the type of melanin, which is genetically determined. As a person ages, the melanin production decreases, and hair tends to lose its colour and becomes grey and/or white.

Nails

The nail bed is a specialised structure of the epidermis that is found at the tips of our fingers and toes. The nail body is formed on the nail bed, and protects the tips of our fingers and toes as they are the farthest extremities and the parts of the body that experience the maximum mechanical stress (Figure 4.2.3). In addition, the nail body forms a back-support for picking up small objects with the fingers. The nail body is composed of densely packed dead keratinocytes. The epidermis in this part of the body has evolved a specialised structure upon which nails can form. The nail body forms at the nail root, which has a matrix of proliferating cells from the stratum basale that enables the nail to grow continuously. The lateral nail fold overlaps the nail on the sides, helping to anchor the nail body. The nail fold that meets the proximal end of the nail body forms the nail cuticle, also called the eponychium. The nail bed is rich in blood vessels, making it appear pink, except at the base, where a thick layer of epithelium over the nail matrix forms a crescent-shaped region called the lunula (the “little moon”). The area beneath the free edge of the nail, furthest from the cuticle, is called the hyponychium. It consists of a thickened layer of stratum corneum.

Sweat Glands

When the body becomes warm, sudoriferous glands produce sweat to cool the body. Sweat glands develop from epidermal projections into the dermis and are classified as merocrine glands; that is, the secretions are excreted by exocytosis through a duct without affecting the cells of the gland. There are two types of sweat glands, each secreting slightly different products.

An eccrine sweat gland is type of gland that produces a hypotonic sweat for thermoregulation. These glands are found all over the skin’s surface, but are especially abundant on the palms of the hand, the soles of the feet, and the forehead (Figure 4.2.4). They are coiled glands lying deep in the dermis, with the duct rising up to a pore on the skin surface, where the sweat is released. This type of sweat, released by exocytosis, is hypotonic and composed mostly of water, with some salt, antibodies, traces of metabolic waste, and dermicidin, an antimicrobial peptide. Eccrine glands are a primary component of thermoregulation in humans and thus help to maintain homeostasis.

An apocrine sweat gland is usually associated with hair follicles in densely hairy areas, such as armpits and genital regions. Apocrine sweat glands are larger than eccrine sweat glands and lie deeper in the dermis, sometimes even reaching the hypodermis, with the duct normally emptying into the hair follicle. In addition to water and salts, apocrine sweat includes organic compounds that make the sweat thicker and subject to bacterial decomposition and subsequent smell. The release of this sweat is under both nervous and hormonal control and plays a role in the poorly understood human pheromone response. Most commercial antiperspirants use an aluminium-based compound as their primary active ingredient to stop sweat. When the antiperspirant enters the sweat gland duct, the aluminium-based compounds precipitate due to a change in pH and form a physical block in the duct, which prevents sweat from coming out of the pore.

Sebaceous Glands

A sebaceous gland is a type of oil gland that is found all over the body and helps to lubricate and waterproof the skin and hair. Most sebaceous glands are associated with hair follicles. They generate and excrete sebum, a mixture of lipids, onto the skin surface, thereby naturally lubricating the dry and dead layer of keratinised cells of the stratum corneum, keeping it pliable. The fatty acids of sebum also have antibacterial properties and prevent water loss from the skin in low-humidity environments. The secretion of sebum is stimulated by hormones, many of which do not become active until puberty. Thus, sebaceous glands are relatively inactive during childhood.

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The skin and accessory structures perform a variety of essential functions, such as protecting the body from invasion by microorganisms, chemicals, and other environmental factors; preventing dehydration; acting as a sensory organ; modulating body temperature and electrolyte balance; and synthesising vitamin D. The underlying hypodermis has important roles in storing fats, forming a “cushion” over underlying structures, and providing insulation from cold temperatures.

Protection

The skin protects the rest of the body from the basic elements of nature such as wind, water, and UV sunlight. It acts as a protective barrier against water loss, due to the presence of layers of keratin and glycolipids in the stratum corneum. It also is the first line of defence against abrasive activity due to contact with grit, microbes, or harmful chemicals. Sweat excreted from sweat glands deters microbes from over-colonising the skin surface by generating dermicidin, which has antibiotic properties.

Everyday Connection

Tattoos and Piercings

The word “armour” evokes several images. You might think of a Roman centurion or a medieval knight in a suit of armour. The skin, in its own way, functions as a form of armour—body armour. It provides a barrier between your vital, life-sustaining organs and the influence of outside elements that could potentially damage them.

For any form of armour, a breach in the protective barrier poses a danger. The skin can be breached when a child skins a knee, or an adult has blood drawn—one is accidental and the other medically necessary. However, you also breach this barrier when you choose to “accessorise” your skin with a tattoo or body piercing. Because the needles involved in producing body art and piercings must penetrate the skin, there are dangers associated with the practice. These include allergic reactions; skin infections; blood-borne diseases, such as tetanus, hepatitis C and hepatitis D; and the growth of scar tissue. Despite the risk, the practice of piercing the skin for decorative purposes has become increasingly popular. According to the American Academy of Dermatology, 24 percent of people from ages 18 to 50 have a tattoo.

Sensory Function

The fact that you can feel an ant crawling on your skin, allowing you to flick it off before it bites, is because the skin, and especially the hairs projecting from hair follicles in the skin, can sense changes in the environment. The hair root plexus surrounding the base of the hair follicle senses a disturbance, and then transmits the information to the central nervous system (brain and spinal cord), which can then respond by activating the skeletal muscles of your eyes to see the ant and the skeletal muscles of the body to act against the ant.

The skin acts as a sense organ because the epidermis, dermis, and the hypodermis contain specialised sensory nerve structures that detect touch, surface temperature, and pain. These receptors are more concentrated on the tips of the fingers, which are most sensitive to touch, especially the Meissner corpuscle (tactile corpuscle) (Figure 4.3.1), which responds to light touch, and the Pacinian corpuscle (lamellated corpuscle), which responds to vibration. Merkel cells, seen scattered in the stratum basale, are also touch receptors. In addition to these specialised receptors, there are sensory nerves connected to each hair follicle, pain and temperature receptors scattered throughout the skin, and motor nerves innervate the arrector pili muscles and glands. This rich innervation helps us sense our environment and react accordingly.

Thermoregulation

The integumentary system helps regulate body temperature through its tight association with the sympathetic nervous system, the division of the nervous system involved in our fight-or-flight responses. The sympathetic nervous system is continuously monitoring body temperature and initiating appropriate motor responses. Recall that sweat glands, accessory structures to the skin, secrete water, salt, and other substances to cool the body when it becomes warm. Even when the body does not appear to be noticeably sweating, approximately 500 mL of sweat (insensible perspiration) are secreted a day. If the body becomes excessively warm due to high temperatures, vigorous activity (Figure 4.3.2ac), or a combination of the two, sweat glands will be stimulated by the sympathetic nervous system to produce large amounts of sweat, as much as 0.7 to 1.5 L per hour for an active person. When the sweat evaporates from the skin surface, the body is cooled as body heat is dissipated.

In addition to sweating, arterioles in the dermis dilate so that excess heat carried by the blood can dissipate through the skin and into the surrounding environment (Figure 4.3.2b). This accounts for the skin redness that many people experience when exercising.

When body temperatures drop, the arterioles constrict to minimise heat loss, particularly in the ends of the digits and tip of the nose. This reduced circulation can result in the skin taking on a whitish hue. Although the temperature of the skin drops as a result, passive heat loss is prevented, and internal organs and structures remain warm. If the temperature of the skin drops too much (such as environmental temperatures below freezing), the conservation of body core heat can result in the skin actually freezing, a condition called frostbite.

Ageing and the Integumentary System

All systems in the body accumulate subtle and some not-so-subtle changes as a person ages. Among these changes are reductions in cell division, metabolic activity, blood circulation, hormonal levels, and muscle strength (Figure 4.3.3). In the skin, these changes are reflected in decreased mitosis in the stratum basale, leading to a thinner epidermis. The dermis, which is responsible for the elasticity and resilience of the skin, exhibits a reduced ability to regenerate, which leads to slower wound healing. The hypodermis, with its fat stores, loses structure due to the reduction and redistribution of fat, which in turn contributes to the thinning and sagging of skin.

The accessory structures also have lowered activity, generating thinner hair and nails, and reduced amounts of sebum and sweat. A reduced sweating ability can cause some elderly to be intolerant to extreme heat. Other cells in the skin, such as melanocytes and dendritic cells, also become less active, leading to a paler skin tone and lowered immunity. Wrinkling of the skin occurs due to breakdown of its structure, which results from decreased collagen and elastin production in the dermis, weakening of muscles lying under the skin, and the inability of the skin to retain adequate moisture.

Many anti-ageing products can be found in stores today. In general, these products try to rehydrate the skin and thereby fill out the wrinkles, and some stimulate skin growth using hormones and growth factors. Additionally, invasive techniques include collagen injections to plump the tissue and injections of BOTOX® (the name brand of the botulinum neurotoxin) that paralyse the muscles that crease the skin and cause wrinkling.

Vitamin D Synthesis

The epidermal layer of human skin synthesises vitamin D when exposed to UV radiation. In the presence of sunlight, a form of vitamin D3 called cholecalciferol is synthesised from a derivative of the steroid cholesterol in the skin. The liver converts cholecalciferol to calcidiol, which is then converted to calcitriol (the active chemical form of the vitamin) in the kidneys. Vitamin D is essential for normal absorption of calcium and phosphorous, which are required for healthy bones. The absence of sun exposure can lead to a lack of vitamin D in the body, leading to a condition called rickets, a painful condition in children where the bones are misshapen due to a lack of calcium, causing bowleggedness. Elderly individuals who suffer from vitamin D deficiency can develop a condition called osteomalacia, a softening of the bones. In present day society, vitamin D is added as a supplement to many foods, including milk and orange juice, compensating for the need for sun exposure.

In addition to its essential role in bone health, vitamin D is essential for general immunity against bacterial, viral, and fungal infections. Recent studies are also finding a link between insufficient vitamin D and cancer.

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The integumentary system is susceptible to a variety of diseases, disorders and injuries. These range from annoying but relatively benign bacterial or fungal infections that are categorised as disorders, to skin cancer and severe burns, which can be fatal. In this section, you will learn several of the most common skin conditions.

Diseases

One of the most talked about diseases is skin cancer. Cancer is a broad term that describes diseases caused by abnormal cells in the body dividing uncontrollably. Most cancers are identified by the organ or tissue in which the cancer originates. One common form of cancer is skin cancer. The Skin Cancer Foundation reports that one in five Americans will experience some type of skin cancer in their lifetime. The degradation of the ozone layer in the atmosphere and the resulting increase in exposure to UV radiation has contributed to its rise. Overexposure to UV radiation damages DNA, which can lead to the formation of cancerous lesions. Although melanin offers some protection against DNA damage from the sun, often it is not enough. The fact that cancers can also occur on areas of the body that are normally not exposed to UV radiation suggests that there are additional factors that can lead to cancerous lesions.

In general, cancers result from an accumulation of DNA mutations. These mutations can result in cell populations that do not die when they should and uncontrolled cell proliferation that leads to tumours. Although many tumours are benign (harmless), some produce cells that can mobilise and establish tumours in other organs of the body; this process is referred to as metastasis. Cancers are characterised by their ability to metastasise.

Basal Cell Carcinoma

Basal cell carcinoma is a form of cancer that affects the mitotically active stem cells in the stratum basale of the epidermis. It is the most common of all cancers that occur in the United States and is frequently found on the head, neck, arms, and back, which are areas that are most susceptible to long-term sun exposure. Although UV rays are the main culprit, exposure to other agents, such as radiation and arsenic, can also lead to this type of cancer. Wounds on the skin due to open sores, tattoos, burns, etc. may be predisposing factors as well. Basal cell carcinomas start in the stratum basale and usually spread along this boundary. At some point, they begin to grow toward the surface and become an uneven patch, bump, growth, or scar on the skin surface (Figure 4.4.1). Like most cancers, basal cell carcinomas respond best to treatment when caught early. Treatment options include surgery, freezing (cryosurgery), and topical ointments (Mayo Clinic 2012).

Squamous Cell Carcinoma

Squamous cell carcinoma is a cancer that affects the keratinocytes of the stratum spinosum and presents as lesions commonly found on the scalp, ears, and hands (Figure 4.4.2). It is the second most common skin cancer. The American Cancer Society reports that two of 10 skin cancers are squamous cell carcinomas, and it is more aggressive than basal cell carcinoma. If not removed, these carcinomas can metastasise. Surgery and radiation are used to cure squamous cell carcinoma.

Melanoma

A melanoma is a cancer characterised by the uncontrolled growth of melanocytes, the pigment-producing cells in the epidermis. Typically, a melanoma develops from a mole. It is the most fatal of all skin cancers, as it is highly metastatic and can be difficult to detect before it has spread to other organs. Melanomas usually appear as asymmetrical brown and black patches with uneven borders and a raised surface (Figure 4.4.3). Treatment typically involves surgical excision and immunotherapy.

Doctors often give their patients the following ABCDE mnemonic to help with the diagnosis of early-stage melanoma. If you observe a mole on your body displaying these signs, consult a doctor.

Asymmetry – the two sides are not symmetrical

Borders – the edges are irregular in shape

Colour – the colour is varied shades of brown or black

Diameter – it is larger than 6 mm (0.24 in)

Evolving – its shape has changed

Some specialists cite the following additional signs for the most serious form, nodular melanoma:

Elevated – it is raised on the skin surface

Firm – it feels hard to the touch

Growing – it is getting larger

Skin Disorders

Two common skin disorders are eczema and acne. Eczema is an inflammatory condition and occurs in individuals of all ages. Acne involves the clogging of pores, which can lead to infection and inflammation, and is often seen in adolescents. Other disorders, not discussed here, include seborrheic dermatitis (on the scalp), psoriasis, cold sores, impetigo, scabies, hives, and warts.

Eczema

Eczema is an allergic reaction that manifests as dry, itchy patches of skin that resemble rashes (Figure 4.4.4). It may be accompanied by swelling of the skin, flaking, and in severe cases, bleeding. Many who suffer from eczema have antibodies against dust mites in their blood, but the link between eczema and allergy to dust mites has not been proven. Symptoms are usually managed with moisturisers, corticosteroid creams and immunosuppressants.

Acne

Acne is a skin disturbance that typically occurs on areas of the skin that are rich in sebaceous glands (face and back). It is most common along with the onset of puberty due to associated hormonal changes but can also occur in infants and continue into adulthood. Hormones, such as androgens, stimulate the release of sebum. An overproduction and accumulation of sebum along with keratin can block hair follicles. This plug is initially white. The sebum, when oxidised by exposure to air, turns black. Acne results from infection by acne-causing bacteria (Propionibacterium and Staphylococcus), which can lead to redness and potential scarring due to the natural wound healing process (Figure 4.4.5).

Injuries

Because the skin is the part of our bodies that meets the world most directly, it is especially vulnerable to injury. Injuries include burns and wounds, as well as scars and calluses. They can be caused by sharp objects, heat, or excessive pressure or friction to the skin.

Skin injuries set off a healing process that occurs in several overlapping stages. The first step to repairing damaged skin is the formation of a blood clot that helps stop the flow of blood and scabs over with time. Many different types of cells are involved in wound repair, especially if the surface area that needs repair is extensive. Before the basal stem cells of the stratum basale can recreate the epidermis, fibroblasts mobilise and divide rapidly to repair the damaged tissue by collagen deposition, forming granulation tissue. Blood capillaries follow the fibroblasts and help increase blood circulation and oxygen supply to the area. Immune cells, such as macrophages, roam the area and engulf any foreign matter to reduce the chance of infection.

Burns

A burn results when the skin is damaged by intense heat, radiation, electricity, or chemicals. The damage results in the death of skin cells, which can lead to a massive loss of fluid. Dehydration, electrolyte imbalance, and renal and circulatory failure follow, which can be fatal. Burn patients are treated with intravenous fluids to offset dehydration, as well as intravenous nutrients that enable the body to repair tissues and replace lost proteins. Another serious threat to the lives of burn patients is infection. Burned skin is extremely susceptible to bacteria and other pathogens, due to the loss of protection by intact layers of skin.

Burns are sometimes measured in terms of the size of the total surface area affected. This is referred to as the “rule of nines”, which associates specific anatomical areas with a percentage that is a factor of nine (Figure 4.4.6). Burns are also classified by the degree of their severity. In Australia, burns are divided into three main categories: superficial, partial thickness, and full thickness. In other countries, such as United States, these are classified by first, second, third and fourth degree burns. Superficial burns (first-degree) appear pink or red in colour with no visible blisters, and only affect the epidermis and dermal papillae. There are no texture changes to the epidermis, however they tend to be hypersensitive to touch. Although the skin may be painful and swollen, these burns typically heal on their own within a few days. Mild sunburn fits into the category of a superficial burn.  Partial thickness burns (second-degree), sometimes referred to as mid or deep dermal burns, refer to burns in which the entire epidermal layer had been destroyed and the injury reaches the dermis. The depth to which dermal layer is injured determines whether it is classified as a mid or deep dermal burn. Generally, partial thickness burns are distinguished by a creamy coloured base. In a mid-partial burn, sweat glands and hair follicles remain undamaged, however they are affected in a deep partial thickness burn. These burns result in swelling and a painful blistering of the skin. It is important to keep the burn site clean and sterile to prevent infection. If this is done, the burn will heal within several weeks. Full thickness burns (third-degree) are classified as those in which all layers of the epidermis, epithelial elements, dermal appendages, and nerve endings are injured. These burns are distinguished by a leathery appearance which may range from a white, brown, deep red or black. Additionally, the texture of these layers appears leathery and tough. Full-thickness burns cannot be repaired by the body, because the local tissues used for repair are damaged and require excision (debridement), or amputation in severe cases, followed by grafting of the skin from an unaffected part of the body, or from skin grown in tissue culture for grafting purposes. Oddly, full thickness burns are usually not as painful because the nerve endings themselves are damaged. A fourth-degree burn is even more severe, affecting the underlying muscle and bone.

Scars and Keloids

Most cuts or wounds, with the exception of ones that only scratch the surface (the epidermis), lead to scar formation. A scar is collagen-rich skin formed after the process of wound healing that differs from normal skin. Scarring occurs in cases in which there is repair of skin damage, but the skin fails to regenerate the original skin structure. Fibroblasts generate scar tissue in the form of collagen, and the bulk of repair is due to the basket-weave pattern generated by collagen fibres and does not result in regeneration of the typical cellular structure of skin. Instead, the tissue is fibrous in nature and does not allow for the regeneration of accessory structures, such as hair follicles, sweat glands, or sebaceous glands.

Sometimes, there is an overproduction of scar tissue, because the process of collagen formation does not stop when the wound is healed; this results in the formation of a raised or hypertrophic scar called a keloid. In contrast, scars that result from acne and chickenpox have a sunken appearance and are called atrophic scars.

Scarring of skin after wound healing is a natural process and does not need to be treated further. Application of mineral oil and lotions may reduce the formation of scar tissue. However, modern cosmetic procedures, such as dermabrasion, laser treatments, and filler injections have been invented as remedies for severe scarring. All of these procedures try to reorganise the structure of the epidermis and underlying collagen tissue to make it look more natural.

Bedsores and Stretch Marks

Skin and its underlying tissue can be affected by excessive pressure. One example of this is called a bedsore. Bedsores, also called decubitis ulcers, are caused by constant, long-term, unrelieved pressure on certain body parts that are bony, reducing blood flow to the area and leading to necrosis (tissue death). Bedsores are most common in elderly patients who have debilitating conditions that cause them to be immobile. Most hospitals and long-term care facilities have the practice of turning the patients every few hours to prevent the incidence of bedsores. If left untreated by removal of necrotised tissue, bedsores can be fatal if they become infected.

The skin can also be affected by pressure associated with rapid growth. A stretch mark results when the dermis is stretched beyond its limits of elasticity, as the skin stretches to accommodate the excess pressure. Stretch marks usually accompany rapid weight gain during puberty and pregnancy. They initially have a reddish hue but lighten over time. Other than for cosmetic reasons, treatment of stretch marks is not required. They occur most commonly over the hips and abdomen.

Calluses

When you wear shoes that do not fit well and are a constant source of abrasion on your toes, you tend to form a callus at the point of contact. This occurs because the basal stem cells in the stratum basale are triggered to divide more often to increase the thickness of the skin at the point of abrasion to protect the rest of the body from further damage. This is an example of a minor or local injury, and the skin manages to react and treat the problem independent of the rest of the body. Calluses can also form on your fingers if they are subject to constant mechanical stress, such as long periods of writing, playing string instruments, or video games. A corn is a specialised form of callus. Corns form from abrasions on the skin that result from an elliptical-type motion.

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Leanne Dooley

Recall that blood is a connective tissue. Like all connective tissues, it is made up of cellular elements and an extracellular matrix. The cellular elements—referred to as the cellular components or formed elements—include red blood cells (RBCs), white blood cells (WBCs), and cell fragments called platelets. The extracellular matrix, called plasma, makes blood unique among connective tissues because it is fluid. This fluid, which is mostly water, perpetually suspends the cellular components and enables them to circulate throughout the body within the cardiovascular system.

Function of Blood

The primary function of blood is to deliver oxygen and nutrients to, and remove wastes from, body tissues and cells, but that is only the beginning of the story. The specific functions of blood also include defence, distribution of heat, and maintenance of homeostasis.

Transportation

Nutrients from the foods we eat are absorbed in the digestive tract. Most of these travel in the bloodstream directly to the liver, where they are processed and released back into the bloodstream for delivery to body cells. Oxygen from the air we breathe diffuses into the blood, which moves from the lungs to the heart, which then pumps it out to the rest of the body. Moreover, endocrine glands scattered throughout the body release their products, called hormones, into the bloodstream, which carries them to distant target cells. Blood also picks up cellular wastes and by-products and transports them to various organs for removal. For instance, blood moves carbon dioxide to the lungs for exhalation from the body, and various other waste products are transported to the kidneys and liver for excretion from the body in the form of urine or bile.

Defence

Many types of WBCs protect the body from external threats, such as disease-causing bacteria that have entered the tissues. Other WBCs seek out and destroy internal threats, such as cells with mutated DNA that could multiply to become cancerous, or body cells infected with viruses.

When damage to the blood vessels results in bleeding, blood platelets and certain proteins dissolved in the plasma, the fluid portion of the blood, interact to patch the ruptured areas of the blood vessels involved. This helps to protect the body from further blood loss and initiates the healing process.

Maintenance of Homeostasis

Recall that body temperature is regulated via a classic negative-feedback loop. If you were exercising on a warm day, your rising core body temperature would trigger several homeostatic mechanisms, including increased transport of blood from your core to your body periphery, which is typically cooler. As blood passes through the vessels of the skin, heat would be dissipated to the environment, and the blood returning to your body core would be cooler. In contrast, on a cold day, blood is diverted away from the skin to maintain a warmer body core. In extreme cases, this may result in frostbite.

Blood also helps to maintain the chemical balance of the body. For example, proteins and other compounds in blood act as pH buffers, which thereby help to regulate the pH of body fluids and cells. Blood also helps to regulate the water content of body cells and tissues.

Composition of Blood

You may have had blood drawn from a superficial vein in your arm, which was then sent to a lab for analysis. Some of the most common blood tests—for instance, those measuring lipid or glucose levels in plasma—determine which substances are present within blood and in what concentrations. Other blood tests check for the composition of the blood itself, including the quantities and types of cellular components.

One such test, called a haematocrit, measures the percentage of RBCs, clinically known as erythrocytes, in a blood sample. It is typically performed by automated analysers but can be performed by spinning the blood sample in a specialised centrifuge, a process that causes the heavier elements suspended within the blood sample to separate from the lightweight, liquid plasma (Figure 5.1.1). Because the heaviest elements in blood are the erythrocytes, these settle at the very bottom of the haematocrit tube. Located above the erythrocytes is a pale, thin layer composed of the remaining cellular components of blood. These are the WBCs, clinically known as leukocytes, and the platelets, cell fragments also called thrombocytes. This layer is referred to as the buffy coat because of its buff colour; it normally constitutes less than 1 percent of a blood sample. Above the buffy coat is the blood plasma, normally a pale, straw-coloured fluid, which constitutes the remainder of the sample.

The volume of erythrocytes after centrifugation is also commonly referred to as packed cell volume (PCV). In normal blood, about 45 percent of a sample is erythrocytes. The haematocrit of any one sample can vary significantly, between about 36 and 50 percent, according to gender and other factors. Normal haematocrit values for females range from 37 to 47, with a mean value of 41; for males, haematocrit ranges from 42 to 52, with a mean of 47. The percentage of other cellular components, the WBCs and platelets, is extremely small so it is not normally considered with the haematocrit. The mean plasma percentage is the percent of blood that is not erythrocytes: for females, it is approximately 59 (or 100 minus 41), and for males, it is approximately 53 (or 100 minus 47).

Characteristics of Blood

When you think about blood, the first characteristic that probably comes to mind is its colour. Blood that has just taken up oxygen in the lungs is bright red, and blood that has released oxygen in the tissues is a darker red colour. This is because the major component of red blood cells, a protein called haemoglobin that binds oxygen, is a pigment that changes colour depending upon the degree of oxygen saturation. Blood is viscous and somewhat sticky to the touch. It has a viscosity approximately five times greater than water. Viscosity is a measure of a fluid’s thickness or resistance to flow and is influenced by the presence of the plasma proteins and cellular components within the blood. The viscosity of blood has a dramatic impact on blood pressure and flow. Consider the difference in flow between water and honey. The more viscous honey would demonstrate a greater resistance to flow than the less viscous water. The same principle applies to blood.

The normal temperature of blood is slightly higher than normal body temperature—about 38°C (or 100.4°F), compared to 37°C (or 98.6°F) for an internal body temperature reading, although daily variations of 0.5 °C are normal. Although the surface of blood vessels is relatively smooth, as blood flows through them, it experiences some friction and resistance, especially as vessels age and lose their elasticity, thereby producing heat. This accounts for its slightly higher temperature.

The pH of blood averages about 7.4; however, it can range from 7.35 to 7.45 in a healthy person. Blood is therefore somewhat more basic (alkaline) on a chemical scale than pure water, which has a pH of 7.0. Blood contains numerous buffers, including bicarbonate, haemoglobin and proteins, that help to regulate pH.

Blood constitutes approximately eight percent of adult body weight. Adult males typically average about five to six litres of blood. Adult females average four to five litres.

Blood Plasma

Like other fluids in the body, plasma is composed primarily of water. In fact, it is about 92 percent water. Dissolved or suspended within this water is a mixture of substances, most of which are proteins. Although there are hundreds of substances dissolved or suspended in the plasma, many of them are present only in very small quantities.

Plasma Proteins

About seven percent of the volume of plasma—nearly all that is not water—is made up of proteins. These include several plasma proteins (proteins that are unique to the plasma), plus a much smaller number of regulatory proteins, including enzymes and some hormones. The major components of plasma are summarised in Figure 5.1.2.

The three major groups of plasma proteins are as follows:

1. Albumin is the most abundant of the plasma proteins. Manufactured by the liver, albumin molecules serve as binding proteins—transport vehicles for fatty acids, calcium and steroid hormones. Recall that lipids are hydrophobic; however, their binding to albumin enables their transport in the watery plasma. Albumin is also the most significant contributor to the osmotic pressure of blood; that is, its presence holds water inside the blood vessels and draws water from the tissues, across blood vessel walls, and into the bloodstream. This in turn helps to maintain both blood volume and blood pressure. Albumin normally accounts for approximately 54 percent of the total plasma protein content, in clinical levels of 35–50 g/L blood.
2. The second most common plasma proteins are the globulins. A heterogeneous group, there are three main subgroups known as alpha, beta, and gamma globulins. The alpha and beta globulins transport iron, lipids, and the fat-soluble vitamins A, D, E, and K to the cells; like albumin, they also contribute to osmotic pressure. The gamma globulins are proteins involved in immunity and are better known as an antibodies or immunoglobulins. Although other plasma proteins are produced by the liver, immunoglobulins are produced by specialised leukocytes known as plasma cells. Antibodies assist in protection against infection by binding to invading microorganisms and marking them for destruction by specialised WBCs. Globulins make up approximately 38 percent of the total plasma protein volume, in clinical levels of 10–15 g/L blood.
3. The least abundant plasma protein is fibrinogen. Like albumin and the alpha and beta globulins, fibrinogen is produced by the liver. It is essential for blood clotting, a process described later in this chapter. Fibrinogen accounts for about 7 percent of the total plasma protein volume, in clinical levels of 2–4.5 g/L blood.

Other Plasma Solutes

In addition to proteins, plasma contains a wide variety of other substances. These include various electrolytes, such as sodium, potassium, and calcium ions; dissolved gases, such as oxygen, carbon dioxide, and nitrogen; various organic nutrients, such as vitamins, lipids, glucose, and amino acids; and metabolic wastes. All these nonprotein solutes combined contribute approximately 1 percent to the total volume of plasma.

Click the drop down below to review the terms learned from this chapter.

Leanne Dooley

The lifespan of the formed elements is very brief. Although one type of leukocyte called memory cells can survive for years, most erythrocytes, leukocytes, and platelets normally live only a few hours to a few months. Thus, the body must form new blood cells and platelets quickly and continuously. When you donate a unit of blood during a blood drive (approximately 475 mL), your body typically replaces the donated plasma within 24 hours, but it takes about 4 to 6 weeks to replace the blood cells. This restricts the frequency with which donors can contribute their blood. The process by which this replacement occurs is called haemopoiesis, or haematopoiesis (from the Greek root haima- = “blood”; -poiesis = “production”).

Sites of Haemopoiesis

Prior to birth, haemopoiesis occurs in a number of tissues, beginning with the yolk sac of the developing embryo and continuing in the foetal liver, spleen, lymphatic tissue and eventually the red bone marrow. Following birth, most haemopoiesis occurs in the red marrow, a connective tissue within the spaces of spongy (cancellous) bone tissue. In children, haemopoiesis can occur in all bones including the medullary cavity of long bones; in adults, the process is largely restricted to the cranial and pelvic bones, the vertebrae, the sternum, and the proximal epiphyses of the femur and humerus.

Throughout adulthood, the liver and spleen maintain their ability to generate the formed elements. This process is referred to as extramedullary haemopoiesis (meaning haemopoiesis outside the medullary cavity of adult bones). When a disease such as bone cancer destroys the bone marrow, causing medullary haemopoiesis to fail, extramedullary haemopoiesis may be initiated.

Differentiation of Formed Elements from Stem Cells

All formed elements arise from stem cells of the red bone marrow. Recall that stem cells undergo mitosis plus cytokinesis (cellular division) to give rise to new daughter cells: One of these remains a stem cell and the other differentiates into one of any number of diverse cell types. Stem cells may be viewed as occupying a hierarchal system, with some loss of the ability to diversify at each step. The totipotent stem cell is the zygote, or fertilised egg. The totipotent (toti- = “all”) stem cell gives rise to all cells of the human body. The next level is the pluripotent stem cell, which gives rise to multiple types of cells of the body and some of the supporting foetal membranes. Beneath this level, the mesenchymal cell is a stem cell that develops only into types of connective tissue, including fibrous connective tissue, bone, cartilage, and blood, but not epithelium, muscle, and nervous tissue. One step lower on the hierarchy of stem cells is the haemopoietic stem cell, or haemocytoblast. All the formed elements of blood originate from this specific type of cell.

Haemopoiesis begins when the haemopoietic stem cell is exposed to appropriate chemical stimuli collectively called haemopoietic growth factors, which prompt it to divide and differentiate. One daughter cell remains a haemopoietic stem cell, allowing haemopoiesis to continue. The other daughter cell becomes either of two types of more specialised stem cells (Figure 5.2.1):

• Lymphoid Stem Cells, also called Common Lymphoid Progenitor Cells, give rise to a class of leukocytes known as lymphocytes, which include the various T cells, B cells, and natural killer (NK) cells, all which function in immunity. However, haemopoiesis of lymphocytes progresses somewhat differently from the process for the other formed elements. In brief, lymphoid stem cells quickly migrate from the bone marrow to lymphatic tissues, including the lymph nodes, spleen, and thymus, where their production and differentiation continues. B cells are so named since they mature in the bone marrow, while T cells mature in the thymus.
• Myeloid Stem Cells, also called Common Myeloid Progenitor Cells, give rise to all the other formed elements, including the erythrocytes; megakaryocytes that produce platelets; and a myeloblast lineage that gives rise to monocytes and three forms of granular leukocytes: neutrophils, eosinophils, and basophils.

Lymphoid and myeloid stem cells do not immediately divide and differentiate into mature formed elements. There are several intermediate stages of precursor cells, many of which can be recognised by their names, which have the suffix -blast. For instance, megakaryoblasts are the precursors of megakaryocytes, and proerythroblasts become reticulocytes, having lost their nucleus and other organelles yet retaining residual ribosomal RNA, before maturing into erythrocytes as illustrated in Figure 5.2.1.

Haemopoietic Growth Factors

Development from stem cells to precursor cells to mature cells is again initiated and controlled by haemopoietic growth factors. These include the following:

Erythropoietin (EPO) is a glycoprotein hormone secreted by the interstitial fibroblast cells of the kidneys in response to low oxygen levels. It prompts the production of haemoglobin and erythrocytes. Some athletes use synthetic EPO as a performance-enhancing drug (called blood doping) to increase RBC counts haemoglobin concentration and subsequently increase oxygen delivery to tissues throughout the body. EPO is a banned substance in most organised sports, but it is also used medically in the treatment of certain types of anaemia, specifically those triggered by certain types of cancer, and other disorders in which increased erythrocyte counts and oxygen levels are desirable.

Thrombopoietin, another glycoprotein hormone, is produced by the liver and kidneys. It triggers the production of megakaryoblasts and the development of megakaryocytes into platelets.

Cytokines are glycoproteins secreted by a wide variety of cells, including red bone marrow, leukocytes, macrophages, fibroblasts, and endothelial cells. They act locally as autocrine or paracrine factors, stimulating the proliferation of progenitor cells and helping to stimulate both nonspecific and specific resistance to disease. There are two major subtypes of cytokines known as colony-stimulating factors and interleukins.

Colony-stimulating factors (CSFs) are glycoproteins that act locally, as autocrine or paracrine factors. Some trigger the differentiation of myeloblasts into granular leukocytes, namely, neutrophils, eosinophils, and basophils. These are referred to as granulocyte CSFs. A different CSF induces the production of monocytes, called monocyte CSF. Both granulocytes and monocytes are stimulated by GM-CSF; granulocytes, monocytes, platelets, and erythrocytes are stimulated by multi-CSF. Synthetic forms of these hormones are often administered to patients, with various forms of cancer who are receiving chemotherapy, to revive their WBC counts.

Interleukins are another class of cytokine signalling molecules important in haemopoiesis. They were initially thought to be secreted uniquely by leukocytes and to communicate only with other leukocytes, and were named accordingly, but are now known to be produced by a variety of cells including bone marrow and endothelium. Researchers now suspect that interleukins may play other roles in body functioning, including differentiation and maturation of cells, producing immunity and inflammation. To date, more than a dozen interleukins have been identified, with others likely to follow. They are generally numbered IL-1, IL-2, IL-3, etc.

Everyday Connection

Blood Doping

In its original intent, the term blood doping was used to describe the practice of injecting by transfusion supplemental RBCs into an individual, typically to enhance performance in a sport. Additional RBCs would deliver more oxygen to the tissues, providing extra aerobic capacity, clinically referred to as VO2 max. The source of the cells was either from the recipient (autologous) or from a donor with compatible blood (homologous). This practice was aided by the well-developed techniques of harvesting, concentrating, and freezing of the RBCs that could be later thawed and injected, yet still retain their functionality. These practices are considered illegal in virtually all sports and run the risk of causing infection, significantly increasing the viscosity of the blood and the potential for transmission of blood-borne pathogens if the blood was collected from another individual.

With the development of synthetic EPO in the 1980s, it became possible to provide additional RBCs by artificially stimulating RBC production in the bone marrow. Originally developed to treat patients suffering from anaemia due to renal failure or cancer treatment, large quantities of EPO can be generated by recombinant DNA technology. Synthetic EPO is injected under the skin and can increase haematocrit for many weeks. It may also induce polycythaemia and raise haematocrit to 70 or greater. This increased viscosity raises the resistance of the blood and forces the heart to pump more powerfully; in extreme cases, it has resulted in death. Other drugs such as cobalt II chloride have been shown to increase natural EPO gene expression. Blood doping has become problematic in many sports, especially cycling. Lance Armstrong, winner of seven Tour de France and many other cycling titles, was stripped of his victories and admitted to blood doping in 2013.

Bone Marrow Sampling and Transplants

Sometimes, a healthcare provider will order a bone marrow biopsy, a diagnostic test of a sample of red bone marrow. This involves inserting a large-bore needle into the region near the posterior iliac crest of the pelvic bones (os coxae) and collecting an aspirate of bone marrow fluid and a core biopsy of bone marrow matrix. These samples are required for the diagnosis and differentiation of various types of leukaemia and other diseases of bone marrow.

A bone marrow (haemopoietic stem cell) transplant is a treatment in which a donor’s healthy bone marrow—and its stem cells—replaces the faulty bone marrow of a patient suffering from diseases such as aplastic anaemia, thalassaemia, sickle cell anaemia and leukaemia. This type of transplant is called an allogeneic transplant. In many cases of leukaemia, the patient’s own haemopoietic stem cells can be harvested when the patient is in remission and transferred back to the patient if the leukaemia reoccurs.  This type of transplant is called an autologous transplant.

In the past, when haemopoietic stem cells were collected from a bone marrow donor, the procedure involved harvesting the stem cells directly from the marrow as described above for bone marrow biopsy: a very invasive and painful procedure. These days, bone marrow donors are pre-treated with CSFs, which mobilise the stem cells from the bone marrow to the peripheral blood where they are easily collected via simple venepuncture. The stem cells are isolated from the other cellular components of the blood and then frozen for later use.

For an individual requiring a transplant, a donor with a matching tissue type is essential to prevent the immune system from destroying the transplanted donor cells—a phenomenon known as tissue rejection. To treat patients with haemopoietic stem cells, it is first necessary to destroy the patient’s own diseased marrow through radiation and/or chemotherapy. Donor bone marrow stem cells are then intravenously infused into the transplant recipient. From the bloodstream, they establish themselves in the recipient’s bone marrow and repopulate the marrow and the blood with healthy blood cells.

Click the drop down below to review the terms learned from this chapter.

Leanne Dooley

The erythrocyte, commonly known as a red blood cell (or RBC), is by far the most common formed element: A single drop of blood contains millions of erythrocytes and just thousands of leukocytes. Specifically, males have about 5.4 million erythrocytes per microlitre (µL) of blood, and females have approximately 4.8 million per µL. In fact, erythrocytes are estimated to make up about 25 percent of the total cells in the body. As you can imagine, they are quite small cells, with a mean diameter of only about 7–8 micrometres (µm) (Figure 5.3.1). The primary functions of erythrocytes are to pick up inhaled oxygen from the lungs and transport it to the body’s tissues, and to pick up some (about 24 percent) carbon dioxide waste at the tissues and transport it to the lungs for exhalation. Erythrocytes remain within the vascular network. Although leukocytes typically leave the blood vessels to perform their defensive functions, movement of erythrocytes from the blood vessels is abnormal.

Shape and Structure of Erythrocytes

As an erythrocyte matures in the red bone marrow, it extrudes its nucleus and most of its other organelles. During the first day or two that it is in the circulation, an immature erythrocyte, known as a reticulocyte, will still typically contain remnants of organelles. Reticulocytes should comprise approximately 1–2 percent of the erythrocyte count and provide a rough estimate of the rate of RBC production, with abnormally low or high rates indicating deviations in the production of these cells. These remnants, primarily of networks (reticulum) of ribosomes, are quickly shed, however, and mature, circulating erythrocytes have few internal cellular structural components. Lacking mitochondria, for example, they rely on anaerobic respiration. This means that they do not utilise any of the oxygen they are transporting, so they can deliver it all to the tissues. They also lack endoplasmic reticula and do not synthesise proteins. Erythrocytes do, however, contain some structural proteins that help the blood cells maintain their unique structure and enable them to change their shape to squeeze through capillaries. This includes the protein spectrin, a cytoskeletal protein element. They also contain enzymes that protect haemoglobin from oxidisation.

Erythrocytes are biconcave disks; that is, they are plump at their periphery and very thin in the centre (Figure 5.3.2). Since they lack most organelles, there is more interior space for the presence of the haemoglobin molecules that, as you will see shortly, transport gases. The biconcave shape also provides a greater surface area across which gas exchange can occur, relative to its volume; a sphere of a similar diameter would have a lower surface area-to-volume ratio. In the capillaries, the oxygen carried by the erythrocytes can diffuse into the plasma and then through the capillary walls to reach the cells, whereas some of the carbon dioxide produced by the cells as a waste product diffuses into the capillaries to be picked up by the erythrocytes. Capillary beds are extremely narrow, slowing the passage of the erythrocytes and providing an extended opportunity for gas exchange to occur. However, the space within capillaries can be so minute that, despite their own small size, erythrocytes may have to fold in on themselves if they are to make their way through. Fortunately, their structural proteins like spectrin are flexible, allowing them to bend over themselves to a surprising degree, then spring back again when they enter a wider vessel. In wider vessels, erythrocytes may stack up much like a roll of coins, forming a rouleaux, from the French word for “roll.”

Haemoglobin

Haemoglobin is a large molecule made up of proteins and iron. It consists of four folded chains of a protein called globin, designated alpha 1 and 2, and beta 1 and 2 (Figure 5.3.3a). Each of these globin molecules is bound to a red pigment molecule called haem, which contains an ion of iron (Fe2+) (Figure 5.3.3b).

Each iron ion in the haem can bind to one oxygen molecule; therefore, each haemoglobin molecule can transport four oxygen molecules. An individual erythrocyte may contain about 300 million haemoglobin molecules and therefore can bind to and transport up to 1.2 billion oxygen molecules (see Figure 5.3.3b).

In the lungs, haemoglobin picks up oxygen, which binds to the iron ions, forming oxyhaemoglobin. The bright red, oxygenated haemoglobin travels to the body tissues, where it releases some of the oxygen molecules, becoming darker red deoxyhemoglobin, sometimes referred to as reduced haemoglobin. Oxygen release depends on the need for oxygen in the surrounding tissues, so haemoglobin rarely if ever leaves all its oxygen behind. In the capillaries, carbon dioxide enters the bloodstream. About 76 percent dissolves in the plasma, some of it remaining as dissolved CO2, and the remainder forming bicarbonate ion. About 23–24 percent of it binds to the amino acids in haemoglobin, forming a molecule known as carbaminohemoglobin. From the capillaries, the haemoglobin carries carbon dioxide back to the lungs, where it releases it for exchange of oxygen.

Changes in the levels of RBCs can have significant effects on the body’s ability to effectively deliver oxygen to the tissues. Ineffective haematopoiesis results in insufficient numbers of RBCs and results in one of several forms of anaemia. An overproduction of RBCs produces a condition called polycythaemia. The primary drawback with polycythaemia is not a failure to directly deliver enough oxygen to the tissues, but rather the increased viscosity of the blood, which makes it more difficult for the heart to circulate the blood and increases the risk of thrombosis (excessive blood clot formation).

In patients with insufficient haemoglobin, the tissues may not receive sufficient oxygen, resulting in another form of anaemia. In determining oxygenation of tissues, the value of greatest interest in healthcare is the percent saturation; that is, the percentage of haemoglobin sites occupied by oxygen in a patient’s blood. Clinically this value is commonly referred to simply as “percent sat.”

Percent saturation is normally monitored using a device known as a pulse oximeter, which is applied to a thin part of the body, typically the tip of the patient’s finger. The device works by sending two different wavelengths of light (one red, the other infrared) through the finger and measuring the light with a photodetector as it exits. Haemoglobin absorbs light differentially depending upon its saturation with oxygen. The machine calibrates the amount of light received by the photodetector against the amount absorbed by the partially oxygenated haemoglobin and presents the data as percent saturation. Normal pulse oximeter readings range from 95–100 percent. Lower percentages reflect hypoxaemia, or low blood oxygen. The term hypoxia is more generic and simply refers to low oxygen levels. Oxygen levels are also directly monitored from free oxygen in the plasma typically following an arterial stick. When this method is applied, the amount of oxygen present is expressed in terms of partial pressure of oxygen or simply pO2 and is typically recorded in units of millimetres of mercury, mm Hg.

The kidneys filter about 180 litres (~380 pints) of blood in an average adult each day and thus serve as ideal sites for receptors that determine oxygen saturation. In response to hypoxaemia, less oxygen will exit the vessels supplying the kidney, resulting in hypoxia (low oxygen concentration) in the tissue fluid of the kidney where oxygen concentration is monitored. Interstitial fibroblasts within the kidney secrete EPO, thereby increasing erythrocyte and haemoglobin production and restoring oxygen levels. In a classic negative-feedback loop, as oxygen saturation rises, EPO secretion falls, and vice versa, thereby maintaining homeostasis. Populations dwelling at high altitudes, with inherently lower levels of oxygen in the atmosphere, naturally maintain a haematocrit higher than people living at sea level. Consequently, people traveling to high altitudes may experience symptoms of hypoxaemia, such as fatigue, headache, and shortness of breath, for a few days after their arrival. In response to the hypoxaemia, the kidneys secrete EPO to step up the production of erythrocytes until homeostasis is achieved once again. To avoid the symptoms of hypoxaemia, or altitude sickness, mountain climbers typically rest for several days to a week or more at a series of camps situated at increasing elevations to allow EPO levels and, consequently, erythrocyte counts to rise. When climbing the tallest peaks, such as Mt. Everest and K2 in the Himalayas, many mountain climbers rely upon bottled oxygen as they near the summit.

Lifecycle of Erythrocytes

Production of erythrocytes in the marrow occurs at the staggering rate of more than 2 million cells per second. For this production to occur, several raw materials must be present in adequate amounts. These include the same nutrients that are essential to the production and maintenance of any cell, such as glucose, lipids, and amino acids. However, erythrocyte production also requires several micronutrients including trace elements and vitamins:

• Iron. We have said that each haem group in a haemoglobin molecule contains an ion of the trace mineral iron. On average, less than 20 percent of the iron we consume is absorbed. Haem iron, from animal foods such as meat, poultry, and fish, is absorbed more efficiently than non-haem iron from plant foods. Upon absorption, iron becomes part of the body’s total iron pool. The bone marrow, liver, and spleen can store iron in the protein compounds ferritin and haemosiderin. Ferroprotein transports the iron across the intestinal cell plasma membranes and from its storage sites into tissue fluid where it enters the blood. When EPO stimulates the production of erythrocytes, iron is released from storage, bound to transferrin, and carried to the red marrow where it attaches to erythrocyte precursors.
• Copper. A trace mineral, copper is a component of two plasma proteins, hephaestin and ceruloplasmin. Without these, haemoglobin could not be adequately produced. Located in intestinal villi, hephaestin enables iron to be absorbed by intestinal cells. Ceruloplasmin transports copper. Both enable the oxidation of iron from Fe²⁺to Fe³⁺, a form in which it can be bound to its transport protein, transferrin, for transport to body cells. In a state of copper deficiency, the transport of iron for haem synthesis decreases, and iron can accumulate in tissues, where it can eventually lead to organ damage.
• Zinc. The trace mineral zinc functions as a co-enzyme that facilitates the synthesis of the haem portion of haemoglobin.
• B vitamins. The B vitamins folate and vitamin B12 function as co-enzymes that facilitate DNA synthesis. Thus, both are critical for the synthesis of new cells, including erythrocytes.

Erythrocytes live up to 120 days in the circulation, after which the worn-out cells are removed by a type of myeloid phagocytic cell called a macrophage, located primarily within the bone marrow, liver, and spleen. The components of the degraded erythrocytes’ haemoglobin are further processed as follows:

Globin, the protein portion of haemoglobin, is broken down into amino acids, which can be sent back to the liver for construction of new proteins.

The iron contained in the haem portion of haemoglobin may be stored in the liver or spleen, primarily in the form of ferritin or hemosiderin, or carried through the bloodstream by transferrin to the red bone marrow for recycling into new erythrocytes.

The non-iron portion of haem is degraded into the waste product biliverdin, a green pigment, and then into another waste product, bilirubin, a yellow pigment. Bilirubin binds to albumin and travels in the blood to the liver, which excretes it in bile, a fluid released into the intestines to help emulsify dietary fats. In the large intestine, bacteria break the bilirubin apart from the bile and convert it to urobilinogen and then into stercobilin. It is then eliminated from the body in the faeces. Broad-spectrum antibiotics typically eliminate these “good” bacteria as well and this may alter the colour of faeces. The kidneys also remove any circulating bilirubin and other related metabolic by-products such as urobilins and secrete them into the urine.

The breakdown pigments formed from the destruction of haemoglobin can be seen in a variety of situations. At the site of an injury, biliverdin from damaged RBCs produces some of the dramatic colours associated with bruising. With a failing liver, bilirubin cannot be removed effectively from circulation and causes the body to assume a yellowish tinge associated with jaundice. Stercobilins within the faeces produce the typical brown colour associated with this waste and the yellow of urine is associated with the urobilins.

The erythrocyte lifecycle is summarised in Figure 5.3.4.

Disorders of Erythrocytes

The size, shape, and number of erythrocytes, and the number of haemoglobin molecules can have a major impact on a person’s health. When the number of RBCs or amount of haemoglobin is deficient, the general condition is called anaemia. There are more than 400 types of anaemia and approximately 4.5% of Australian adults are at risk of anaemia. Anaemia can be broken down into three major groups: those caused by blood loss, those caused by faulty or decreased RBC production, and those caused by excessive destruction of RBCs. Clinicians often use two groupings in diagnosis: The kinetic approach focuses on evaluating the production, destruction, and removal of RBCs, whereas the morphological approach examines the RBCs themselves, paying particular emphasis to their size. A common test is the mean cell volume (MCV), which measures RBC size. Normal-sized cells are referred to as normocytic, smaller-than-normal cells are referred to as microcytic, and larger-than-normal cells are referred to as macrocytic. Reticulocyte counts are also important and may reveal inadequate production of RBCs. The effects of the various anaemias are widespread, because reduced numbers of RBCs or haemoglobin will result in lower levels of oxygen being delivered to body tissues. Since oxygen is required for tissue functioning, anaemia produces fatigue, lethargy, and an increased risk for infection. An oxygen deficit in the brain impairs the ability to think clearly and may prompt headaches and irritability. Lack of oxygen leaves the patient short of breath, even as the heart and lungs work harder in response to the deficit.

Anaemias resulting from acute blood loss are usually easy to identify. In addition to bleeding from external wounds or other visible lesions, blood loss anaemias may be due to chronic bleeding from ulcers, haemorrhoids, inflammation of the stomach (gastritis) and some cancers of the gastrointestinal tract. The excessive use of aspirin or other nonsteroidal anti-inflammatory drugs such as ibuprofen can trigger ulceration and gastritis leading to chronic blood loss. Excessive menstruation and loss of blood during childbirth are also potential causes of anaemia.

Anaemias caused by faulty or decreased RBC production include sickle cell anaemia, iron deficiency, vitamin deficiency anaemia and diseases of the bone marrow and stem cells.

A characteristic change in the shape of erythrocytes is seen in sickle cell disease (also referred to as sickle cell anaemia).  Sickle cell anaemia is caused by production of an abnormal type of haemoglobin, called haemoglobin S, which delivers less oxygen to tissues and causes erythrocytes to assume a sickle (or crescent) shape, especially at low oxygen concentrations (Figure 5.3.5). These abnormally shaped cells can then become lodged in narrow capillaries because they are unable to fold in on themselves to squeeze through, blocking blood flow to tissues and causing a variety of serious problems from painful joints to delayed growth and even blindness and cerebrovascular accidents (strokes). Sickle cell anaemia is a genetic or inherited blood disorder more commonly found in individuals of African, Middle Eastern, Asian, Indian and Mediterranean descent.

Iron deficiency anaemia is the most common type of anaemia and results when the amount of available iron is insufficient to allow production of sufficient haemoglobin. This condition can occur in individuals with a deficiency of iron in the diet and is especially common in teens and children as well as in vegans and vegetarians. Additionally, iron deficiency anaemia may be caused by either an inability to absorb and transport iron, or slow chronic bleeding usually from the gastrointestinal tract or through heavy menstruation.

Vitamin-deficient anaemias generally involve insufficient vitamin B12 and folate.

Megaloblastic anaemia is the result of a deficiency of vitamin B12 and/or folate, and often involves diets deficient in these essential nutrients. Lack of animal products or viable alternate sources in the diet can lead to a lack of vitamin B12 and overcooking or eating insufficient amounts of vegetables may lead to a lack of folate.

Pernicious anaemia is a type of megaloblastic anaemia caused by poor absorption of vitamin B12 and is often seen in patients with Crohn’s disease (a severe intestinal disorder often treated by surgery), surgical removal of the intestines or stomach (common in some weight loss surgeries), the presence of intestinal parasites and AIDS.

Pregnancies, some medications, excessive alcohol consumption, and some diseases such as coeliac disease are also associated with vitamin deficiencies. It is essential to provide sufficient folic acid during the early stages of pregnancy to reduce the risk of neurological defects, including spina bifida, a failure of the neural tube to close.

Assorted disease processes can also interfere with the production and formation of RBCs and haemoglobin. If myeloid stem cells are defective or replaced by cancer cells, there will be insufficient quantities of RBCs produced.

Aplastic anaemia is the condition in which there are deficient numbers of RBC stem cells. Aplastic anaemia is often inherited, or it may be triggered by radiation, medication, chemotherapy, or infection, particularly by Parvo virus B19.

Thalassaemia is an inherited condition typically occurring in individuals from the Middle East, the Mediterranean, Africa, and Southeast Asia, in which the lifespan of RBCs is shortened due to unbalanced production of globin chains.

Hereditary spherocytosis is another inherited form of anaemia associated with shortened RBC survival. In this case the spectrin in the RBC membrane is defective resulting in loss of membrane without loss of cell contents as the cells circulate through small capillaries. This change in the surface area to volume ratio causes the RBCs to lose their bi-concave disc shape and become spherical (spherocytes). Spherocytes are less flexible than normal RBC and become trapped in the spleen, where they are removed by splenic macrophages.

Lead exposure from industrial sources or even dust from paint chips of iron-containing paints or pottery that has not been properly glazed may also lead to destruction of the red marrow.

Various disease processes can also lead to anaemias. These include chronic kidney diseases often associated with decreased production of EPO, hypothyroidism, some forms of cancer, especially leukaemia and bone cancers, and autoimmune diseases such as lupus, and rheumatoid arthritis.

In contrast to anaemia, an elevated RBC count is called polycythaemia and is detected in a patient’s elevated haematocrit. It can occur transiently in a person who is dehydrated; when water intake is inadequate or water losses are excessive, the plasma volume falls. As a result, the haematocrit rises. For reasons mentioned earlier, a mild form of polycythaemia is chronic but normal in people living at high altitudes. Some elite athletes train at high altitudes specifically to induce this phenomenon. Finally, a type of bone marrow disease called polycythaemia vera (from the Greek vera = “true”) causes an excessive production of immature erythrocytes. Polycythaemia vera can dangerously elevate the viscosity of blood, raising blood pressure and making it more difficult for the heart to pump blood throughout the body. It is a relatively rare disease that occurs more often in men than women and is more likely to be present in people over 60 years of age.

Click the drop down below to review the terms learned from this chapter.

Leanne Dooley

The leukocyte, commonly known as a white blood cell (or WBC), is a major component of the body’s defences against disease. Leukocytes protect the body against invading microorganisms and body cells with mutated DNA, and they clean up debris. Platelets are essential for the repair of damaged blood vessels; they also provide growth factors for healing and repair.

Characteristics of Leukocytes

Although leukocytes and erythrocytes both originate from hematopoietic stem cells in the bone marrow, they are very different from each other in many significant ways. For instance, leukocytes are far less numerous than erythrocytes: Typically, there are only 5000 to 10,000 per µL. They are also larger than erythrocytes and are the only formed elements that are complete cells, possessing a nucleus and organelles. And although there is just one type of erythrocyte, there are many types of leukocytes. Most of these types have a much shorter lifespan than that of erythrocytes, some as short as a few hours or even a few minutes in the case of cells responding to acute infection.

One of the most distinctive characteristics of leukocytes is their movement. Whereas erythrocytes spend their days circulating within the blood vessels, leukocytes routinely leave the bloodstream to perform their defensive functions in the body’s tissues. For leukocytes, the vascular network is simply a highway they travel and soon exit to reach their true destination. When they arrive, they are often given distinct names, such as macrophage or microglia, depending on their function. As shown in Figure 5.4.1, they leave the capillaries—the smallest blood vessels—or other small vessels through a process known as emigration (from the Latin for “removal”) or diapedesis (dia- = “through”; -pedan = “to leap”) or extravasation (extra = “outside”; vas = “vessel”) in which they squeeze through adjacent cells in a blood vessel wall.

Once they have exited the capillaries, some leukocytes will take up fixed positions in lymphatic tissue, bone marrow, the spleen, the thymus, liver or other organs. Others will move about through the tissue spaces very much like amoebas, continuously extending their plasma membranes, sometimes wandering freely, and sometimes moving toward the direction in which they are drawn by chemical signals. This attracting of leukocytes occurs because of positive chemotaxis (movement in response to chemicals), a phenomenon in which injured or infected cells and nearby leukocytes emit the equivalent of a chemical “000” (or “911” in U.S.A) call, attracting more leukocytes to the site.

Classification of Leukocytes

When scientists first began to observe stained blood slides, it quickly became evident that leukocytes could be divided into two groups, according to whether their cytoplasm contained highly visible granules:

Granular leukocytes, or granulocytes, contain abundant granules within the cytoplasm. They include neutrophils, eosinophils, and basophils.

While granules are not totally lacking in agranular leukocytes, they are far fewer and less obvious on stained blood slides. Agranular leukocytes include monocytes, which mature into macrophages that are phagocytic, and lymphocytes, which arise from the lymphoid stem cell line.

Granular Leukocytes

We will consider the granular leukocytes in order from most common to least common. All of these are produced in the red bone marrow and have a short lifespan of hours to days. They typically have a lobed nucleus and are classified according to which type of stain best highlights their granules (Figure 5.4.2).

The most common of all the leukocytes, neutrophils will normally comprise 50–70 percent of the total leukocyte count. They are 10–12 µm in diameter, significantly larger than erythrocytes. They are called neutrophils because their granules show up most clearly with stains that are chemically neutral (neither acidic nor basic). The granules are numerous but quite fine and normally appear light lilac. The nucleus has a distinct lobed appearance and may have two to five lobes, the number increasing with the age of the cell. Older neutrophils have increasing numbers of lobes and are often referred to as polymorphonuclear (a nucleus with many forms), or simply “polys.” Younger and immature neutrophils begin to develop lobes and are known as “bands.”

Neutrophils are rapid responders to the site of infection and are efficient phagocytes with a preference for bacteria. Their granules contain lysozyme, an enzyme capable of lysing, or breaking down, bacterial cell walls; oxidants such as hydrogen peroxide; and defensins, proteins that bind to and puncture bacterial and fungal plasma membranes, so that the cell contents leak out. Abnormally high counts of neutrophils indicate infection and/or inflammation, particularly triggered by bacteria, but are also found in burn patients and others experiencing unusual stress. A burn injury increases the proliferation of neutrophils in order to fight off infection that can result from the destruction of the barrier of the skin. Low counts may be caused by drug toxicity and other disorders, including leukaemia and bone marrow failure, and may increase an individual’s susceptibility to infection.

Eosinophils typically represent 2–4 percent of the total leukocyte count. They are also 10–12 µm in diameter. The granules of eosinophils stain best with an acidic stain known as eosin. The nucleus of the eosinophil will typically have two to three lobes and, if stained properly, the granules will have a distinct red to orange colour.

The granules of eosinophils contain antihistamine molecules, which counteract the activities of histamines, inflammatory chemicals produced by basophils and mast cells. Some eosinophil granules contain molecules toxic to parasitic worms, which can enter the body through the integument, or when an individual consumes raw or undercooked fish or meat. Eosinophils are also capable of phagocytosis and are particularly effective when antibodies bind to the target and form an antigen-antibody complex. High counts of eosinophils are associated with allergies, parasitic worm infestations, and some autoimmune diseases. Low counts may be due to drug toxicity and stress.

Basophils are the least common leukocytes, typically comprising less than one percent of the total leukocyte count. They are slightly smaller than neutrophils and eosinophils at 8–10 µm in diameter. The granules of basophils stain best with basic (alkaline) stains. Basophils contain large granules that pick up a dark blue stain and are so dark and numerous they may make it difficult to see the two-lobed nucleus.

In general, basophils intensify the inflammatory response. They share this trait with mast cells. In the past, mast cells were considered to be basophils that had left the circulation. However, this appears not to be the case, as the two cell types develop from different lineages.

The granules of basophils release histamines, which contribute to inflammation, and heparin, which opposes blood clotting. High counts of basophils are associated with allergies, parasitic infections, and hypothyroidism. Low counts are associated with pregnancy, stress, and hyperthyroidism.

Agranular Leukocytes

Agranular leukocytes contain smaller, less-visible granules in their cytoplasm than do granular leukocytes. The nucleus is simple in shape, sometimes with an indentation but without distinct lobes. There are two major types of agranulocytes: lymphocytes and monocytes.

Lymphocytes are the only formed element of blood that arises from lymphoid stem cells. Although they form initially in the bone marrow, much of their subsequent development and proliferation occurs in the lymphatic tissues. Lymphocytes are the second most common type of leukocyte, accounting for about 20–30 percent of all leukocytes, and are essential for the immune response. The size range of lymphocytes is quite extensive, with some authorities recognising two size classes and others three. Typically, the large cells are 10–14 µm and have a smaller nucleus-to-cytoplasm ratio and more obvious granules. The smaller cells, referred to as “small resting lymphocytes” or “naive lymphocytes” are typically 6–9 µm with a larger volume of nucleus to cytoplasm. A few cells may fall outside these ranges, at 14–17 µm. This finding has led to the three size range classification.

The three major groups of lymphocytes include natural killer cells, B cells, and T cells. Natural killer (NK) cells are capable of recognising cells that do not express “self” proteins on their plasma membrane or that contain foreign or abnormal markers. These “non-self” cells include cancer cells, cells infected with a virus, and other cells with atypical surface proteins. Thus, they provide generalised, nonspecific immunity. The larger more granular lymphocytes are typically NK cells.

B cells and T cells, also called B lymphocytes and T lymphocytes, play prominent roles in defending the body against specific pathogens (disease-causing microorganisms) and are involved in specific immunity. One form of B cells (plasma cells) produces the antibodies or immunoglobulins that bind to specific foreign or abnormal components of plasma membranes. These B cells and the antibodies they produce form part of the immune response referred to as humoral (body fluid) immunity. T cells provide cell-mediated immunity by physically attacking foreign or diseased cells. A memory cell is a variety of both B and T cells that develops after exposure to a pathogen and mounts rapid responses upon subsequent exposures to the same pathogen. Unlike other leukocytes, memory cells live for many years. B cells undergo a maturation process in the bone marrow, whereas T cells undergo maturation in the thymus. This site of the maturation process gives rise to the name B and T cells. The functions of lymphocytes are complex and will be covered in detail in the chapter covering the lymphatic system and immunity. Smaller lymphocytes are either B or T cells that have not yet encountered a foreign invader, although they cannot be differentiated in a normal blood smear.

Abnormally high lymphocyte counts are characteristic of viral infections and Bordetella pertussis (Whooping cough) as well as some types of cancer, particularly lymphomas. Abnormally low lymphocyte counts are characteristic of prolonged (chronic) illness or immunosuppression, including that caused by HIV infection and drug therapies that often involve steroids.

Monocytes originate from myeloid stem cells. They normally represent 2–8 percent of the total leukocyte count. They are typically easily recognised by their large size of 12–20 µm and indented or horseshoe-shaped nuclei. Macrophages are monocytes that have left the circulation and they phagocytose debris, foreign pathogens, aged or damaged erythrocytes, and many other dead, worn out, or damaged cells. Macrophages also release antimicrobial defensins and chemotactic chemicals that attract other leukocytes to the site of an infection or tissue damage. Some macrophages occupy fixed locations, whereas others wander through the tissue fluid.

Abnormally high counts of monocytes are associated with viral or fungal infections, tuberculosis, and some forms of leukaemia and other chronic diseases. Abnormally low counts are typically caused by suppression of the bone marrow. Figure 5.4.4 illustrates the five main types of circulating leukocytes. In clinical medicine, the differential counts of the types and percentages of leukocytes present in a blood sample are often key indicators in making a diagnosis and selecting a treatment.

Lifecycle of Leukocytes

Most leukocytes have a relatively short lifespan, typically measured in hours or days. Production of all leukocytes begins in the bone marrow under the influence of CSFs and interleukins. Secondary production and maturation of lymphocytes occurs in specific regions of lymphatic tissue known as germinal centres. Lymphocytes are fully capable of mitosis and may produce clones of cells with identical properties. This capacity enables an individual to maintain immunity throughout life to many threats that have been encountered in the past.

Disorders of Leukocytes

Leukopenia is a condition in which too few leukocytes are produced. Leukopenic individuals may be unable to ward off infectious diseases. Excessive leukocyte proliferation is known as leukocytosis. Leukocytosis is often an indicator of the presence of infection or inflammation.

Leukaemia is a cancer involving over production of abnormal leukocytes. It usually involves only one specific type of leukocyte from either the myeloid line (myeloid leukaemia) or the lymphoid line (lymphocytic leukaemia). In chronic leukaemia, mature leukocytes accumulate and fail to die. In acute leukaemia, there is an overproduction of abnormal immature leukocytes. Both conditions arise from a genetic mutation in a single cell and in both conditions the cells do not function properly.

Lymphoma is a form of cancer in which masses of malignant T and/or B lymphocytes collect in lymph nodes, the spleen, the liver and other tissues. As in leukaemia, the malignant leukocytes do not function properly, and the patient is vulnerable to infection. Some forms of lymphoma tend to progress slowly and respond well to treatment. Others tend to progress quickly and require aggressive treatment, without which they are rapidly fatal.

Platelets

You may occasionally see platelets referred to as thrombocytes, but because this name suggests they are a type of cell, it is not accurate. A platelet is not a cell but rather a fragment of the cytoplasm of a cell called a megakaryocyte that is surrounded by a plasma membrane. Megakaryocytes are descended from myeloid stem cells and are large, typically 50–100 µm in diameter, and contain an enlarged, multi-lobed nucleus. As noted earlier, thrombopoietin, a glycoprotein secreted by the kidneys and liver, stimulates the proliferation of megakaryoblasts, which mature into megakaryocytes. These remain within bone marrow tissue and ultimately form platelet-precursor extensions that extend through the walls of bone marrow capillaries to release into the circulation thousands of cytoplasmic fragments, each enclosed in a plasma membrane. These enclosed fragments are platelets. Each megakaryocyte releases 2000–3000 platelets during its lifespan. Following platelet release, megakaryocyte remnants, which are little more than a cell nucleus, are consumed by macrophages. The process of platelet production, thrombopoiesis, is summarised in figure 5.4.4.

Platelets are relatively small, 2–4 µm in diameter, but numerous, with typically 150,000–160,000 per µL of blood. After entering the circulation, approximately one-third migrate to the spleen for storage for later release in response to any rupture in a blood vessel. When a blood vessel is damaged, platelets become activated to perform their primary function, which is to limit blood loss. Platelets remain in the circulation for only about 10 days and are then phagocytosed by macrophages.

In addition to their critical role in haemostasis, the stoppage of blood loss following damage to a blood vessel. Platelets also secrete a variety of growth factors essential for growth and repair of tissue, particularly connective tissue. Infusions of concentrated platelets are now being used in some therapies to stimulate healing. Platelet rich plasma injections are also used by beauty therapists to “reinvigorate” the skin of their clients.

Disorders of Platelets

Thrombocytosis is a condition in which there are too many platelets. This may trigger formation of unwanted blood clots (thrombosis), a potentially fatal disorder. If there is an insufficient number of platelets, called thrombocytopenia, blood may not clot properly, and excessive bleeding may result. Inherited and acquired disorders of platelet function can also lead to excessive bleeding despite normal platelet numbers.

Click the drop down below to review the terms learned from this chapter.

Leanne Dooley

Platelets are key players in haemostasis, the process by which the body seals a ruptured blood vessel and prevents further loss of blood. Although rupture of larger vessels usually requires medical intervention, haemostasis is quite effective in dealing with small, simple wounds and small internal bleeds. There are three steps to the process: vascular spasm, the formation of a platelet plug, and coagulation (blood clotting). Failure of any of these steps will result in haemorrhage—excessive bleeding. The vascular response and platelet plug formation are referred to as primary haemostasis and coagulation is referred to a secondary haemostasis.

Vascular Spasm

When a blood vessel is severed or punctured, or when the wall of a vessel is damaged, vascular spasm occurs. In vascular spasm, the smooth muscle in the walls of the vessel contracts dramatically. This smooth muscle has both circular layers; larger vessels also have longitudinal layers. The circular layers tend to constrict, which narrows the vessel lumen, and slows the flow of blood. The longitudinal layers, when present, draw the vessel back into the surrounding tissue, often making it more difficult for a surgeon to locate, clamp, and tie off a severed vessel. The vascular spasm response is believed to be triggered by several chemicals called endothelins that are released by vessel-lining (endothelial) cells and by pain receptors in response to vessel injury. This phenomenon typically lasts for up to 30 minutes, although it can last for hours.

Formation of the Platelet Plug

In the second step, platelets, which normally float free in the plasma, encounter exposed underlying connective tissue and collagenous fibres at the site of blood vessel damage. The platelets bind (adhesion) to the exposed collagen and become activated. Activated platelets are spiked and sticky and bind to other activated platelets (aggregation) and the endothelial lining. Platelet adhesion is assisted by a glycoprotein released from neighbouring endothelial cells called von Willebrand factor, which helps stabilise the growing platelet plug. Platelet aggregation is aided by the plasma protein, fibrinogen, which forms bridges between adjacent platelets at the site of bleed vessel damage. As platelets collect, they simultaneously release chemicals from their granules into the plasma that further contribute to haemostasis. Among the substances released by the platelets are:

• adenosine diphosphate (ADP), which helps additional platelets to adhere to the injury site, reinforcing and expanding the platelet plug
• serotonin, which maintains vasoconstriction
• prostaglandins and phospholipids, which also maintain vasoconstriction and help to activate further clotting chemicals, as discussed next
• Von Willebrand factor which aids in the adhesion of platelets to exposed collagen

A platelet plug can temporarily seal a small opening in a blood vessel. Plug formation, in essence, buys the body time while more sophisticated and durable repairs are being made. In a similar manner, even modern naval warships still carry an assortment of wooden plugs to temporarily repair small breaches in their hulls until permanent repairs can be made.

Coagulation

Those more sophisticated and more durable repairs are collectively called coagulation, the formation of a blood clot. The process is sometimes characterised as a cascade, because one event prompts the next as in a multi-level waterfall. The result is the production of a gelatinous but robust clot made up of a mesh of fibrin—an insoluble filamentous protein derived from fibrinogen, the plasma protein introduced earlier—in which platelets and blood cells are trapped. Figure 5.5.1 summarises the three steps of haemostasis.

Clotting Factors Involved in Coagulation

In the coagulation cascade, plasma proteins called clotting factors (or coagulation factors) prompt reactions that activate still more coagulation factors. The process is complex, but is initiated along two basic pathways:

• The extrinsic pathway, which is triggered when clotting factors come into contact with substances outside of the blood vessel.
• The intrinsic pathway, which is triggered when clotting factors come into contact with substances inside the blood vessel.

Both of these pathways merge into a third pathway, referred to as the common pathway (see Figure 5.5.1b). All three pathways are dependent upon the 12 known clotting factors, including Ca2+ and vitamin K (Table 5.5.1). Clotting factors are secreted as inactive enzymes primarily by the liver and the platelets. The liver requires the fat-soluble vitamin K to produce many of them. Vitamin K (along with biotin and folate) is somewhat unusual among vitamins in that it is not only consumed in the diet but is also synthesised by bacteria residing in the large intestine. The calcium ion, considered factor IV, is derived from the diet and from the breakdown of bone. Some recent evidence indicates that activation of various clotting factors occurs on specific receptor sites on the surfaces of activated platelets.

The 12 clotting factors are numbered I through XIII according to the order of their discovery. Factor VI was once believed to be a distinct clotting factor, but is now thought to be identical to factor V. Rather than renumber the other factors, factor VI was allowed to remain as a placeholder and also a reminder that knowledge changes over time. Activated factors are denoted by the additions of the letter “a” after the factor number. For example, factor Va denotes activated factor five.

Table 5.5.1. Clotting factors

*Vitamin K Required

Extrinsic Pathway

The quicker responding and more direct extrinsic pathway (also known as the tissue factor pathway) begins when damage occurs to the surrounding tissues, such as in a traumatic injury. Damaged extravascular cells, which are extrinsic to the bloodstream, express factor III, also known as tissue factor or thromboplastin. When factor VII in the plasma comes into contact with exposed factor III, it becomes activated to factor VIIa. Factor VIII, Factor VIIa and Ca2+ then form an active enzyme complex. This enzyme complex leads to activation of factor X (Stuart–Prower Factor), which activates the common pathway discussed below. The events in the extrinsic pathway are completed in a matter of seconds.

Intrinsic Pathway

The intrinsic pathway (also known as the contact activation pathway) is longer and more complex. In this case, the factors involved are intrinsic to (present within) the bloodstream. The pathway can be prompted by damage to the tissues, resulting from internal factors such as arterial disease; however, it is most often initiated when factor XII (Hageman factor) comes into contact with negatively charged molecules, such as phospholipids expressed on the surface of activated platelets. Factor XII can also be activated by contact with foreign materials such as artificial heart valves and the surface of some bacteria. Factor XII is also activated when blood comes into contact with glass, in a test tube for example. Factor XIIa sets off a series of reactions that in turn activates factor XI (plasma thromboplastin antecedent) then factor IX (antihemophilic factor B or plasma thromboplasmin). In the meantime, substances released by the platelets increase the rate of these activation reactions. Finally, factor IXa binds to its cofactor, factor VIII (antihemophilic factor A) to form an enzyme complex that activates factor X (Stuart-Prower Factor or thrombokinase), leading to the common pathway. The events in the intrinsic pathway are completed in a few minutes.

Common Pathway

Both the intrinsic and extrinsic pathways lead to the common pathway, in which fibrin is produced to seal off the vessel. Once factor X has been activated to become the enzyme prothrombinase (factor Xa) by either the intrinsic or extrinsic pathway, it converts factor II, the inactive enzyme prothrombin, into the active enzyme thrombin. (Note that if the enzyme thrombin were not normally in an inactive form, clots would form spontaneously, a condition not consistent with life.) Then, thrombin converts factor I, the soluble plasma protein fibrinogen, into the insoluble protein fibrin protein strands. Fibrin molecules spontaneously join together to form a mesh, which is stabilised by cross-linking reactions catalysed by Factor XIIIa.

Fibrinolysis

The stabilised clot undergoes contraction via the action of contractile proteins within platelets. As these proteins contract, they pull on the fibrin threads, bringing the edges of the clot more tightly together, somewhat as we do when tightening loose shoelaces. This process also wrings out of the clot a small amount of fluid called serum, which is blood plasma without its clotting factors.

To restore normal blood flow as the vessel heals, the clot must eventually be removed. The process by which the clot is gradually degraded is called fibrinolysis. Like coagulation, fibrinolysis involves a fairly complicated series of protein catabolising reactions. During this process, the inactive protein plasminogen, released by endothelial cells around the site of blood vessel damage, is converted into the active enzyme plasmin, which gradually breaks down the fibrin of the clot. Additionally, bradykinin, a vasodilator, released from damaged tissues as a pain signal, reverses the effects of the serotonin and prostaglandins secreted by the platelets. This allows the smooth muscle in the walls of the vessels to relax and helps to restore the circulation.

Plasma Anticoagulants

An anticoagulant is any substance that opposes coagulation. Several circulating plasma anticoagulants play a role in limiting the coagulation process to the region of injury and restoring a normal, clot-free condition of blood. For instance, a cluster of proteins collectively referred to as the protein C system inactivates clotting factors involved in the intrinsic pathway. TFPI (tissue factor pathway inhibitor) inhibits the conversion of the inactive factor VII to the active form in the extrinsic pathway. Antithrombin inactivates factor X and opposes the conversion of prothrombin (factor II) to thrombin in the common pathway. And as noted earlier, basophils release heparin, a short-acting anticoagulant that also opposes prothrombin. Heparin is also found on the surfaces of cells lining the blood vessels. A pharmaceutical form of heparin is often administered therapeutically, for example, in surgical patients at risk for blood clots.

Disorders of Clotting

Either an insufficient or an excessive production of platelets can lead to severe bleeding on the hand or excessive platelet plug formation on the other. Both of these situations can be life-threatening. As discussed earlier, an insufficient number of platelets, called thrombocytopenia, typically results in the inability of blood to form clots. This can lead to excessive bleeding, even from minor wounds.

Another reason for failure of the blood to clot is the inadequate production of functional amounts of one or more clotting factors. This is the case in the genetic disorder haemophilia, which is actually a group of related disorders, the most common of which is haemophilia A, accounting for approximately 80 percent of cases. This disorder results in the inability to synthesise enough factor VIII. Haemophilia B is the second most common form, accounting for approximately 20 percent of cases. In this case, there is a deficiency of factor IX. Both of these defects are linked to the X chromosome and are typically passed from a healthy (carrier) mother to her male offspring, since males are XY. Females would need to inherit a defective gene from each parent to manifest the disease, since they are XX. Patients with haemophilia bleed from even minor internal and external wounds, and leak blood into joint spaces after exercise and into urine and stool. Haemophilia C is a rare condition that is triggered by an autosomal (not sex) chromosome defect that renders factor XI non-functional. It is not a true recessive condition, since even individuals with a single copy of the mutant gene show a tendency to bleed. Regular infusions of clotting factors isolated from healthy donors, or manufactured as recombinant proteins, can help prevent bleeding in haemophiliac patients. At some point, genetic therapy will become a viable option.

In contrast to the disorders characterised by thrombocytopenia is thrombocytosis, also mentioned earlier, a condition characterised by excessive numbers of platelets that increases the risk for excessive clot formation, a condition known as thrombosis. Inherited or acquired failures in the control or regulation of coagulation can also result in a tendency towards thrombosis: a condition referred to as thrombophilia or hypercoagulation. Deficiencies of protein C or antithrombin, for example, can predispose an individual to thrombosis. Acquired forms of thrombophilia include the autoimmune disease lupus, immune reactions to heparin, polycythaemia vera, sickle cell disease, pregnancy, and even obesity. A thrombus (plural = thrombi) is an aggregation of platelets, erythrocytes, and even WBCs typically trapped within a mass of fibrin strands. While the formation of a clot is normal following the haemostatic response to blood vessel damage just described, thrombi can form within an intact or only slightly damaged blood vessel. In a large vessel, a thrombus will adhere to the vessel wall and decrease the flow of blood and is referred to as a mural thrombus. In a small vessel, it may totally block the flow of blood and is termed an occlusive thrombus. Thrombi are most caused by vessel damage to the endothelial lining, which activates the clotting mechanism. These may include venous stasis, when blood in the veins, particularly in the legs, remains stationary for long periods. This is one of the dangers of long airplane flights in crowded conditions and may lead to deep vein thrombosis or atherosclerosis, an accumulation of fats, macrophages and cell debris in the walls of arteries. A thrombus can seriously impede blood flow to or from a region and will cause a local increase in blood pressure. If flow is to be maintained, the heart will need to generate a greater pressure to overcome the resistance.

When a portion of a thrombus breaks free from the vessel wall and enters the circulation, it is referred to as an embolus. An embolus that is carried through the bloodstream can be large enough to block a vessel critical to a major organ. When it becomes trapped, an embolus is called an embolism. In the heart, brain, or lungs, an embolism may accordingly cause a heart attack, a stroke, or a pulmonary embolism. These are medical emergencies.

Among the many known biochemical activities of aspirin is its role as an anticoagulant. Aspirin (acetylsalicylic acid) is very effective at inhibiting the aggregation of platelets. Physicians sometimes recommend that patients at risk for cardiovascular disease, which can lead to heart attack or stroke, take a low dose of aspirin on a daily basis as a preventive measure. However, aspirin can also lead to serious side effects, including increasing the risk of gastrointestinal ulcers. A patient is well advised to consult a physician before beginning any aspirin regimen.

A class of drugs collectively known as thrombolytic agents can help speed up the degradation of an abnormal clot. If a thrombolytic agent is administered to a patient within 3 hours following a thrombotic stroke, the patient’s prognosis improves significantly. However, some strokes are not caused by thrombi, but by haemorrhage. Thus, the cause must be determined before treatment begins. Tissue plasminogen activator is an enzyme that catalyses the conversion of plasminogen to plasmin, the primary enzyme that breaks down clots. It is released naturally by endothelial cells but is also used in clinical medicine. New research is progressing using compounds isolated from the venom of some species of snakes, particularly vipers and cobras, which may eventually have therapeutic value as thrombolytic agents. Streptokinase, an enzyme produced by some species of streptococci, has long been used to help degrade the thrombus in heart attack cases.

Click the drop down below to review the terms learned from this chapter.

Leanne Dooley

Blood transfusions in humans were risky procedures until the discovery of the major human blood groups by Karl Landsteiner, an Austrian biologist and physician, in 1900. Until that point, physicians did not understand why rapid death often followed blood transfusions. They assumed that all human blood was the same. Landsteiner discovered that the plasma of some individuals caused the red blood cells of some other individuals to clump together (agglutinate), and he surmised that fatal transfusion reaction occurred when the type of donor blood infused into the patient was incompatible with the patient’s own blood. Blood groups are determined by the presence or absence of specific marker molecules on the plasma membranes of erythrocytes. With the discovery of these inherited markers, it became possible for the first time to match patient-donor blood types and prevent severe haemolytic transfusion reactions and deaths.

Antigens, Antibodies and Transfusion Reactions

Antigens are substances that the body does not recognise as belonging to the “self” and that therefore trigger a defensive response from the leukocytes of the immune system. (Seek more content for additional information on immunity.) Here, we will focus on the role of antibody-mediated (humoral) immunity in blood transfusion reactions. With RBCs in particular, you may see the antigens referred to as isoantigens or agglutinogens (surface antigens) and the antibodies referred to as isoantibodies or agglutinins. In this chapter, we will use the more common terms antigens and antibodies.

Antigens are generally large proteins, but may include other classes of organic molecules, including carbohydrates, lipids, and nucleic acids. Following an infusion of incompatible blood, erythrocytes with foreign antigens appear in the bloodstream and trigger an immune response. Proteins called antibodies (immunoglobulins), which are produced by certain B lymphocytes called plasma cells, attach to the antigens on the plasma membranes of the infused erythrocytes. Large antibodies, called IgM antibodies, can cause direct destruction of incompatible RBC via activation of group of plasma proteins called complement. This type of RBC destruction is called intravascular haemolysis and the reaction is referred to as an acute haemolytic transfusion reaction, which can be fatal after infusion of as little as 10mL of incompatible RBC. Smaller antibodies, called IgG antibodies, bind to the incompatible RBC and mark them for destruction by macrophages in the spleen. This type of RBC destruction is called extravascular haemolysis and the reaction is called a delayed haemolytic transfusion reaction, which is not often fatal but leads to removal of the transfused RBC, effectively making the transfusion a waste of time.

During an acute haemolytic transfusion reaction haemoglobin is released into the bloodstream as a result of intravascular haemolysis. This haemoglobin travels to the kidneys, which are responsible for filtration of the blood. However, haemoglobin is toxic to endothelial cells in the kidney and the patient can quickly develop kidney failure. In addition, damage to these endothelial cells can trigger coagulation and acute inflammatory response that can lead to shock and death within minutes.

More than 50 antigens have been identified on erythrocyte membranes, but by far the most significant in terms of their potential harm to patients are the A and B antigens of the ABO blood group system discovered by Landsteiner. The next most clinically significant antigen is the D antigen of the Rhesus or Rh blood group system.

The ABO Blood Group

Although the ABO blood group name consists of three letters, ABO blood typing designates the presence or absence of just two antigens, A and B. Both are carbohydrate or saccharide antigens and their presence or absence on the RBC membrane is genetically determined. People who have A antigens only on their erythrocyte membrane surfaces are designated blood type A, and those whose erythrocytes have B antigens only are blood type B. People can also have both A and B antigens on their erythrocytes, in which case they are blood type AB. People with neither A nor B antigens are designated blood type O.

Normally the body must be exposed to a foreign antigen before an antibody can be produced. This is not the case for the ABO blood group. Individuals with type A blood—without any prior exposure to incompatible blood—have pre-formed or naturally occurring antibodies to the B antigen circulating in their blood plasma. These antibodies, referred to as anti-B antibodies, are IgM type antibodies and will cause agglutination and haemolysis if they ever encounter erythrocytes with B antigens. Similarly, an individual with type B blood has pre-formed anti-A antibodies. Individuals with type AB blood, which has both antigens, do not have pre-formed antibodies to either of these. People with type O blood lack antigens A and B on their erythrocytes, but both anti-A and anti-B antibodies circulate in their blood plasma. Anti-A and anti-B antibodies are not present at birth but develop during the first six months of life in response to A and B-like substances in the environment, especially of the surface of bacteria.

Rh Blood Groups

The Rhesus or Rh blood group is classified according to the presence or absence of a second erythrocyte antigen identified as Rh. (It was first discovered in a type of primate known as a rhesus macaque, which is often used in research, because its blood is like that of humans.) Although dozens of Rh antigens have been identified, the antigen, designated D, is the most clinically important. Those who have the Rh D antigen present on their erythrocytes—about 85 percent of Americans—are described as Rh positive (Rh+) and those who lack it are Rh negative (Rh−). Note that the Rh group is distinct from the ABO group, so any individual, no matter their ABO blood type, may or may not have Rh antigen on their RBCs. When identifying a patient’s blood type, the Rh group is designated by adding the word positive or negative to the ABO type. For example, A positive (A+) means ABO group A blood with the Rh(D) antigen present, and AB negative (AB−) means ABO group AB blood without the Rh(D) antigen.

In contrast to the ABO group antibodies, which are preformed, antibodies to the Rh antigen are produced only in Rh− individuals after exposure to the antigen. This process, called sensitisation, occurs following a transfusion with Rh-incompatible blood or, more commonly, with the birth of an Rh+ baby to an Rh− mother. Problems are rare in a first pregnancy, since the baby’s Rh+ cells rarely cross the placenta (the organ of gas and nutrient exchange between the baby and the mother). However, during or immediately after birth, the Rh− mother can be exposed to the baby’s Rh+ cells (Figure 5.6.1). Research has shown that this occurs in about 13−14 percent of such pregnancies. After exposure, the mother’s immune system begins to generate anti-Rh (anti-D) antibodies. If the mother should then conceive another Rh+ baby, the Rh antibodies she has produced, which are small IgG antibodies, can cross the placenta into the foetal bloodstream and mark the foetal RBCs fir destruction by macrophages in the foetal spleen. This condition, known as haemolytic disease of the foetus and newborn (HDFN) or erythroblastosis foetalis, may cause anaemia in mild cases, but the haemolysis can be so severe that without treatment the foetus may die in the uterus or shortly after birth. An Rh- mother can also produce Rh antibodies after a miscarriage, termination of pregnancy or abdominal trauma during pregnancy with an Rh+ foetus.

Rh (D) immune globulin (Rh(D)Ig), derived from the plasma of women who have developed Rh antibodies, can temporarily prevent the development of Rh antibodies in the Rh− mother, thereby averting this potentially serious disease for the foetus. The anti-Rh antibodies, injected into the Rh- mother destroy any foetal Rh+ erythrocytes that may cross the placental barrier and enter the mother’s circulation. This effectively prevents sensitisation and the mother’s immune system does not begin to produce Rh antibodies. Rh(D)Ig is normally administered to Rh− mothers during weeks 26−28 of pregnancy, within 72 hours following birth of an Rh+ baby and following any potentially sensitive event. It has proven remarkably effective in decreasing the incidence of HDFN. Earlier we noted that the incidence of HDFN in an Rh+ subsequent pregnancy to an Rh− mother is about 13–14 percent without preventive treatment.

Determining ABO Blood Types

Laboratory technicians and scientists are able to determine a patient’s blood type quickly and easily using commercially prepared antibodies. A drop of the patient’s blood sample is placed into separate wells on a plastic tile or into separate glass test tubes. Into one well a drop of commercially prepared anti-A antibody is added and to another a drop of anti-B antibody is added. If the antigen is present, the antibodies will cause visible agglutination of the cells (Figure 5.6.2). The patient’s blood should also be tested for the Rh(D) antigen using commercially prepared anti-Rh(D) antibodies.

ABO Transfusion Protocols

To avoid transfusion reactions, it is best to transfuse only matching blood types; that is, a type B+ recipient should ideally receive blood only from a type B+ donor and so on. That said, in emergency situations, when acute haemorrhage threatens the patient’s life, there may not be time for blood typing and cross matching. In these cases, blood from a universal RBC donor—an individual with type O− blood—may be transfused. Recall that type O erythrocytes do not display A or B antigens. Thus, anti-A or anti-B antibodies that might be circulating in the patient’s blood plasma will not encounter any erythrocyte surface antigens on the donated blood and therefore will not be provoked into a response. A patient with blood type AB+ is known as the universal RBC recipient. This patient can theoretically receive RBC of any type of blood, because the patient’s own plasma – having both A and B antigens on the erythrocyte surface – does not contain anti-A or anti-B antibodies. Figure 5.6.3 summarises the ABO blood types and their associated antigen and antibody profiles.

Note that type A RBC can be given to recipients with type A or type AB blood, because both cases, the recipient’s plasma does not contain anti-A antibodies. However, type AB RBC cannot be given to recipients with type A blood because in this case the patient’s plasma will contain anti-B antibodies, which will react with the B antigens on the donor blood.

While most transfusions involve infusion of RBC only, some patients require plasma transfusions. In the case of plasma transfusion, type AB is the universal donor because type AB plasma does not contain either anti-A or anti-B. The Rh(D) antigen also plays a role in blood transfusion. If Rh− individuals receiving blood have had prior exposure to Rh antigen, antibodies for this antigen may be present in the plasma and will trigger delayed haemolytic transfusion reaction and extravascular haemolysis. Although it is always preferable to type and cross match a patient’s blood before transfusing, in a true life-threatening emergency, this is not always possible, and type O- RBC or type AB plasma can be given until the patient’s blood type is established.

At the scene of multiple-vehicle accidents, military engagements, and natural or human-caused disasters, many victims may suffer simultaneously from acute haemorrhage, yet type O blood may not be immediately available. In these circumstances, medics may at least try to replace some of the volume of blood that has been lost. This is done by intravenous administration of a saline solution that provides fluids and electrolytes in proportions equivalent to those of normal blood plasma. Research is ongoing to develop a safe and effective artificial blood that would perform the oxygen-carrying function of blood without the RBCs, enabling transfusions in the field without concern for incompatibility.

Click the drop down below to review the terms learned from this chapter.

The vital importance of the heart is obvious. If one assumes an average rate of contraction of 75 contractions per minute, a human heart would contract approximately 108,000 times in one day, more than 39 million times in one year and nearly 3 billion times during a 75-year lifespan! Each of the major pumping chambers of the heart ejects approximately 70 mL blood per contraction in a resting adult. This would be equal to 5.25 litres of fluid per minute and approximately 14,000 litres per day. Over one year, that would equal 10,000,000 litres (2.6 million gallons) of blood sent through roughly 97,000 kilometres (60,000 miles) of vessels. In order to understand how that happens, it is necessary to understand the anatomy and physiology of the heart.

Location of the Heart

The human heart is located within the thoracic cavity, medially between the lungs in the space known as the mediastinum. Figure 6.1.1 shows the position of the heart within the thoracic cavity. Within the mediastinum, the heart is separated from the other mediastinal structures by a tough membrane known as the pericardium, or pericardial sac, and sits in its own space called the pericardial cavity. The dorsal surface of the heart lies near the bodies of the vertebrae, and its anterior surface sits deep to the sternum and costal cartilages. The great veins, the superior and inferior venae cavae, and the great arteries, the aorta and pulmonary trunk, are attached to the superior surface of the heart, called the base. The base of the heart is located at the level of the third costal cartilage, as seen in Figure 6.1.1. The inferior tip of the heart, the apex, lies just to the left of the sternum between the junction of the fourth and fifth ribs near their articulation with the costal cartilages. The right side of the heart is deflected anteriorly, and the left side is deflected posteriorly. It is important to remember the position and orientation of the heart when placing a stethoscope on the chest of a patient and listening for heart sounds, and when looking at images taken from a midsagittal perspective. The slight deviation of the apex to the left is reflected in a depression in the medial surface of the inferior lobe of the left lung, called the cardiac notch.

Everyday Connection

CPR
The position of the heart in the torso between the vertebrae and sternum (see Figure 6.1.1 for the position of the heart within the thorax) allows for individuals to apply an emergency technique known as cardiopulmonary resuscitation (CPR) if the heart of a patient should stop. In adults, pressure is applied with the flat portion of one hand on the sternum in the area between the line at T4 and T9 (Figure 6.1.2), it is possible to manually compress the blood within the heart enough to push some of the blood within it into the pulmonary and systemic circuits. This is particularly critical for the brain, as irreversible damage and death of neurons occur within minutes of loss of blood flow. Current standards call for compression of the chest at least 5 cm deep and at a rate of 100-120 compressions per minute, a rate equal to the beat in “Staying Alive,” recorded in 1977 by the Bee Gees. If you are unfamiliar with this song, a version is available on www.youtube.com. At this stage, the emphasis is on performing high-quality chest compressions, rather than providing artificial respiration, but typically compression to ventilation ratio is 30:2. CPR is generally performed until the patient regains spontaneous contraction or is declared dead by an experienced healthcare professional.

When performed by untrained or overzealous individuals, CPR can result in broken ribs or a broken sternum and can inflict additional severe damage on the patient. It is also possible, if the hands are placed too low on the sternum, to manually drive the xiphoid process into the liver, a consequence that may prove fatal for the patient. Proper training is essential. This proven life-sustaining technique is so valuable that virtually all medical personnel as well as concerned members of the public should be certified and routinely recertified in its application. CPR courses are offered at a variety of locations, including colleges, hospitals, the Australian Red Cross and some commercial companies. They normally include practice of the compression technique on a mannequin.

Shape and Size of the Heart

The shape of the heart is similar to a pinecone, rather broad at the superior surface and tapering to the apex (see Figure 6.1.1). A typical heart is approximately the size of your fist: 12 cm (5 in) in length, 8 cm (3.5 in) wide, and 6 cm (2.5 in) in thickness. Given the size difference between most members of the sexes, the weight of a female heart is approximately 250–300 grams (9 to 11 ounces), and the weight of a male heart is approximately 300–350 grams (11 to 12 ounces). The heart of a well-trained athlete, especially one specialising in aerobic sports, can be considerably larger than this. Cardiac muscle responds to exercise in a manner like that of skeletal muscle. That is, exercise results in the addition of protein myofilaments that increase the size of the individual cells without increasing their numbers, a concept called hypertrophy. Hearts of athletes can pump blood more effectively at lower rates than those of nonathletes. Enlarged hearts are not always a result of exercise; they can result from pathologies, such as hypertrophic cardiomyopathy. The cause of an abnormally enlarged heart muscle is unknown, but the condition is often undiagnosed and can cause sudden death in apparently otherwise healthy young people.

Chambers and Circulation Through the Heart

The human heart consists of four chambers: The left side and the right side each have one atrium and one ventricle. Each of the upper chambers, the right atrium (plural = atria) and the left atrium, acts as a receiving chamber and contracts to push blood into the lower chambers, the right ventricle and the left ventricle. The ventricles serve as the primary pumping chambers of the heart, propelling blood to the lungs or to the rest of the body.

There are two distinct but linked circuits in the human circulation called the pulmonary and systemic circuits. Although both circuits transport blood and everything it carries, we can initially view the circuits from the point of view of gases. The pulmonary circuit transports blood to and from the lungs, where it picks up oxygen and delivers carbon dioxide for exhalation. The systemic circuit transports oxygenated blood to virtually all the tissues of the body and returns relatively deoxygenated blood and carbon dioxide to the heart to be sent back to the pulmonary circulation.

The right ventricle pumps deoxygenated blood into the pulmonary trunk, which leads toward the lungs and bifurcates into the left and right pulmonary arteries. These vessels in turn branch many times before reaching the pulmonary capillaries, where gas exchange occurs: Carbon dioxide exits the blood and oxygen enters. The pulmonary trunk arteries and their branches are the only arteries in the post-natal body that carry relatively deoxygenated blood. Highly oxygenated blood returning from the pulmonary capillaries in the lungs passes through a series of vessels that join together to form the pulmonary veins—the only post-natal veins in the body that carry highly oxygenated blood. The pulmonary veins conduct blood into the left atrium, which pumps the blood into the left ventricle, which in turn pumps oxygenated blood into the aorta and on to the many branches of the systemic circuit. Eventually, these vessels will lead to the systemic capillaries, where exchange with the tissue fluid and cells of the body occurs. In this case, oxygen and nutrients exit the systemic capillaries to be used by the cells in their metabolic processes, and carbon dioxide and waste products will enter the blood.

The blood exiting the systemic capillaries is lower in oxygen concentration than when it entered. The capillaries will ultimately unite to form venules, joining to form ever-larger veins, eventually flowing into the two major systemic veins, the superior vena cava and the inferior vena cava, which return blood to the right atrium. The blood in the superior and inferior venae cavae flows into the right atrium, which pumps blood into the right ventricle. This process of blood circulation continues as long as the individual remains alive. Understanding the flow of blood through the pulmonary and systemic circuits is critical to all health professions (Figure 6.1.3).

Membranes, Surface Features and Layers

Our exploration of more in-depth heart structures begins by examining the membrane that surrounds the heart, the prominent surface features of the heart and the layers that form the wall of the heart. Each of these components plays its own unique role in terms of function.

Membranes

The membrane that directly surrounds the heart and defines the pericardial cavity is called the pericardium or pericardial sac. It also surrounds the “roots” of the major vessels, or the areas of closest proximity to the heart. The pericardium, which literally translates as “around the heart,” consists of two distinct sublayers: the sturdy outer fibrous pericardium and the inner serous pericardium. The fibrous pericardium is made of tough, dense connective tissue that protects the heart and maintains its position in the thorax. The more delicate serous pericardium consists of two layers: the parietal pericardium, which is fused to the fibrous pericardium, and an inner visceral pericardium, or epicardium, which is fused to the heart and is part of the heart wall. The pericardial cavity, filled with lubricating serous fluid, lies between the epicardium and the pericardium.

In most organs within the body, visceral serous membranes such as the epicardium are microscopic. However, in the case of the heart, it is not a microscopic layer but rather a macroscopic layer, consisting of a simple squamous epithelium called a mesothelium, reinforced with loose, irregular, or areolar connective tissue that attaches to the pericardium. This mesothelium secretes the lubricating serous fluid that fills the pericardial cavity and reduces friction as the heart contracts. Figure 6.1.4 illustrates the pericardial membranes and the layers of the heart.

Disorders of the Heart: Cardiac Tamponade

If excess fluid builds within the pericardial space, it can lead to a condition called cardiac tamponade, or pericardial tamponade. With each contraction of the heart, more fluid—in most instances, blood—accumulates within the pericardial cavity. In order to fill with blood for the next contraction, the heart must relax. However, the excess fluid in the pericardial cavity puts pressure on the heart and prevents full relaxation, so the chambers within the heart contain slightly less blood as they begin each heart cycle. Over time, less and less blood is ejected from the heart. If the fluid builds up slowly, as in hypothyroidism, the pericardial cavity may be able to expand gradually to accommodate this extra volume. Some cases of fluid in excess of one litre within the pericardial cavity have been reported. Rapid accumulation of as little as 100 mL of fluid following trauma may trigger cardiac tamponade. Other common causes include myocardial rupture, pericarditis, cancer, or even cardiac surgery. Removal of this excess fluid requires insertion of drainage tubes into the pericardial cavity. Premature removal of these drainage tubes, for example, following cardiac surgery, or clot formation within these tubes are causes of this condition. Untreated, cardiac tamponade can lead to death.

Surface Features of the Heart

Inside the pericardium, the surface features of the heart are visible, including the four chambers. There is a superficial leaf-like extension of the atria near the superior surface of the heart, one on each side, called an auricle—a name that means “ear like”—because its shape resembles the external ear of a human (Figure 6.1.5). Auricles are relatively thin-walled structures that can fill with blood and empty into the atria or upper chambers of the heart. You may also hear them referred to as atrial appendages. Also prominent is a series of fat-filled grooves, each of which is known as a sulcus (plural = sulci), along the superior surfaces of the heart. Major coronary blood vessels are located in these sulci. The deep coronary sulcus is located between the atria and ventricles. Located between the left and right ventricles are two additional sulci that are not as deep as the coronary sulcus. The anterior interventricular sulcus is visible on the anterior surface of the heart, whereas the posterior interventricular sulcus is visible on the posterior surface of the heart. Figure 6.1.5 illustrates anterior and posterior views of the surface of the heart.

Layers

The wall of the heart is composed of three layers of unequal thickness. From superficial to deep, these are the epicardium, the myocardium and the endocardium (see Figure 6.1.4). The outermost layer of the wall of the heart is also the innermost layer of the pericardium, the epicardium, or the visceral pericardium discussed earlier.

The middle and thickest layer is the myocardium, made largely of cardiac muscle cells. It is built upon a framework of collagenous fibres, plus the blood vessels that supply the myocardium and the nerve fibres that help regulate the heart. It is the contraction of the myocardium that pumps blood through the heart and into the major arteries. The muscle pattern is elegant and complex, as the muscle cells swirl and spiral around the chambers of the heart. They form a figure 8 pattern around the atria and around the bases of the great vessels. Deeper ventricular muscles also form a figure 8 around the two ventricles and proceed toward the apex. More superficial layers of ventricular muscle wrap around both ventricles. This complex swirling pattern allows the heart to pump blood more effectively than a simple linear pattern would. Figure 6.1.6 illustrates the arrangement of muscle cells.

Although the ventricles on the right and left sides pump the same amount of blood per contraction, the muscle of the left ventricle is much thicker and better developed than that of the right ventricle. In order to overcome the high resistance required to pump blood into the long systemic circuit, the left ventricle must generate a great amount of pressure. The right ventricle does not need to generate as much pressure, since the pulmonary circuit is shorter and provides less resistance. Figure 6.1.7 illustrates the differences in muscular thickness needed for each of the ventricles.

The innermost layer of the heart wall, the endocardium, is joined to the myocardium with a thin layer of connective tissue. The endocardium lines the chambers where the blood circulates and covers the heart valves. It is made of simple squamous epithelium called endothelium, which is continuous with the endothelial lining of the blood vessels (see Figure 6.1.4).

Once regarded as a simple lining layer, recent evidence indicates that the endothelium of the endocardium and the coronary capillaries may play active roles in regulating the contraction of the muscle within the myocardium. The endothelium may also regulate the growth patterns of the cardiac muscle cells throughout life, and the endothelins it secretes create an environment in the surrounding tissue fluids that regulates ionic concentrations and states of contractility. Endothelins are potent vasoconstrictors and, in a normal individual, establish a homeostatic balance with other vasoconstrictors and vasodilators.

Internal Structure of the Heart

Recall that the heart’s contraction cycle follows a dual pattern of circulation—the pulmonary and systemic circuits—because of the pairs of chambers that pump blood into the circulation. In order to develop a more precise understanding of cardiac function, it is first necessary to explore the internal anatomical structures in more detail.

Septa of the Heart

The word septum is derived from the Latin for “something that encloses;” in this case, a septum (plural = septa) refers to a wall or partition that divides the heart into chambers. The septa are physical extensions of the myocardium lined with endocardium. Located between the two atria is the interatrial septum. Normally in an adult heart, the interatrial septum bears an oval-shaped depression known as the fossa ovalis, a remnant of an opening in the foetal heart known as the foramen ovale. The foramen ovale allowed blood in the foetal heart to pass directly from the right atrium to the left atrium, allowing some blood to bypass the pulmonary circuit. Within seconds after birth, a flap of tissue known as the septum primum that previously acted as a valve closes the foramen ovale and establishes the typical cardiac circulation pattern.

Between the two ventricles is a second septum known as the interventricular septum. Unlike the interatrial septum, the interventricular septum is normally intact after its formation during foetal development. It is substantially thicker than the interatrial septum, since the ventricles generate far greater pressure when they contract.

The septum between the atria and ventricles is known as the atrioventricular septum. It is marked by the presence of four openings that allow blood to move from the atria into the ventricles and from the ventricles into the pulmonary trunk and aorta. Located in each of these openings between the atria and ventricles is a valve, a specialised structure that ensures one-way flow of blood. The valves between the atria and ventricles are known generically as atrioventricular valves. The valves at the openings that lead to the pulmonary trunk and aorta are known generically as semilunar valves. The interventricular septum is visible in Figure 6.1.8. In this figure, the atrioventricular septum has been removed to better show the bicuspid and tricuspid valves; the interatrial septum is not visible, since its location is covered by the aorta and pulmonary trunk. Since these openings and valves structurally weaken the atrioventricular septum, the remaining tissue is heavily reinforced with dense connective tissue called the cardiac skeleton, or skeleton of the heart. It includes four rings that surround the openings between the atria and ventricles, and the openings to the pulmonary trunk and aorta, and serve as the point of attachment for the heart valves. The cardiac skeleton also provides an important boundary in the heart electrical conduction system.

Disorders of the Heart: Heart Defects

One very common form of interatrial septum pathology is patent foramen ovale, which occurs when the septum primum does not close at birth, and the fossa ovalis is unable to fuse. The word patent is from the Latin root patens for “open.” It may be benign or asymptomatic, perhaps never being diagnosed, or in extreme cases, it may require surgical repair to close the opening permanently. As much as 20–25 percent of the general population may have a patent foramen ovale, but fortunately, most have the benign, asymptomatic version. Patent foramen ovale is normally detected by auscultation of a heart murmur (an abnormal heart sound) and confirmed by imaging with an echocardiogram. Despite its prevalence in the general population, the causes of patent ovale are unknown, and there are no known risk factors. In nonlife-threatening cases, it is better to monitor the condition than to risk heart surgery to repair and seal the opening.

Coarctation of the aorta is a congenital abnormal narrowing of the aorta that is normally located at the insertion of the ligamentum arteriosum, the remnant of the foetal shunt called the ductus arteriosus. If severe, this condition drastically restricts blood flow through the primary systemic artery, which is life threatening. In some individuals, the condition may be benign and not detected until later in life. Detectable symptoms in an infant include difficulty breathing, poor appetite, trouble feeding, or failure to thrive. In older individuals, symptoms include dizziness, fainting, shortness of breath, chest pain, fatigue, headache, and nosebleeds. Treatment involves surgery to resect (remove) the affected region or angioplasty to open the abnormally narrow passageway. Studies have shown that the earlier the surgery is performed, the better the chance of survival.

A patent ductus arteriosus is a congenital condition in which the ductus arteriosus fails to close. The condition may range from severe to benign. Failure of the ductus arteriosus to close results in blood flowing from the higher-pressure aorta into the lower pressure pulmonary trunk. This additional fluid moving toward the lungs increases pulmonary pressure and makes respiration difficult. Symptoms include shortness of breath (dyspnoea), tachycardia, enlarged heart, a widened pulse pressure, and poor weight gain in infants. Treatments include surgical closure (ligation), manual closure using platinum coils or specialised mesh inserted via the femoral artery or vein, or nonsteroidal anti-inflammatory drugs to block the synthesis of prostaglandin E2, which maintains the vessel in an open position. If untreated, the condition can result in congestive heart failure.

Septal defects are not uncommon in individuals and may be congenital or caused by various disease processes. Tetralogy of Fallot is a congenital condition that may also occur from exposure to unknown environmental factors; it occurs when there is an opening in the interventricular septum caused by blockage of the pulmonary trunk, normally at the pulmonary semilunar valve. This allows blood that is relatively low in oxygen from the right ventricle to flow into the left ventricle and mix with the blood that is relatively high in oxygen. Symptoms include a distinct heart murmur, low blood oxygen percent saturation, dyspnoea or difficulty in breathing, polycythaemia, broadening (clubbing) of the fingers and toes, and in children, difficulty in feeding or failure to grow and develop. It is the most common cause of cyanosis following birth. The term “tetralogy” is derived from the four components of the condition, although only three may be present in an individual patient: pulmonary infundibular stenosis (rigidity of the pulmonary valve), overriding aorta (the aorta is shifted above both ventricles), ventricular septal defect (opening), and right ventricular hypertrophy (enlargement of the right ventricle). Other heart defects may also accompany this condition, which is typically confirmed by echocardiography imaging. Tetralogy of Fallot occurs in approximately 400 out of one million live births. Normal treatment involves extensive surgical repair, including the use of stents to redirect blood flow and replacement of valves and patches to repair the septal defect, but the condition has a relatively high mortality. Survival rates are currently 75 percent during the first year of life; 60 percent by four years of age; 30 percent by 10 years; and five percent by 40 years.

In the case of severe septal defects, including both tetralogy of Fallot and patent foramen ovale, failure of the heart to develop properly can lead to a condition commonly known as a “blue baby.” Regardless of normal skin pigmentation, individuals with this condition have an insufficient supply of oxygenated blood, which leads to cyanosis, a blue or purple coloration of the skin, especially when active.

Septal defects are commonly first detected through auscultation, listening to the chest using a stethoscope. In this case, instead of hearing normal heart sounds attributed to the flow of blood and closing of heart valves, unusual heart sounds may be detected. This is often followed by medical imaging to confirm or rule out a diagnosis. In many cases, treatment may not be needed. Some common congenital heart defects are illustrated in Figure 6.1.9.

Right Atrium

The right atrium serves as the receiving chamber for blood returning to the heart from the systemic circulation. The two major systemic veins, the superior and inferior venae cavae, and the large coronary vein called the coronary sinus that drains the heart myocardium empty into the right atrium. The superior vena cava drains blood from regions superior to the diaphragm: the head, neck, upper limbs, and the thoracic region. It empties into the superior and posterior portions of the right atrium. The inferior vena cava drains blood from areas inferior to the diaphragm: the lower limbs and abdominopelvic region of the body. It, too, empties into the posterior portion of the atria, but inferior to the opening of the superior vena cava. Immediately superior and slightly medial to the opening of the inferior vena cava on the posterior surface of the atrium is the opening of the coronary sinus. This thin-walled vessel drains most of the coronary veins that return systemic blood from the heart. The majority of the internal heart structures discussed in this and subsequent sections are illustrated in Figure 6.1.8.

While the bulk of the internal surface of the right atrium is smooth, the depression of the fossa ovalis is medial, and the anterior surface demonstrates prominent ridges of muscle called the pectinate muscles. The right auricle also has pectinate muscles. The left atrium does not have pectinate muscles except in the auricle.

The atria receive venous blood on a nearly continuous basis, preventing venous flow from stopping while the ventricles are contracting. While most ventricular filling occurs while the atria are relaxed, they do demonstrate a contractile phase and actively pump blood into the ventricles just prior to ventricular contraction. The opening between the atrium and ventricle is guarded by the tricuspid valve.

Right Ventricle

The right ventricle receives blood from the right atrium through the tricuspid valve. Each flap of the valve is attached to strong strands of connective tissue, the chordae tendineae, literally “tendinous cords,” or sometimes more poetically referred to as “heart strings.” There are several chordae tendineae associated with each of the flaps. They are composed of approximately 80 percent collagenous fibres with the remainder consisting of elastic fibres and endothelium. They connect each of the flaps to a papillary muscle that extends from the inferior ventricular surface. There are three papillary muscles in the right ventricle, called the anterior, posterior, and septal muscles, which correspond to the three sections of the valves.

When the myocardium of the ventricle contracts, pressure within the ventricular chamber rises. Blood, like any fluid, flows from higher pressure to lower pressure areas, in this case, toward the pulmonary trunk and the atrium. To prevent any potential backflow, the papillary muscles also contract, generating tension on the chordae tendineae. This prevents the flaps of the valves from being forced into the atria and regurgitation of the blood back into the atria during ventricular contraction. Figure 6.1.10 shows papillary muscles and chordae tendineae attached to the tricuspid valve.

The walls of the ventricle are lined with trabeculae carneae, ridges of cardiac muscle covered by endocardium. In addition to these muscular ridges, a band of cardiac muscle, also covered by endocardium, known as the moderator band (see Figure 6.1.8) reinforces the thin walls of the right ventricle and plays a crucial role in cardiac conduction. It arises from the inferior portion of the interventricular septum and crosses the interior space of the right ventricle to connect with the inferior papillary muscle.

When the right ventricle contracts, it ejects blood into the pulmonary trunk, which branches into the left and right pulmonary arteries that carry it to each lung. The superior surface of the right ventricle begins to taper as it approaches the pulmonary trunk. At the base of the pulmonary trunk is the pulmonary semilunar valve that prevents backflow from the pulmonary trunk.

Left Atrium

After exchange of gases in the pulmonary capillaries, blood returns to the left atrium high in oxygen via one of the four pulmonary veins. While the left atrium does not contain pectinate muscles, it does have an auricle that includes these pectinate ridges. Blood flows nearly continuously from the pulmonary veins back into the atrium, which acts as the receiving chamber, and from here through an opening into the left ventricle. Most blood flows passively into the heart while both the atria and ventricles are relaxed, but toward the end of the ventricular relaxation period, the left atrium will contract, pumping blood into the ventricle. This atrial contraction accounts for approximately 20 percent of ventricular filling. The opening between the left atrium and ventricle is guarded by the mitral valve.

Left Ventricle

Recall that, although both sides of the heart will pump the same amount of blood, the muscular layer is much thicker in the left ventricle compared to the right (see Figure 6.1.7). Like the right ventricle, the left also has trabeculae carneae, but there is no moderator band. The mitral valve is connected to papillary muscles via chordae tendineae. There are two papillary muscles on the left—the anterior and posterior—as opposed to three on the right.

The left ventricle is the major pumping chamber for the systemic circuit; it ejects blood into the aorta through the aortic semilunar valve.

Heart Valve Structure and Function

A transverse section through the heart slightly above the level of the atrioventricular septum reveals all four heart valves along the same plane (Figure 6.1.11). The valves ensure unidirectional blood flow through the heart. Between the right atrium and the right ventricle is the right atrioventricular valve, or tricuspid valve. It typically consists of three flaps, or leaflets, made of endocardium reinforced with additional connective tissue. The flaps are connected by chordae tendineae to the papillary muscles, which control the opening and closing of the valves.

Emerging from the right ventricle at the base of the pulmonary trunk is the pulmonary semilunar valve, or the pulmonary valve; it is also known as the pulmonic valve or the right semilunar valve. The pulmonary valve is comprised of three small flaps of endothelium reinforced with connective tissue. When the ventricle relaxes, the pressure differential causes blood to flow back into the ventricle from the pulmonary trunk. This flow of blood fills the pocket-like flaps of the pulmonary valve, causing the valve to close and producing an audible sound. Unlike the atrioventricular valves, there are no papillary muscles or chordae tendineae associated with the pulmonary valve.

Located at the opening between the left atrium and left ventricle is the mitral valve, also called the bicuspid valve or the left atrioventricular valve. Structurally, this valve consists of two cusps, known as the anterior medial cusp and the posterior medial cusp, compared to the three cusps of the tricuspid valve. In a clinical setting, the valve is referred to as the mitral valve, rather than the bicuspid valve. The two cusps of the mitral valve are attached by chordae tendineae to two papillary muscles that project from the wall of the ventricle.

At the base of the aorta is the aortic semilunar valve, or the aortic valve, which prevents backflow from the aorta. It normally is composed of three flaps. When the ventricle relaxes and blood attempts to flow back into the ventricle from the aorta, blood will fill the cusps of the valve, causing it to close and producing an audible sound.

In Figure 6.1.12a, the two atrioventricular valves are open and the two semilunar valves are closed. This occurs when both atria and ventricles are relaxed and when the atria contract to pump blood into the ventricles. Figure 6.1.12b shows a frontal view. Although only the left side of the heart is illustrated, the process is virtually identical on the right.

Figure 6.1.13a shows the atrioventricular valves closed while the two semilunar valves are open. This occurs when the ventricles contract to eject blood into the pulmonary trunk and aorta. Closure of the two atrioventricular valves prevents blood from being forced back into the atria. This stage can be seen from a frontal view in Figure 6.1.13b.

When the ventricles begin to contract, pressure within the ventricles rises and blood flows toward the area of lowest pressure, which is initially in the atria. This backflow causes the cusps of the tricuspid and mitral (bicuspid) valves to close. These valves are tied down to the papillary muscles by chordae tendineae. During the relaxation phase of the cardiac cycle, the papillary muscles are also relaxed and the tension on the chordae tendineae is slight (see Figure 6.1.12b). However, as the myocardium of the ventricle contracts, so do the papillary muscles. This creates tension on the chordae tendineae (see Figure 6.1.13b), helping to hold the cusps of the atrioventricular valves in place and preventing them from being blown back into the atria.

The aortic and pulmonary semilunar valves lack the chordae tendineae and papillary muscles associated with the atrioventricular valves. Instead, they consist of pocket-like folds of endocardium reinforced with additional connective tissue. When the ventricles relax and the change in pressure forces the blood toward the ventricles, the blood presses against these cusps and seals the openings.

Disorders of the Heart Valves

When heart valves do not function properly, they are often described as incompetent and result in valvular heart disease, which can range from benign to lethal. Some of these conditions are congenital, that is, the individual was born with the defect, whereas others may be attributed to disease processes or trauma. Some malfunctions are treated with medications, others require surgery, and still others may be mild enough that the condition is merely monitored since treatment might trigger more serious consequences.

Valvular disorders are often caused by carditis, or inflammation of the heart. One common trigger for this inflammation is rheumatic fever, or scarlet fever, an autoimmune response to the presence of a bacterium, Streptococcus pyogenes, normally a disease of childhood.

While any of the heart valves may be involved in valve disorders, mitral regurgitation is the most common, detected in approximately 2 percent of the population, and the pulmonary semilunar valve is the least frequently involved. When a valve malfunctions, the flow of blood to a region will often be disrupted. The resulting inadequate flow of blood to this region will be described in general terms as an insufficiency. The specific type of insufficiency is named for the valve involved: aortic insufficiency, mitral insufficiency, tricuspid insufficiency, or pulmonary insufficiency.

If one of the cusps of the valve is forced backward by the force of the blood, the condition is referred to as a prolapsed valve. Prolapse may occur if the chordae tendineae are damaged or broken, causing the closure mechanism to fail. The failure of the valve to close properly disrupts the normal one-way flow of blood and results in regurgitation, when the blood flows backward from its normal path. Using a stethoscope, the disruption to the normal flow of blood produces a heart murmur.

Stenosis is a condition in which the heart valves become rigid and may calcify over time. The loss of flexibility of the valve interferes with normal function and may cause the heart to work harder to propel blood through the valve, which eventually weakens the heart. Aortic stenosis affects approximately two percent of the population over 65 years of age, and the percentage increases to approximately four percent in individuals over 85 years. Occasionally, one or more of the chordae tendineae will tear or the papillary muscle itself may die as a component of a myocardial infarction (heart attack). In this case, the patient’s condition will deteriorate dramatically and rapidly, and immediate surgical intervention may be required.

Auscultation, or listening to a patient’s heart sounds, is one of the most useful diagnostic tools, since it is proven, safe, and inexpensive. The term auscultation is derived from the Latin for “to listen,” and the technique has been used for diagnostic purposes as far back as the ancient Egyptians. Valve and septal disorders will trigger abnormal heart sounds. If a valvular disorder is detected or suspected, a test called an echocardiogram, or simply an “echo,” may be ordered. Echocardiograms are sonograms of the heart and can help in the diagnosis of valve disorders as well as a wide variety of heart pathologies.

Coronary Circulation

You will recall that the heart is a remarkable pump composed largely of cardiac muscle cells that are incredibly active throughout life. Like all other cells, a cardiomyocyte requires a reliable supply of oxygen and nutrients, and a way to remove wastes, so it needs a dedicated, complex, and extensive coronary circulation. And because of the critical and nearly ceaseless activity of the heart throughout life, this need for a blood supply is even greater than for a typical cell. However, coronary circulation is not continuous; rather, it cycles, reaching a peak when the heart muscle is relaxed and nearly ceasing while it is contracting.

Coronary Arteries

Coronary arteries supply blood to the myocardium and other components of the heart. The first portion of the aorta after it arises from the left ventricle gives rise to the coronary arteries. There are three dilations in the wall of the aorta just superior to the aortic semilunar valve. Two of these, the left posterior aortic sinus and anterior aortic sinus, give rise to the left and right coronary arteries, respectively. The third sinus, the right posterior aortic sinus, typically does not give rise to a vessel. Coronary vessel branches that remain on the surface of the artery and follow the sulci are called epicardial coronary arteries.

The left coronary artery distributes blood to the left side of the heart, the left atrium and ventricle, and the interventricular septum. The circumflex artery arises from the left coronary artery and follows the coronary sulcus to the left. Eventually, it will fuse with the small branches of the right coronary artery. The larger anterior interventricular artery, also known as the left anterior descending artery (LAD), is the second major branch arising from the left coronary artery. It follows the anterior interventricular sulcus around the pulmonary trunk. Along the way it gives rise to numerous smaller branches that interconnect with the branches of the posterior interventricular artery, forming anastomoses. An anastomosis is an area where vessels unite to form interconnections that normally allow blood to circulate to a region even if there may be partial blockage in another branch. The anastomoses in the heart are very small. Therefore, this ability is somewhat restricted in the heart, so a coronary artery blockage often results in death of the cells (myocardial infarction) supplied by the particular vessel.

The right coronary artery proceeds along the coronary sulcus and distributes blood to the right atrium, portions of both ventricles, and the heart conduction system. Normally, one or more marginal arteries arise from the right coronary artery inferior to the right atrium. The marginal arteries supply blood to the superficial portions of the right ventricle. On the posterior surface of the heart, the right coronary artery gives rise to the posterior interventricular artery, also known as the posterior descending artery. It runs along the posterior portion of the interventricular sulcus toward the apex of the heart, giving rise to branches that supply the interventricular septum and portions of both ventricles. Figure 6.1.14 presents views of the coronary circulation from both the anterior and posterior views.

Diseases of the Heart: Myocardial Infarction

Myocardial infarction (MI) is the formal term for what is commonly referred to as a heart attack. It normally results from a lack of blood flow (ischaemia) and oxygen (hypoxia) to a region of the heart, resulting in death of the cardiac muscle cells. An MI often occurs when a coronary artery is blocked by the build-up of atherosclerotic plaque consisting of lipids, cholesterol and fatty acids, and white blood cells, primarily macrophages. It can also occur when a portion of an unstable atherosclerotic plaque travels through the coronary arterial system and lodges in one of the smaller vessels. The resulting blockage restricts the flow of blood and oxygen to the myocardium and causes death of the tissue. MIs may be triggered by excessive exercise, in which the partially occluded artery is no longer able to pump sufficient quantities of blood, or severe stress, which may induce spasm of the smooth muscle in the walls of the vessel.

In the case of acute MI, there is often sudden pain beneath the sternum (retrosternal pain) called angina pectoris, often radiating down the left arm in males but not in female patients. Until this anomaly between the sexes was discovered, many female patients suffering MIs were misdiagnosed and sent home. In addition, patients typically present with difficulty breathing and shortness of breath (dyspnoea), irregular heartbeat (palpations), nausea and vomiting, sweating (diaphoresis), anxiety and fainting (syncope), although not all of these symptoms may be present. Many of the symptoms are shared with other medical conditions, including anxiety attacks and simple indigestion, so differential diagnosis is critical. It is estimated that between 22 and 64 percent of MIs present without any symptoms.

An MI can be confirmed by examining the patient’s ECG, which frequently reveals alterations in the ST and Q components. Some classification schemes of MI are referred to as ST-elevated MI (STEMI) and non-elevated MI (non-STEMI). In addition, echocardiography or cardiac magnetic resonance imaging may be employed. Common blood tests indicating an MI include elevated levels of creatine kinase MB (an enzyme that catalyses the conversion of creatine to phosphocreatine, consuming ATP) and cardiac troponin (the regulatory protein for muscle contraction), both of which are released by damaged cardiac muscle cells.

Immediate treatments for MI are essential and include administering supplemental oxygen, aspirin that helps to break up clots, and nitroglycerine administered sublingually (under the tongue) to facilitate its absorption. Despite its unquestioned success in treatments and use since the 1880s, the mechanism of nitroglycerine is still incompletely understood but is believed to involve the release of nitric oxide, a known vasodilator, and endothelium-derived releasing factor, which also relaxes the smooth muscle in the tunica media of coronary vessels. Longer-term treatments include injections of thrombolytic agents such as streptokinase that dissolve the clot, the anticoagulant heparin, balloon angioplasty and stents to open blocked vessels, and bypass surgery to allow blood to pass around the site of blockage. If the damage is extensive, coronary replacement with a donor heart or coronary assist device, a sophisticated mechanical device that supplements the pumping activity of the heart, may be employed. Despite the attention, development of artificial hearts to augment the severely limited supply of heart donors has proven less than satisfactory but will likely improve in the future.

MIs may trigger cardiac arrest, but the two are not synonymous. Important risk factors for MI include cardiovascular disease, age, smoking, high blood levels of the low-density lipoprotein (LDL, often referred to as “bad” cholesterol), low levels of high-density lipoprotein (HDL, or “good” cholesterol), hypertension, diabetes mellitus, obesity, lack of physical exercise, chronic kidney disease, excessive alcohol consumption, and use of illegal drugs.

Coronary Veins

Coronary veins drain the heart and generally parallel the large surface arteries (see Figure 6.1.14). The great cardiac vein can be seen initially on the surface of the heart following the interventricular sulcus, but it eventually flows along the coronary sulcus into the coronary sinus on the posterior surface. The great cardiac vein initially parallels the anterior interventricular artery and drains the areas supplied by this vessel. It receives several major branches, including the posterior cardiac vein, the middle cardiac vein, and the small cardiac vein. The posterior cardiac vein parallels and drains the areas supplied by the marginal artery branch of the circumflex artery. The middle cardiac vein parallels and drains the areas supplied by the posterior interventricular artery. The small cardiac vein parallels the right coronary artery and drains the blood from the posterior surfaces of the right atrium and ventricle. The coronary sinus is a large, thin-walled vein on the posterior surface of the heart lying within the atrioventricular sulcus and emptying directly into the right atrium. The anterior cardiac veins parallel the small cardiac arteries and drain the anterior surface of the right ventricle. Unlike these other cardiac veins, it bypasses the coronary sinus and drains directly into the right atrium.

Diseases of the Heart: Coronary Artery Disease

Coronary artery disease is the leading cause of death worldwide. It occurs when the build-up of plaque—a fatty material including cholesterol, connective tissue, white blood cells, and some smooth muscle cells—within the walls of the arteries obstructs the flow of blood and decreases the flexibility or compliance of the vessels. This condition is called atherosclerosis, a hardening of the arteries that involves the accumulation of plaque. As the coronary blood vessels become occluded, the flow of blood to the tissues will be restricted, a condition called ischaemia that causes the cells to receive insufficient amounts of oxygen, called hypoxia. Figure 6.1.15 shows the blockage of coronary arteries highlighted by the injection of dye. Some individuals with coronary artery disease report pain radiating from the chest called angina pectoris, but others remain asymptomatic. If untreated, coronary artery disease can lead to MI or a heart attack.

The disease progresses slowly and often begins in children and can be seen as fatty “streaks” in the vessels. It then gradually progresses throughout life. Well-documented risk factors include smoking, family history, hypertension, obesity, diabetes, high alcohol consumption, lack of exercise, stress, and hyperlipidaemia or high circulating levels of lipids in the blood. Treatments may include medication, changes to diet and exercise, angioplasty with a balloon catheter, insertion of a stent, or coronary bypass procedure.

Angioplasty is a procedure in which the occlusion is mechanically widened with a balloon. A specialised catheter with an expandable tip is inserted into a superficial vessel, normally in the leg, and then directed to the site of the occlusion. At this point, the balloon is inflated to compress the plaque material and to open the vessel to increase blood flow. Then, the balloon is deflated and retracted. A stent consisting of a specialised mesh is typically inserted at the site of occlusion to reinforce the weakened and damaged walls. Stent insertions have been routine in cardiology for more than 40 years.

Coronary bypass surgery may also be performed. This surgical procedure grafts a replacement vessel obtained from another, less vital portion of the body to bypass the occluded area. This procedure is clearly effective in treating patients experiencing a MI, but overall does not increase longevity. Nor does it seem advisable in patients with stable although diminished cardiac capacity since frequently loss of mental acuity occurs following the procedure. Long-term changes to behaviour, emphasising diet and exercise plus a medicine regime tailored to lower blood pressure, lower cholesterol and lipids, and reduce clotting are equally as effective.

Click the drop down below to review the terms learned from this chapter.

Recall that cardiac muscle shares a few characteristics with both skeletal muscle and smooth muscle, but it has some unique properties of its own. Not the least of these exceptional properties is its ability to initiate an electrical potential at a fixed rate that spreads rapidly from cell to cell to trigger the contractile mechanism. This property is known as autorhythmicity. Neither smooth nor skeletal muscle can do this. Even though cardiac muscle has autorhythmicity, heart rate is modulated by the endocrine and nervous systems.

There are two major types of cardiac muscle cells: myocardial contractile cells and myocardial conducting cells. The myocardial contractile cells constitute the bulk (99 percent) of the cells in the atria and ventricles. Contractile cells conduct impulses and are responsible for contractions that pump blood through the body. The myocardial conducting cells (1 percent of the cells) form the conduction system of the heart. Except for Purkinje cells, they are generally much smaller than the contractile cells and have few of the myofibrils or filaments needed for contraction. Their function is similar in many respects to neurons, although they are specialised muscle cells. Myocardial conduction cells initiate and propagate the action potential (the electrical impulse) that travels throughout the heart and triggers the contractions that propel the blood.

Structure of Cardiac Muscle

Compared to the giant cylinders of skeletal muscle, cardiac muscle cells, or cardiomyocytes, are considerably shorter with much smaller diameters. Cardiac muscle also demonstrates striations, the alternating pattern of dark A bands and light I bands attributed to the precise arrangement of the myofilaments and fibrils that are organised in sarcomeres along the length of the cell (Figure 6.2.1a). These contractile elements are virtually identical to skeletal muscle. T (transverse) tubules penetrate from the surface plasma membrane, the sarcolemma, to the interior of the cell, allowing the electrical impulse to reach the interior. The T tubules are only found at the Z discs, whereas in skeletal muscle, they are found at the junction of the A and I bands. Therefore, there are one-half as many T tubules in cardiac muscle as in skeletal muscle. In addition, the sarcoplasmic reticulum stores few calcium ions, so most of the calcium ions must come from outside the cells. The result is a slower onset of contraction. Mitochondria are plentiful, providing energy for the contractions of the heart. Typically, cardiomyocytes have a single, central nucleus, but two or more nuclei may be found in some cells.

Cardiac muscle cells branch freely. A junction between two adjoining cells is marked by a critical structure called an intercalated disc, which helps support the synchronised contraction of the muscle (Figure 6.2.1b). The sarcolemmas from adjacent cells bind together at the intercalated discs. They consist of desmosomes, specialised linking proteoglycans, tight junctions, and large numbers of gap junctions that allow the passage of ions between the cells and help to synchronise the contraction (Figure 6.2.1c). Intercellular connective tissue also helps to bind the cells together. The importance of strongly binding these cells together is necessitated by the forces exerted by contraction.

Cardiac muscle undergoes aerobic respiration patterns, primarily metabolising lipids and carbohydrates. Myoglobin, lipids, and glycogen are all stored within the cytoplasm. Cardiac muscle cells undergo twitch-type contractions with long refractory periods followed by brief relaxation periods. The relaxation is essential so the heart can fill with blood for the next cycle. The refractory period is very long to prevent the possibility of tetany, a condition in which muscle remains involuntarily contracted. In the heart, tetany is not compatible with life, since it would prevent the heart from pumping blood.

Everyday Connection

Repair and Replacement

Damaged cardiac muscle cells have extremely limited abilities to repair themselves or to replace dead cells via mitosis. Recent evidence indicates that at least some stem cells remain within the heart that continue to divide and at least potentially replace these dead cells. However, newly formed or repaired cells are rarely as functional as the original cells, and cardiac function is reduced. In the event of a heart attack or MI, dead cells are often replaced by patches of scar tissue. Autopsies performed on individuals who had successfully received heart transplants show some proliferation of original cells. If researchers can unlock the mechanism that generates new cells and restore full mitotic capabilities to heart muscle, the prognosis for heart attack survivors will be greatly enhanced. To date, myocardial cells produced within the patient (in situ) by cardiac stem cells seem to be non-functional, although those grown in Petri dishes (in vitro) do beat. Perhaps soon this mystery will be solved, and new advances in treatment will be commonplace.

Conduction System of the Heart

If embryonic heart cells are separated into a Petri dish and kept alive, each can generate its own electrical impulse followed by contraction. When two independently beating embryonic cardiac muscle cells are placed together, the cell with the higher inherent rate sets the pace, and the impulse spreads from the faster to the slower cell to trigger a contraction. As more cells are joined together, the fastest cell continues to assume control of the rate. A fully developed adult heart maintains the capability of generating its own electrical impulse, triggered by the fastest cells, as part of the cardiac conduction system. The components of the cardiac conduction system include the sinoatrial node, the atrioventricular node, the atrioventricular bundle, the atrioventricular bundle branches, and the Purkinje cells (Figure 6.2.2).

Sinoatrial (SA) Node

Normal cardiac rhythm is established by the sinoatrial (SA) node, a specialised clump of myocardial conducting cells located in the superior and posterior walls of the right atrium in close proximity to the orifice of the superior vena cava. The SA node has the highest inherent rate of depolarisation and is known as the pacemaker of the heart. It initiates the sinus rhythm, or normal electrical pattern followed by contraction of the heart.

This impulse spreads from its initiation in the SA node throughout the atria through specialised internodal pathways, to the atrial myocardial contractile cells and the atrioventricular node. The internodal pathways consist of three bands (anterior, middle, and posterior) that lead directly from the SA node to the next node in the conduction system, the atrioventricular node (see Figure 6.2.2). The impulse takes approximately 50 ms (milliseconds) to travel between these two nodes. The relative importance of this pathway has been debated since the impulse would reach the atrioventricular node simply following the cell-by-cell pathway through the contractile cells of the myocardium in the atria. In addition, there is a specialised pathway called Bachmann’s bundle or the interatrial band that conducts the impulse directly from the right atrium to the left atrium. Regardless of the pathway, as the impulse reaches the atrioventricular septum, the connective tissue of the cardiac skeleton prevents the impulse from spreading into the myocardial cells in the ventricles except at the atrioventricular node. Figure 6.2.3 illustrates the initiation of the impulse in the SA node that then spreads the impulse throughout the atria to the atrioventricular node.

The electrical event, the wave of depolarisation, is the trigger for muscular contraction. The wave of depolarisation begins in the right atrium, and the impulse spreads across the superior portions of both atria and then down through the contractile cells. The contractile cells then begin contraction from the superior to the inferior portions of the atria, efficiently pumping blood into the ventricles.

Atrioventricular (AV) Node

The atrioventricular (AV) node is a second clump of specialised myocardial conductive cells, located in the inferior portion of the right atrium within the atrioventricular septum. The septum prevents the impulse from spreading directly to the ventricles without passing through the AV node. There is a critical pause before the AV node depolarises and transmits the impulse to the atrioventricular bundle (see Figure 6.2.3, step 3). This delay in transmission is partially attributable to the small diameter of the cells of the node, which slow the impulse. Also, conduction between nodal cells is less efficient than between conducting cells. These factors mean that it takes the impulse approximately 100 ms to pass through the node. This pause is critical to heart function, as it allows the atrial cardiomyocytes to complete their contraction that pumps blood into the ventricles before the impulse is transmitted to the cells of the ventricle itself. With extreme stimulation by the SA node, the AV node can transmit impulses maximally at 220 per minute. This establishes the typical maximum heart rate in a healthy young individual. Damaged hearts or those stimulated by drugs can contract at higher rates, but at these rates, the heart can no longer effectively pump blood.

Atrioventricular Bundle (Bundle of His), Bundle Branches and Purkinje fibres

Arising from the AV node, the atrioventricular bundle, or bundle of His, proceeds through the interventricular septum before dividing into two atrioventricular bundle branches, commonly called the left and right bundle branches. The left bundle branch has two fascicles. The left bundle branch supplies the left ventricle, and the right bundle branch the right ventricle. Since the left ventricle is much larger than the right, the left bundle branch is also considerably larger than the right. Portions of the right bundle branch are found in the moderator band and supply the right papillary muscles. Because of this connection, each papillary muscle receives the impulse at approximately the same time, so they begin to contract simultaneously just prior to the remainder of the myocardial contractile cells of the ventricles. This is believed to allow tension to develop on the chordae tendineae prior to right ventricular contraction. There is no corresponding moderator band on the left. Both bundle branches descend and reach the apex of the heart where they connect with the Purkinje fibres (see Figure 6.2.3, step 4). This passage takes approximately 25 ms.

The Purkinje fibres are additional myocardial conductive fibres that spread the impulse to the myocardial contractile cells in the ventricles. They extend throughout the myocardium from the apex of the heart toward the atrioventricular septum and the base of the heart. The Purkinje fibres have a fast inherent conduction rate, and the electrical impulse reaches all the ventricular muscle cells in about 75 ms (see Figure 6.2.3, step 5). Since the electrical stimulus begins at the apex, the contraction also begins at the apex and travels toward the base of the heart, like squeezing a tube of toothpaste from the bottom. This allows the blood to be pumped out of the ventricles and into the aorta and pulmonary trunk. The total time elapsed from the initiation of the impulse in the SA node until depolarisation of the ventricles is approximately 225 ms.

Membrane Potentials and Ion Movement in Cardiac Conductive Cells

Action potentials are considerably different between cardiac conductive cells and cardiac contractive cells. While Na⁺ and K⁺ play essential roles, Ca²⁺ is also critical for both types of cells. Unlike skeletal muscles and neurons, cardiac conductive cells do not have a stable resting potential. Conductive cells contain a series of sodium ion channels that allow a normal and slow influx of sodium ions that causes the membrane potential to rise slowly from an initial value of −60 mV up to about –40 mV. The resulting movement of sodium ions creates spontaneous depolarisation (or prepotential depolarisation). At this point, calcium ion channels open and Ca²⁺ enters the cell, further depolarising it at a more rapid rate until it reaches a value of approximately +5 mV. At this point, the calcium ion channels close and K+ channels open, allowing outflux of K⁺ and resulting in repolarisation. When the membrane potential reaches approximately −60 mV, the K⁺ channels close and Na⁺ channels open, and the prepotential phase begins again. This phenomenon explains the autorhythmicity properties of cardiac muscle (Figure 6.2.4).

Membrane Potentials and Ion Movement in Cardiac Contractile Cells

There is a distinctly different electrical pattern involving the contractile cells. In this case, there is a rapid depolarisation, followed by a plateau phase and then repolarisation. This phenomenon accounts for the long refractory periods required for the cardiac muscle cells to pump blood effectively before they are capable of firing for a second time. These cardiac myocytes normally do not initiate their own electrical potential, although they can do so, but rather wait for an impulse to reach them.

Contractile cells demonstrate a much more stable resting phase than conductive cells at approximately −80 mV for cells in the atria and −90 mV for cells in the ventricles. Despite this initial difference, the other components of their action potentials are virtually identical. In both cases, when stimulated by an action potential, voltage-gated channels rapidly open, beginning the positive-feedback mechanism of depolarisation. This rapid influx of positively charged ions raises the membrane potential to approximately +30 mV, at which point the sodium channels close. The rapid depolarisation period typically lasts 3–5 ms. Depolarisation is followed by the plateau phase, in which membrane potential declines relatively slowly. This is due in large part to the opening of the slow Ca²⁺ channels, allowing Ca2+ to enter the cell while few K⁺ channels are open, allowing K⁺ to exit the cell. The relatively long plateau phase lasts approximately 175 ms. Once the membrane potential reaches approximately zero, the Ca²⁺ channels close and K⁺ channels open, allowing K⁺ to exit the cell. The repolarisation lasts approximately 75 ms. At this point, membrane potential drops until it reaches resting levels once more and the cycle repeats. The entire event lasts between 250 and 300 ms (Figure 6.2.5).

The absolute refractory period for cardiac contractile muscle lasts approximately 200 ms, and the relative refractory period lasts approximately 50 ms, for a total of 250 ms. This extended period is critical, since the heart muscle must contract to pump blood effectively and the contraction must follow the electrical events. Without extended refractory periods, premature contractions would occur in the heart and would not be compatible with life.

Calcium Ions

Calcium ions play two critical roles in the physiology of cardiac muscle. Their influx through slow calcium channels accounts for the prolonged plateau phase and absolute refractory period that enable cardiac muscle to function properly. Calcium ions also combine with the regulatory protein troponin in the troponin-tropomyosin complex; this complex removes the inhibition that prevents the heads of the myosin molecules from forming cross bridges with the active sites on actin that provide the power stroke of contraction. This mechanism is virtually identical to that of skeletal muscle. Approximately 20 percent of the calcium required for contraction is supplied by the influx of Ca²⁺ during the plateau phase. The remaining Ca²⁺ for contraction is released from storage in the sarcoplasmic reticulum.

Comparative Rates of Conduction System Firing

The pattern of prepotential or spontaneous depolarisation, followed by rapid depolarisation and repolarisation just described, are seen in the SA node and a few other conductive cells in the heart. Since the SA node is the pacemaker, it reaches threshold faster than any other component of the conduction system. It will initiate the impulses spreading to the other conducting cells. The SA node, without nervous or endocrine control, would initiate a heart impulse approximately 80–100 times per minute. Although each component of the conduction system can generate its own impulse, the rate progressively slows as you proceed from the SA node to the Purkinje fibres. Without the SA node, the AV node would generate a heart rate of 40–60 beats per minute. If the AV node were blocked, the atrioventricular bundle would fire at a rate of approximately 30–40 impulses per minute. The bundle branches would have an inherent rate of 20–30 impulses per minute, and the Purkinje fibres would fire at 15–20 impulses per minute. While a few exceptionally trained aerobic athletes demonstrate resting heart rates in the range of 30–40 beats per minute (the lowest recorded figure is 28 beats per minute for Miguel Indurain, a cyclist), for most individuals, rates lower than 50 beats per minute would indicate a condition called bradycardia. Depending upon the specific individual, as rates fall much below this level, the heart would be unable to maintain adequate flow of blood to vital tissues, initially resulting in decreasing loss of function across the systems, unconsciousness, and ultimately death.

Electrocardiogram

By careful placement of surface electrodes on the body, it is possible to record the complex, compound electrical signal of the heart. This tracing of the electrical signal is the electrocardiogram (ECG), also commonly abbreviated EKG (K coming kardiology, from the German term for cardiology). Careful analysis of the ECG reveals a detailed picture of both normal and abnormal heart function and is an indispensable clinical diagnostic tool. The standard electrocardiograph (the instrument that generates an ECG) uses 3, 5, or 12 leads. The greater the number of leads an electrocardiograph uses, the more information the ECG provides. The term “lead” may be used to refer to the cable from the electrode to the electrical recorder, but it typically describes the voltage difference between two of the electrodes. The 12-lead electrocardiograph uses 10 electrodes placed in standard locations on the patient’s skin (Figure 6.2.6). In continuous ambulatory electrocardiographs, the patient wears a small, portable, battery-operated device known as a Holter monitor, or simply a Holter, that continuously monitors heart electrical activity, typically for a period of 24 hours during the patient’s normal routine.

A normal ECG tracing is presented in Figure 6.2.7. Each component, segment and interval is labelled and corresponds to important electrical events, demonstrating the relationship between these events and contraction in the heart.

There are five prominent points on the ECG: the P wave, the QRS complex and the T wave. The small P wave represents the depolarisation of the atria. The atria begin contracting approximately 25 ms after the start of the P wave. The large QRS complex represents the depolarisation of the ventricles, which requires a much stronger electrical signal because of the larger size of the ventricular cardiac muscle. The ventricles begin to contract as the QRS reaches the peak of the R wave. Lastly, the T wave represents the repolarisation of the ventricles. The repolarisation of the atria occurs during the QRS complex, which masks it on an ECG.

The major segments and intervals of an ECG tracing are indicated in Figure 6.2.7. Segments are defined as the regions between two waves. Intervals include one segment plus one or more waves. For example, the PR segment begins at the end of the P wave and ends at the beginning of the QRS complex. The PR interval starts at the beginning of the P wave and ends with the beginning of the QRS complex. The PR interval is more clinically relevant, as it measures the duration from the beginning of atrial depolarisation (the P wave) to the initiation of the QRS complex. Since the Q wave may be difficult to view in some tracings, the measurement is often extended to the R that is more easily visible. Should there be a delay in passage of the impulse from the SA node to the AV node, it would be visible in the PR interval. Figure 6.2.8 correlates events of heart contraction to the corresponding segments and intervals of an ECG.

Everyday Connection

ECG Abnormalities

Occasionally, an area of the heart other than the SA node will initiate an impulse that will be followed by a premature contraction. Such an area, which may be a component of the conduction system or some other contractile cells, is known as an ectopic focus or ectopic pacemaker. An ectopic focus may be stimulated by localised ischaemia; exposure to certain drugs, including caffeine, digitalis, or acetylcholine; elevated stimulation by both sympathetic or parasympathetic divisions of the autonomic nervous system; or several disease or pathological conditions. Occasional occurrences are generally transitory and nonlife threatening, but if the condition becomes chronic, it may lead to either an arrhythmia, a deviation from the normal pattern of impulse conduction and contraction, or to fibrillation, an uncoordinated beating of the heart.

While interpretation of an ECG is possible and extremely valuable after some training, a full understanding of the complexities and intricacies generally requires several years of experience. In general, the size of the electrical variations, the duration of the events, and detailed vector analysis provide the most comprehensive picture of cardiac function. For example, an amplified P wave may indicate enlargement of the atria, an enlarged Q wave may indicate a MI, and an enlarged suppressed or inverted Q wave often indicates enlarged ventricles. T waves often appear flatter when insufficient oxygen is being delivered to the myocardium. An elevation of the ST segment above baseline is often seen in patients with an acute MI and may appear depressed below the baseline when hypoxia is occurring.

As useful as analysing these electrical recordings may be, there are limitations. For example, not all areas suffering a MI may be obvious on the ECG. Additionally, it will not reveal the effectiveness of the pumping, which requires further testing, such as an ultrasound test called an echocardiogram or nuclear medicine imaging. It is also possible for there to be pulseless electrical activity, which will show up on an ECG tracing, although there is no corresponding pumping action. Common abnormalities that may be detected by the ECGs are shown in Figure 6.2.9.

Everyday Connection

External Automated Defibrillators

If the electrical activity of the heart is severely disrupted, cessation of electrical activity or fibrillation may occur. In fibrillation, the heart beats in a wild, uncontrolled manner, which prevents it from being able to pump effectively. Atrial fibrillation (see Figure 6.2.9b) is a serious condition, but as long as the ventricles continue to pump blood, the patient’s life may not be in immediate danger. Ventricular fibrillation (see Figure 6.2.9d) is a medical emergency that requires life support, because the ventricles are not effectively pumping blood. In a hospital setting, it is often described as “code blue.” If untreated for as little as a few minutes, ventricular fibrillation may lead to brain death. The most common treatment is defibrillation, which uses special paddles to apply a charge to the heart from an external electrical source in an attempt to establish a normal sinus rhythm (Figure 6.2.10). A defibrillator effectively stops the heart so that the SA node can trigger a normal conduction cycle. Because of their effectiveness in re-establishing a normal sinus rhythm, external automated defibrillators (EADs) are being placed in areas frequented by large numbers of people, such as schools, restaurants, and airports. These devices contain simple and direct verbal instructions that can be followed by nonmedical personnel to save a life.

A heart block refers to an interruption in the normal conduction pathway. The nomenclature for these is very straightforward. SA nodal blocks occur within the SA node. AV nodal blocks occur within the AV node. Infra-Hisian blocks involve the bundle of His. Bundle branch blocks occur within either the left or right atrioventricular bundle branches. Hemiblocks are partial and occur within one or more fascicles of the atrioventricular bundle branch. Clinically, the most common types are the AV nodal and infra-Hisian blocks.

AV blocks are often described by degrees. A first-degree or partial block indicates a delay in conduction between the SA and AV nodes. This can be recognised on the ECG as an abnormally long PR interval. A second-degree or incomplete block occurs when some impulses from the SA node reach the AV node and continue, while others do not. In this instance, the ECG would reveal some P waves not followed by a QRS complex, while others would appear normal. In the third-degree or complete block, there is no correlation between atrial activity (the P wave) and ventricular activity (the QRS complex). Even in the event of a total SA block, the AV node will assume the role of pacemaker and continue initiating contractions at 40–60 contractions per minute, which is adequate to maintain consciousness.

When arrhythmias become a chronic problem, the heart maintains a junctional rhythm, which originates in the AV node. In order to speed up the heart rate and restore full sinus rhythm, a cardiologist can implant an artificial pacemaker, which delivers electrical impulses to the heart muscle to ensure that the heart continues to contract and pump blood effectively. These artificial pacemakers are programmable by the cardiologists and can either provide stimulation temporarily upon demand or on a continuous basis. Some devices also contain built-in defibrillators.

Cardiac Muscle Metabolism

Normally, cardiac muscle metabolism is entirely aerobic. Oxygen from the lungs is brought to the heart, and every other organ, attached to the haemoglobin molecules within the erythrocytes. Heart cells also store appreciable amounts of oxygen in myoglobin. Normally, these two mechanisms, circulating oxygen and oxygen attached to myoglobin, can supply sufficient oxygen to the heart, even during peak performance.

Fatty acids and glucose from the circulation are broken down within the mitochondria to release energy in the form of ATP. Both fatty acid droplets and glycogen are stored within the sarcoplasm and provide additional nutrient supply.

Click the drop down below to review the terms learned from this chapter.

The period of time that begins with contraction of the atria and ends with ventricular relaxation is known as the cardiac cycle (Figure 6.3.1). The period of contraction that the heart undergoes while it pumps blood into circulation is called systole. The period of relaxation that occurs as the chambers fill with blood is called diastole. Both the atria and ventricles undergo systole and diastole, and it is essential that these components be carefully regulated and coordinated to ensure blood is pumped efficiently to the body.

Pressures and Flow

Fluids, whether gases or liquids, are materials that flow according to pressure gradients—that is, they move from regions that are higher in pressure to regions that are lower in pressure. Accordingly, when the heart chambers are relaxed (diastole), blood will flow into the atria from the veins, which are higher in pressure. As blood flows into the atria, the pressure will rise, so the blood will initially move passively from the atria into the ventricles. When the action potential triggers the muscles in the atria to contract (atrial systole), the pressure within the atria rises further, pumping blood into the ventricles. During ventricular systole, pressure rises in the ventricles, pumping blood into the pulmonary trunk from the right ventricle and into the aorta from the left ventricle. Again, as you consider this flow and relate it to the conduction pathway, the elegance of the system should become apparent.

Phases of the Cardiac Cycle

At the beginning of the cardiac cycle, both the atria and ventricles are relaxed (diastole). Blood is flowing into the right atrium from the superior and inferior venae cavae and the coronary sinus. Blood flows into the left atrium from the four pulmonary veins. The two atrioventricular valves, the tricuspid and mitral valves, are both open, so blood flows unimpeded from the atria and into the ventricles. Approximately 70–80 percent of ventricular filling occurs by this method. The two semilunar valves, the pulmonary and aortic valves, are closed, preventing backflow of blood into the right and left ventricles from the pulmonary trunk on the right and the aorta on the left.

Atrial Systole and Diastole

Contraction of the atria follows depolarisation, represented by the P wave of the ECG. As the atrial muscles contract from the superior portion of the atria toward the atrioventricular septum, pressure rises within the atria and blood is pumped into the ventricles through the open atrioventricular (tricuspid, and mitral or bicuspid) valves. At the start of atrial systole, the ventricles are normally filled with approximately 70–80 percent of their capacity due to inflow during diastole. Atrial contraction, also referred to as the “atrial kick,” contributes the remaining 20–30 percent of filling (see Figure 6.3.1). Atrial systole lasts approximately 100 ms and ends prior to ventricular systole, as the atrial muscle returns to diastole.

Ventricular Systole

Ventricular systole (see Figure 6.3.1) follows the depolarisation of the ventricles and is represented by the QRS complex in the ECG. It may be conveniently divided into two phases, lasting a total of 270 ms. At the end of atrial systole and just prior to atrial contraction, the ventricles contain approximately 130 mL blood in a resting adult in a standing position. This volume is known as the end diastolic volume (EDV) or preload.

Initially, as the muscles in the ventricle contract, the pressure of the blood within the chamber rises, but it is not yet high enough to open the semilunar (pulmonary and aortic) valves and be ejected from the heart. However, blood pressure quickly rises above that of the atria that are now relaxed and in diastole. This increase in pressure causes blood to flow back toward the atria, closing the tricuspid and mitral valves. Since blood is not being ejected from the ventricles at this early stage, the volume of blood within the chamber remains constant. Consequently, this initial phase of ventricular systole is known as isovolumic contraction, also called isovolumetric contraction (see Figure 6.3.1).

In the second phase of ventricular systole, the ventricular ejection phase, the contraction of the ventricular muscle has raised the pressure within the ventricle to the point that it is greater than the pressures in the pulmonary trunk and the aorta. Blood is pumped from the heart, pushing open the pulmonary and aortic semilunar valves. Pressure generated by the left ventricle will be appreciably greater than the pressure generated by the right ventricle, since the existing pressure in the aorta will be so much higher. Nevertheless, both ventricles pump the same amount of blood. This quantity is referred to as stroke volume. Stroke volume will normally be in the range of 70–80 mL. Since ventricular systole began with an EDV of approximately 130 mL of blood, this means that there is still 50–60 mL of blood remaining in the ventricle following contraction. This volume of blood is known as the end systolic volume (ESV).

Ventricular Diastole

Ventricular relaxation, or diastole, follows repolarisation of the ventricles and is represented by the T wave of the ECG. It too is divided into two distinct phases and lasts approximately 430 ms.

During the early phase of ventricular diastole, as the ventricular muscle relaxes, pressure on the remaining blood within the ventricle begins to fall. When pressure within the ventricles drops below pressure in both the pulmonary trunk and aorta, blood flows back toward the heart, producing the dicrotic notch (small dip) seen in blood pressure tracings. The semilunar valves close to prevent backflow into the heart. Since the atrioventricular valves remain closed at this point, there is no change in the volume of blood in the ventricle, so the early phase of ventricular diastole is called the isovolumic ventricular relaxation phase, also called isovolumetric ventricular relaxation phase (see Figure 6.3.1).

In the second phase of ventricular diastole, called late ventricular diastole, as the ventricular muscle relaxes, pressure on the blood within the ventricles drops even further. Eventually, it drops below the pressure in the atria. When this occurs, blood flows from the atria into the ventricles, pushing open the tricuspid and mitral valves. As pressure drops within the ventricles, blood flows from the major veins into the relaxed atria and from there into the ventricles. Both chambers are in diastole, the atrioventricular valves are open, and the semilunar valves remain closed (see Figure 6.3.1). The cardiac cycle is complete.

Figure 6.3.2 illustrates the relationship between the cardiac cycle and the ECG.

Heart Sounds

One of the simplest, yet effective, diagnostic techniques applied to assess the state of a patient’s heart is auscultation using a stethoscope.

In a normal, healthy heart, there are only two audible heart sounds: S1 and S2. S1 is the sound created by the closing of the atrioventricular valves during ventricular contraction and is normally described as a “lub,” or first heart sound. The second heart sound, S2, is the sound of the closing of the semilunar valves during ventricular diastole and is described as a “dub” (Figure 6.3.3). In both cases, as the valves close, the openings within the atrioventricular septum guarded by the valves will become reduced, and blood flow through the opening will become more turbulent until the valves are fully closed. There is a third heart sound, S3, but it is rarely heard in healthy individuals. It may be the sound of blood flowing into the atria, or blood sloshing back and forth in the ventricle, or even tensing of the chordae tendineae. S3 may be heard in youth, some athletes, and pregnant women. If the sound is heard later in life, it may indicate congestive heart failure, warranting further tests. Some cardiologists refer to the collective S1, S2, and S3 sounds as the “Kentucky gallop,” because they mimic those produced by a galloping horse. The fourth heart sound, S4, results from the contraction of the atria pushing blood into a stiff or hypertrophic ventricle, indicating failure of the left ventricle. S4 occurs prior to S1 and the collective sounds S4, S1, and S2 are referred to by some cardiologists as the “Tennessee gallop,” because of their similarity to the sound produced by a galloping horse with a different gait. A few individuals may have both S3 and S4, and this combined sound is referred to as S7.

The term murmur is used to describe an unusual sound coming from the heart that is caused by the turbulent flow of blood. Murmurs are graded on a scale of 1 to 6, with 1 being the most common, the most difficult sound to detect, and the least serious. The most severe is a 6. Phonocardiograms or auscultograms can be used to record both normal and abnormal sounds using specialised electronic stethoscopes.

During auscultation, it is common practice for the clinician to ask the patient to breathe deeply. This procedure not only allows for listening to airflow, but it may also amplify heart murmurs. Inhalation increases blood flow into the right side of the heart and may increase the amplitude of right-sided heart murmurs. Expiration partially restricts blood flow into the left side of the heart and may amplify left-sided heart murmurs. Figure 6.3.4 indicates proper placement of the bell of the stethoscope to facilitate auscultation.

Click the drop down below to review the terms learned from this chapter.

The autorhythmicity inherent in cardiac cells keeps the heart beating at a regular pace; however, the heart is regulated by and responds to outside influences as well. Neural and endocrine controls are vital to the regulation of cardiac function. In addition, the heart is sensitive to several environmental factors, including electrolytes.

Resting Cardiac Output

Cardiac output (CO) is a measurement of the amount of blood pumped by each ventricle in one minute. To calculate this value, multiply stroke volume (SV), the amount of blood pumped by each ventricle, by heart rate (HR), in contractions per minute (or beats per minute, bpm). It can be represented mathematically by the following equation:

CO = HR × SV

SV is normally measured using an echocardiogram to record EDV and ESV and calculating the difference: SV = EDV – ESV. SV can also be measured using a specialised catheter, but this is an invasive procedure and far more dangerous to the patient. A mean SV for a resting 70-kg (150-lb) individual would be approximately 70 mL. There are several important variables, including size of the heart, physical and mental condition of the individual, sex, contractility, duration of contraction, preload or EDV, and afterload or resistance. Normal range for SV would be 55–100 mL. An average resting HR would be approximately 75 bpm but could range from 60–100 in some individuals.

Using these numbers, the mean CO is 5.25 L/min, with a range of 4.0–8.0 L/min. Remember, however, that these numbers refer to CO from each ventricle separately, not the total for the heart. Factors influencing CO are summarised in Figure 6.4.1.

SVs are also used to calculate ejection fraction, which is the portion of the blood that is pumped or ejected from the heart with each contraction. To calculate ejection fraction, SV is divided by EDV. Despite the name, the ejection fraction is normally expressed as a percentage. Ejection fractions range from approximately 55–70 percent, with a mean of 58 percent.

Exercise and Maximum Cardiac Output

In healthy young individuals, HR may increase to 150 bpm during exercise. SV can also increase from 70 to approximately 130 mL due to increased strength of contraction. This would increase CO to approximately 19.5 L/min, 4–5 times the resting rate. Top cardiovascular athletes can achieve even higher levels. At their peak performance, they may increase resting CO by 7–8 times.

Since the heart is a muscle, exercising it increases its efficiency. The difference between maximum and resting CO is known as the cardiac reserve. It measures the residual capacity of the heart to pump blood.

Heart Rates

HRs vary considerably, not only with exercise and fitness levels, but also with age. Newborn resting HRs may be 120 bpm. HR gradually decreases until young adulthood and then gradually increases again with age.

Maximum HRs are normally in the range of 200–220 bpm, although there are some extreme cases in which they may reach higher levels. As one ages, the ability to generate maximum rates decreases. This may be estimated by taking the maximal value of 220 bpm and subtracting the individual’s age. So, a 40-year-old individual would be expected to hit a maximum rate of approximately 180, and a 60-year-old person would achieve a HR of 160.

Disorders of the Heart: Abnormal Heart Rates

For an adult, normal resting HR will be in the range of 60–100 bpm. Bradycardia is the condition in which resting rate drops below 60 bpm, and tachycardia is the condition in which the resting rate is above 100 bpm. Trained athletes typically have very low HRs. If the patient is not exhibiting other symptoms, such as weakness, fatigue, dizziness, fainting, chest discomfort, palpitations, or respiratory distress, bradycardia is not considered clinically significant. However, if any of these symptoms are present, they may indicate that the heart is not providing sufficient oxygenated blood to the tissues. The term relative bradycardia may be used with a patient who has a HR in the normal range but is still suffering from these symptoms. Most patients remain asymptomatic if the HR remains above 50 bpm.

Bradycardia may be caused by either inherent factors or causes external to the heart. While the condition may be inherited, typically it is acquired in older individuals. Inherent causes include abnormalities in either the SA or AV node. If the condition is serious, a pacemaker may be required. Other causes include ischaemia to the heart muscle or diseases of the heart vessels or valves. External causes include metabolic disorders, pathologies of the endocrine system often involving the thyroid, electrolyte imbalances, neurological disorders including inappropriate autonomic responses, autoimmune pathologies, over-prescription of beta blocker drugs that reduce HR, recreational drug use, or even prolonged bed rest. Treatment relies upon establishing the underlying cause of the disorder and may necessitate supplemental oxygen.

Tachycardia is not normal in a resting patient but may be detected in pregnant women or individuals experiencing extreme stress. In the latter case, it would likely be triggered by stimulation from the limbic system or disorders of the autonomic nervous system. In some cases, tachycardia may involve only the atria. Some individuals may remain asymptomatic, but when present, symptoms may include dizziness, shortness of breath, light-headedness, rapid pulse, heart palpations, chest pain, or fainting (syncope). While tachycardia is defined as a HR above 100 bpm, there is considerable variation among people. Further, the normal resting HRs of children are often above 100 bpm, but this is not considered to be tachycardia Many causes of tachycardia may be benign, but the condition may also be correlated with fever, anaemia, hypoxia, hyperthyroidism, hypersecretion of catecholamines, some cardiomyopathies, some disorders of the valves, and acute exposure to radiation. Elevated rates in an exercising or resting patient are normal and expected. Resting rate should always be taken after recovery from exercise. Treatment depends upon the underlying cause but may include medications, implantable cardioverter defibrillators, ablation or surgery.

Correlation Between Heart Rates and Cardiac Output

Initially, physiological conditions that cause HR to increase also trigger an increase in SV. During exercise, the rate of blood returning to the heart increases. However, as the HR rises, there is less time spent in diastole and consequently less time for the ventricles to fill with blood. Even though there is less filling time, SV will initially remain high. However, as HR continues to increase, SV gradually decreases due to decreased filling time. CO will initially stabilise as the increasing HR compensates for the decreasing SV, but at very high rates, CO will eventually decrease as increasing rates are no longer able to compensate for the decreasing SV. Consider this phenomenon in a healthy young individual. Initially, as HR increases from resting to approximately 120 bpm, CO will rise. As HR increases from 120 to 160 bpm, CO remains stable, since the increase in rate is offset by decreasing ventricular filling time and, consequently, SV. As HR continues to rise above 160 bpm, CO decreases as SV falls faster than HR increases. So, although aerobic exercises are critical to maintain the health of the heart, individuals are cautioned to monitor their HR to ensure they stay within the target heart rate range of between 120 and 160 bpm, so CO is maintained. The target HR is loosely defined as the range in which both the heart and lungs receive the maximum benefit from the aerobic workout and is dependent upon age.

Cardiovascular Centres

Nervous control over HR is centralised within the two paired cardiovascular centres of the medulla oblongata (Figure 6.4.2). The cardioaccelerator regions stimulate activity via sympathetic stimulation of the cardioaccelerator nerves, and the cardioinhibitory centres decrease heart activity via parasympathetic stimulation as one component of the vagus nerve, cranial nerve X. During rest, both centres provide slight stimulation to the heart, contributing to autonomic tone. This is a similar concept to tone in skeletal muscles. Normally, vagal stimulation predominates as, left unregulated, the SA node would initiate a sinus rhythm of approximately 100 bpm.

Both sympathetic and parasympathetic stimulations flow through a paired complex network of nerve fibres known as the cardiac plexus near the base of the heart. The cardioaccelerator centres also sends additional fibres, forming the cardiac nerves via sympathetic ganglia (the cervical ganglia plus superior thoracic ganglia T1–T4) to both the SA and AV nodes, plus additional fibres to the atria and ventricles. The ventricles are more richly innervated by sympathetic fibres than parasympathetic fibres. Sympathetic stimulation causes the release of the neurotransmitter noradrenaline (NA) at the neuromuscular junction of the cardiac nerves. NA shortens the repolarisation period, thus speeding the rate of depolarisation and contraction, which results in an increase in HR. It opens chemical- or ligand-gated sodium and calcium ion channels, allowing an influx of positively charged ions.

NA binds to the beta-1 receptor. Some cardiac medications (for example, beta blockers) work by blocking these receptors, thereby slowing HR and are one possible treatment for hypertension. Over prescription of these drugs may lead to bradycardia and even stoppage of the heart.

Parasympathetic stimulation originates from the cardioinhibitory region with impulses traveling via the vagus nerve (cranial nerve X). The vagus nerve sends branches to both the SA and AV nodes, and to portions of both the atria and ventricles. Parasympathetic stimulation releases the neurotransmitter acetylcholine (ACh) at the neuromuscular junction. ACh slows HR by opening chemical- or ligand-gated potassium ion channels to slow the rate of spontaneous depolarisation, which extends repolarisation and increases the time before the next spontaneous depolarisation occurs. Without any nervous stimulation, the SA node would establish a sinus rhythm of approximately 100 bpm. Since resting rates are considerably less than this, it becomes evident that parasympathetic stimulation normally slows HR. This is like an individual driving a car with one foot on the brake pedal. To speed up, one need merely remove one’s foot from the break and let the engine increase speed. In the case of the heart, decreasing parasympathetic stimulation decreases the release of ACh, which allows HR to increase up to approximately 100 bpm. Any increases beyond this rate would require sympathetic stimulation. Figure 6.4.3 illustrates the effects of parasympathetic and sympathetic stimulation on the normal sinus rhythm.

Input to the Cardiovascular Centre

The cardiovascular centre receives input from a series of visceral receptors with impulses traveling through visceral sensory fibres within the vagus and sympathetic nerves via the cardiac plexus. Among these receptors are various proprioreceptors, baroreceptors, and chemoreceptors, plus stimuli from the limbic system. Collectively, these inputs normally enable the cardiovascular centre to regulate heart function precisely, a process known as cardiac reflexes. Increased physical activity results in increased rates of firing by various proprioreceptors located in muscles, joint capsules, and tendons. Any such increase in physical activity would logically warrant increased blood flow. The cardiac centre monitor these increased rates of firing and suppress parasympathetic stimulation and increase sympathetic stimulation as needed in order to increase blood flow.

Similarly, baroreceptors are stretch receptors located in the aortic sinus, carotid bodies, the venae cavae, and other locations, including pulmonary vessels and the right side of the heart itself. Rates of firing from the baroreceptors represent blood pressure, level of physical activity, and the relative distribution of blood. The cardiac centre monitor baroreceptor firing to maintain cardiac homeostasis, a mechanism called the baroreceptor reflex. With increased pressure and stretch, the rate of baroreceptor firing increases, and the cardiac centre decrease sympathetic stimulation and increase parasympathetic stimulation. As pressure and stretch decrease, the rate of baroreceptor firing decreases, and the cardiac centre increase sympathetic stimulation and decrease parasympathetic stimulation.

There is a similar reflex, called the atrial reflex or Bainbridge reflex, associated with varying rates of blood flow to the atria. Increased venous return stretches the walls of the atria where specialised baroreceptors are located. However, as the atrial baroreceptors increase their rate of firing and as they stretch due to the increased blood pressure, the cardiac centre responds by increasing sympathetic stimulation and inhibiting parasympathetic stimulation to increase HR. The opposite is also true.

Increased metabolic by-products associated with increased activity, such as carbon dioxide, hydrogen ions, and lactic acid, plus falling oxygen levels, are detected by a suite of chemoreceptors innervated by the glossopharyngeal and vagus nerves. These chemoreceptors provide feedback to the cardiovascular centre about the need for increased or decreased blood flow, based on the relative levels of these substances.

The limbic system can also significantly impact HR related to emotional state. During periods of stress, it is not unusual to identify higher than normal HRs, often accompanied by a surge in the stress hormone cortisol. Individuals experiencing extreme anxiety may manifest panic attacks with symptoms that resemble those of heart attacks. These events are typically transient and treatable. Meditation techniques have been developed to ease anxiety and have been shown to lower HR effectively. Doing simple deep and slow breathing exercises with one’s eyes closed can also significantly reduce this anxiety and HR.

Disorders of the Heart: Broken Heart Syndrome

Extreme stress from such life events as the death of a loved one, an emotional break up, loss of income, or foreclosure of a home may lead to a condition commonly referred to as broken heart syndrome. This condition may also be called Takotsubo cardiomyopathy, transient apical ballooning syndrome, apical ballooning cardiomyopathy, stress-induced cardiomyopathy, Gebrochenes-Herz syndrome, and stress cardiomyopathy. The recognised effects on the heart include congestive heart failure due to a profound weakening of the myocardium not related to lack of oxygen. This may lead to acute heart failure, lethal arrhythmias, or even the rupture of a ventricle. The exact aetiology is not known, but several factors have been suggested, including transient vasospasm, dysfunction of the cardiac capillaries, or thickening of the myocardium—particularly in the left ventricle—that may lead to the critical circulation of blood to this region. While many patients survive the initial acute event with treatment to restore normal function, there is a strong correlation with death. Careful statistical analysis by the Cass Business School, a prestigious institution located in London, published in 2008, revealed that within one year of the death of a loved one, women are more than twice as likely to die and males are six times as likely to die as would otherwise be expected.

Other Factors Influencing Heart Rate

Using a combination of autorhythmicity and innervation, the cardiovascular centre can provide relatively precise control over HR. However, there are a number of other factors that have an impact on HR as well, including adrenaline, noradrenaline and thyroid hormones; levels of various ions including calcium, potassium, and sodium; body temperature; hypoxia; and pH balance (Table 6.4.1 and Table 6.4.2). After reading this section, the importance of maintaining homeostasis should become even more apparent.

Table 6.4.1. Major factors increasing heart rate and force of contraction

Table 6.4.2. Factors decreasing heart rate and force of contraction

Adrenaline (A) and Noradrenaline (NA)

The catecholamines, adrenaline and noradrenaline, secreted by the adrenal medulla form one component of the extended fight-or-flight mechanism. The other component is sympathetic stimulation. Adrenaline and NA have similar effects: binding to the beta-1 receptors, and opening sodium and calcium ion chemical- or ligand-gated channels. The rate of depolarisation is increased by this additional influx of positively charged ions, so the threshold is reached more quickly and the period of repolarisation is shortened. However, massive releases of these hormones coupled with sympathetic stimulation may actually lead to arrhythmias. There is no parasympathetic stimulation to the adrenal medulla.

Thyroid Hormones

In general, increased levels of thyroid hormone, or thyroxine, increase cardiac rate and contractility. The impact of thyroid hormone is typically of a much longer duration than that of the catecholamines. The physiologically active form of thyroid hormone, T₃ or triiodothyronine, has been shown to directly enter cardiomyocytes and alter activity at the level of the genome. It also impacts the beta adrenergic response similar to adrenaline and NA described above. Excessive levels of thyroxine may trigger tachycardia.

Calcium

Calcium ion levels have great impacts upon both HR and contractility; as the levels of calcium ions increase, so do HR and contractility. High levels of calcium ions (hypercalcaemia) may be implicated in a short QT interval and a widened T wave in the ECG. The QT interval represents the time from the start of depolarisation to repolarisation of the ventricles and includes the period of ventricular systole. Extremely high levels of calcium may induce cardiac arrest. Drugs known as calcium channel blockers slow HR by binding to these channels and blocking or slowing the inward movement of calcium ions.

Caffeine and Nicotine

Caffeine and nicotine are not found naturally within the body. Both of these nonregulated drugs have an excitatory effect on membranes of neurons in general and have a stimulatory effect on the cardiac centres specifically, causing an increase in HR. Caffeine works by increasing the rates of depolarisation at the SA node, whereas nicotine stimulates the activity of the sympathetic neurons that deliver impulses to the heart.

Although it is the world’s most widely consumed psychoactive drug, caffeine is legal and not regulated. While precise quantities have not been established, “normal” consumption is not considered harmful to most people, although it may cause disruptions to sleep and acts as a diuretic. Its consumption by pregnant women is cautioned against, although no evidence of negative effects has been confirmed. Tolerance and even physical and mental addiction to the drug result in individuals who routinely consume the substance.

Nicotine, too, is a stimulant and produces addiction. While legal and nonregulated, concerns about nicotine’s safety and documented links to respiratory and cardiac disease and cancer have resulted in warning labels on cigarette packages.

Factors Decreasing Heart Rate

HR can be slowed when a person experiences altered sodium and potassium levels, hypoxia, acidosis, alkalosis and hypothermia (see Table 6.4.2). The relationship between electrolytes and HR is complex but maintaining electrolyte balance is critical to the normal wave of depolarisation. Of the two ions, potassium has the greater clinical significance. Initially, both hyponatraemia (low sodium levels) and hypernatraemia (high sodium levels) may lead to tachycardia. Severely high hypernatraemia may lead to fibrillation, which may cause CO to cease. Severe hyponatraemia leads to both bradycardia and other arrhythmias. Hypokalaemia (low potassium levels) also leads to arrhythmias, whereas hyperkalaemia (high potassium levels) causes the heart to become weak and flaccid, and ultimately to fail.

Heart muscle relies exclusively on aerobic metabolism for energy. Hypoxia (an insufficient supply of oxygen) leads to decreasing HRs, since metabolic reactions fuelling heart contraction are restricted.

Acidosis is a condition in which excess hydrogen ions are present, and the patient’s blood expresses a low pH value. Alkalosis is a condition in which there are too few hydrogen ions, and the patient’s blood has an elevated pH. Normal blood pH falls in the range of 7.35–7.45, so a number lower than this range represents acidosis and a higher number represents alkalosis. Recall that enzymes are the regulators or catalysts of virtually all biochemical reactions; they are sensitive to pH and will change shape slightly with values outside their normal range. These variations in pH and accompanying slight physical changes to the active site on the enzyme decrease the rate of formation of the enzyme-substrate complex, subsequently decreasing the rate of many enzymatic reactions, which can have complex effects on HR. Severe changes in pH will lead to denaturation of the enzyme.

The last variable is body temperature. Elevated body temperature is called hyperthermia, and suppressed body temperature is called hypothermia. Slight hyperthermia results in increasing HR and strength of contraction. Hypothermia slows the rate and strength of heart contractions. This distinct slowing of the heart is one component of the larger diving reflex that diverts blood to essential organs while submerged. If sufficiently chilled, the heart will stop beating, a technique that may be employed during open heart surgery. In this case, the patient’s blood is normally diverted to an artificial heart-lung machine to maintain the body’s blood supply and gas exchange until the surgery is complete, and sinus rhythm can be restored. Excessive hyperthermia and hypothermia will both result in death, as enzymes drive the body systems to cease normal function, beginning with the central nervous system.

Stroke Volume

Many of the same factors that regulate HR also impact cardiac function by altering SV. While several variables are involved, SV is ultimately dependent upon the difference between EDV and ESV. The three primary factors to consider are preload, or the stretch on the ventricles prior to contraction; the contractility, or the force or strength of the contraction itself; and afterload, the force the ventricles must generate to pump blood against the resistance in the vessels. These factors are summarised in Table 6.4.1 and Table 6.4.2.

Preload

Preload is another way of expressing EDV. Therefore, the greater the EDV is, the greater the preload is. One of the primary factors to consider is filling time, or the duration of ventricular diastole during which filling occurs. The more rapidly the heart contracts, the shorter the filling time becomes, and the lower the EDV and preload are. This effect can be partially overcome by increasing the second variable, contractility, and raising SV, but over time, the heart is unable to compensate for decreased filling time, and preload also decreases.

With increasing ventricular filling, both EDV or preload increase, and the cardiac muscle itself is stretched to a greater degree. At rest, there is little stretch of the ventricular muscle, and the sarcomeres remain short. With increased ventricular filling, the ventricular muscle is increasingly stretched and the sarcomere length increases. As the sarcomeres reach their optimal lengths, they will contract more powerfully, because more of the myosin heads can bind to the actin on the thin filaments, forming cross bridges and increasing the strength of contraction and SV. If this process were to continue and the sarcomeres stretched beyond their optimal lengths, the force of contraction would decrease. However, due to the physical constraints of the location of the heart, this excessive stretch is not a concern.

The relationship between ventricular stretch and contraction has been stated in the well-known Frank-Starling mechanism or simply Starling’s Law of the Heart. This principle states that, within physiological limits, the force of heart contraction is directly proportional to the initial length of the muscle fibre. This means that the greater the stretch of the ventricular muscle (within limits), the more powerful the contraction is, which in turn increases SV. Therefore, by increasing preload, you increase the second variable, contractility.

Otto Frank (1865–1944) was a German physiologist; among his many published works are detailed studies of this important heart relationship. Ernest Starling (1866–1927) was an important English physiologist who also studied the heart. Although they worked largely independently, their combined efforts and similar conclusions have been recognised in the name “Frank-Starling mechanism.”

Any sympathetic stimulation to the venous system will increase venous return to the heart, which contributes to ventricular filling, and EDV and preload. While much of the ventricular filling occurs while both atria and ventricles are in diastole, the contraction of the atria, the atrial kick, plays a crucial role by providing the last 20–30 percent of ventricular filling.

Contractility

It is virtually impossible to consider preload or ESV without including an early mention of the concept of contractility. Indeed, the two parameters are intimately linked. Contractility refers to the force of the contraction of the heart muscle, which controls SV, and is the primary parameter for impacting ESV. The more forceful the contraction is, the greater the SV and smaller the ESV are. Less forceful contractions result in smaller SVs and larger ESVs. Factors that increase contractility are described as positive inotropic factors, and those that decrease contractility are described as negative inotropic factors (ino- = “fibre;” -tropic = “turning toward”).

Not surprisingly, sympathetic stimulation is a positive inotrope, whereas parasympathetic stimulation is a negative inotrope. Sympathetic stimulation triggers the release of NE at the neuromuscular junction from the cardiac nerves and stimulates the adrenal cortex to secrete adrenaline and NE. In addition to their stimulatory effects on HR, they also bind to both alpha and beta receptors on the cardiac muscle cell membrane to increase metabolic rate and the force of contraction. This combination of actions has the net effect of increasing SV and leaving a smaller residual ESV in the ventricles. In comparison, parasympathetic stimulation releases ACh at the neuromuscular junction from the vagus nerve. The membrane hyperpolarises and inhibits contraction to decrease the strength of contraction and SV, and to raise ESV. Since parasympathetic fibres are more widespread in the atria than in the ventricles, the primary site of action is in the upper chambers. Parasympathetic stimulation in the atria decreases the atrial kick and reduces EDV, which decreases ventricular stretch and preload, thereby further limiting the force of ventricular contraction. Stronger parasympathetic stimulation also directly decreases the force of contraction of the ventricles.

Several synthetic drugs, including dopamine and isoproterenol, have been developed that mimic the effects of adrenaline and NE by stimulating the influx of calcium ions from the extracellular fluid. Higher concentrations of intracellular calcium ions increase the strength of contraction. Excess calcium (hypercalcaemia) also acts as a positive inotropic agent. The drug digitalis lowers HR and increases the strength of the contraction, acting as a positive inotropic agent by blocking the sequestering of calcium ions into the sarcoplasmic reticulum. This leads to higher intracellular calcium levels and greater strength of contraction. In addition to the catecholamines from the adrenal medulla, other hormones also demonstrate positive inotropic effects. These include thyroid hormones and glucagon from the pancreas.

Negative inotropic agents include hypoxia, acidosis, hyperkalaemia, and a variety of synthetic drugs. These include numerous beta blockers and calcium channel blockers. Early beta blocker drugs include propranolol and pronethalol and are credited with revolutionising treatment of cardiac patients experiencing angina pectoris. There is also a large class of dihydropyridine, phenylalkylamine, and benzothiazepine calcium channel blockers that may be administered decreasing the strength of contraction and SV.

Afterload

Afterload refers to the tension that the ventricles must develop to pump blood effectively against the resistance in the vascular system. Any condition that increases resistance requires a greater afterload to force open the semilunar valves and pump the blood. Damage to the valves, such as stenosis, which makes them harder to open will also increase afterload. Any decrease in resistance decreases the afterload. Figure 6.4.4 summarises the major factors influencing SV, Figure 6.4.5 summarises the major factors influencing CO, and Table 6.4.3 and Table 6.4.4 summarise cardiac responses to increased and decreased blood flow and pressure in order to restore homeostasis.

Table 6.4.3. Cardiac response to decreasing blood flow and pressure due to decreasing cardiac output

Table 6.4.4. Cardiac response to increasing blood flow and pressure due to increasing cardiac output

Click the drop down below to review the terms learned from this chapter.

The human heart is the first functional organ to develop. It begins beating and pumping blood around day 21 or 22, a mere three weeks after fertilisation. This emphasises the critical nature of the heart in distributing blood through the vessels and the vital exchange of nutrients, oxygen, and wastes both to and from the developing baby. The critical early development of the heart is reflected by the prominent heart bulge that appears on the anterior surface of the embryo.

The heart forms from an embryonic tissue called mesoderm around 18 to 19 days after fertilisation. Mesoderm is one of the three primary germ layers that differentiates early in development that collectively gives rise to all subsequent tissues and organs. The heart begins to develop near the head of the embryo in a region known as the cardiogenic area. Following chemical signals called factors from the underlying endoderm (another of the three primary germ layers), the cardiogenic area begins to form two strands called the cardiogenic cords (Figure 6.5.1). As the cardiogenic cords develop, a lumen rapidly develops within them. At this point, they are referred to as endocardial tubes. The two tubes migrate together and fuse to form a single primitive heart tube. The primitive heart tube quickly forms five distinct regions. From head to tail, these include the truncus arteriosus, bulbus cordis, primitive ventricle, primitive atrium, and the sinus venosus. Initially, all venous blood flows into the sinus venosus, and contractions propel the blood from tail to head, or from the sinus venosus to the truncus arteriosus. This is a very different pattern from that of an adult.

The five regions of the primitive heart tube develop into recognisable structures in a fully developed heart. The truncus arteriosus will eventually divide and give rise to the ascending aorta and pulmonary trunk. The bulbus cordis develops into the right ventricle. The primitive ventricle forms the left ventricle. The primitive atrium becomes the anterior portions of both the right and left atria, and the two auricles. The sinus venosus develops into the posterior portion of the right atrium, the SA node, and the coronary sinus.

As the primitive heart tube elongates, it begins to fold within the pericardium, eventually forming an S shape, which places the chambers and major vessels into an alignment like the adult heart. This process occurs between days 23 and 28. The remainder of the heart development pattern includes development of septa and valves and remodelling of the actual chambers. Partitioning of the atria and ventricles by the interatrial septum, interventricular septum, and atrioventricular septum is complete by the end of the fifth week, although the foetal blood shunts remain until birth or shortly after. The atrioventricular valves form between weeks five and eight, and the semilunar valves form between weeks five and nine.

Click the drop down below to review the terms learned from this chapter.

Blood is carried through the body via blood vessels. An artery is a blood vessel that carries blood away from the heart, where it branches into ever-smaller vessels. Eventually, the smallest arteries, vessels called arterioles, further branch into tiny capillaries, where nutrients and wastes are exchanged, and then combine with other vessels that exit capillaries to form venules, small blood vessels that carry blood to a vein, a larger blood vessel that returns blood to the heart.

Arteries and veins transport blood in two distinct circuits: the systemic circuit and the pulmonary circuit (Figure 6.6.1). Systemic arteries provide blood rich in oxygen to the body’s tissues. The blood returned to the heart through systemic veins has less oxygen, since much of the oxygen carried by the arteries has been delivered to the cells. In contrast, in the pulmonary circuit, arteries carry blood low in oxygen exclusively to the lungs for gas exchange. Pulmonary veins then return freshly oxygenated blood from the lungs to the heart to be pumped back out into systemic circulation. Although arteries and veins differ structurally and functionally, they share certain features.

Shared Structures

Different types of blood vessels vary slightly in their structures, but they share the same general features. Arteries and arterioles have thicker walls than veins and venules because they are closer to the heart and receive blood that is surging at a far greater pressure (Figure 6.6.2). Each type of vessel has a lumen—a hollow passageway through which blood flows. Arteries have smaller lumens than veins, a characteristic that helps to maintain the pressure of blood moving through the system. Together, their thicker walls and smaller diameters give arterial lumens a more rounded appearance in cross section than the lumens of veins.

By the time blood has passed through capillaries and entered venules, the pressure initially exerted upon it by heart contractions has diminished. In other words, in comparison to arteries, venules and veins withstand a much lower pressure from the blood that flows through them. Their walls are considerably thinner and their lumens are correspondingly larger in diameter, allowing more blood to flow with less vessel resistance. In addition, many veins of the body, particularly those of the limbs, contain valves that assist the unidirectional flow of blood toward the heart. This is critical because blood flow becomes sluggish in the extremities, as a result of the lower pressure and the effects of gravity.

The walls of arteries and veins are largely composed of living cells and their products (including collagenous and elastic fibres); the cells require nourishment and produce waste. Since blood passes through the larger vessels relatively quickly, there is limited opportunity for blood in the lumen of the vessel to provide nourishment to or remove waste from the vessel’s cells. Further, the walls of the larger vessels are too thick for nutrients to diffuse through to all of the cells. Larger arteries and veins contain small blood vessels within their walls known as the vasa vasorum—literally “vessels of the vessel”—to provide them with this critical exchange. Since the pressure within arteries is relatively high, the vasa vasorum must function in the outer layers of the vessel (see Figure 6.2.2) or the pressure exerted by the blood passing through the vessel would collapse it, preventing any exchange from occurring. The lower pressure within veins allows the vasa vasorum to be located closer to the lumen. The restriction of the vasa vasorum to the outer layers of arteries is thought to be one reason that arterial diseases are more common than venous diseases, since its location makes it more difficult to nourish the cells of the arteries and remove waste products. There are also minute nerves within the walls of both types of vessels that control the contraction and dilation of smooth muscle. These minute nerves are known as the nervi vasorum.

Both arteries and veins have the same three distinct tissue layers, called tunics (from the Latin term tunica), for the garments first worn by ancient Romans; the term tunic is also used for some modern garments. From the most interior layer to the outer, these tunics are the tunica intima, the tunica media, and the tunica externa (see Figure 6.6.2). Table 6.6.1 compares and contrasts the tunics of the arteries and veins.

Table 6.6.1. Comparison of tunics in arteries and veins

Tunica Intima

The tunica intima (also called the tunica interna) is composed of epithelial and connective tissue layers. Lining the tunica intima is the specialised simple squamous epithelium called the endothelium, which is continuous throughout the entire vascular system, including the lining of the chambers of the heart. Damage to this endothelial lining and exposure of blood to the collagenous fibres beneath is one of the primary causes of clot formation. Until recently, the endothelium was viewed simply as the boundary between the blood in the lumen and the walls of the vessels. Recent studies, however, have shown that it is physiologically critical to such activities as helping to regulate capillary exchange and altering blood flow. The endothelium releases local chemicals called endothelins that can constrict the smooth muscle within the walls of the vessel to increase blood pressure. Uncompensated overproduction of endothelins may contribute to hypertension (high blood pressure) and cardiovascular disease.

Next to the endothelium is the basement membrane, or basal lamina, that effectively binds the endothelium to the connective tissue. The basement membrane provides strength while maintaining flexibility, and it is permeable, allowing materials to pass through it. The thin outer layer of the tunica intima contains a small amount of areolar connective tissue that consists primarily of elastic fibres to provide the vessel with additional flexibility; it also contains some collagenous fibres to provide additional strength.

In larger arteries, there is also a thick, distinct layer of elastic fibres known as the internal elastic membrane (also called the internal elastic lamina) at the boundary with the tunica media. Like the other components of the tunica intima, the internal elastic membrane provides structure while allowing the vessel to stretch. It is permeated with small openings that allow exchange of materials between the tunics. The internal elastic membrane is not apparent in veins. In addition, many veins, particularly in the lower limbs, contain valves formed by sections of thickened endothelium that are reinforced with connective tissue, extending into the lumen.

Under the microscope, the lumen and the entire tunica intima of a vein will appear smooth, whereas those of an artery will normally appear wavy because of the partial constriction of the smooth muscle in the tunica media, the next layer of blood vessel walls.

Tunica Media

The tunica media is the substantial middle layer of the vessel wall (see Figure 6.6.2). It is generally the thickest layer in arteries, and it is much thicker in arteries than it is in veins. The tunica media consists of layers of smooth muscle supported by connective tissue that is primarily made up of elastic fibres, most of which are arranged in circular sheets. Toward the outer portion of the tunic, there are also layers of longitudinal muscle. Contraction and relaxation of the circular muscles decrease and increase the diameter of the vessel lumen, respectively. Specifically, in arteries vasoconstriction decreases blood flow as the smooth muscle in the walls of the tunica media contracts, making the lumen narrower and increasing blood pressure. Similarly, vasodilation increases blood flow as the smooth muscle relaxes, allowing the lumen to widen and blood pressure to drop. Both vasoconstriction and vasodilation are regulated in part by small vascular nerves, known as nervi vasorum, or “nerves of the vessel,” that run within the walls of blood vessels. These are generally all sympathetic fibres, although some trigger vasodilation and others induce vasoconstriction, depending upon the nature of the neurotransmitter and receptors located on the target cell. Parasympathetic stimulation does trigger vasodilation as well as erection during sexual arousal in the external genitalia of both sexes. Nervous control over vessels tends to be more generalised than the specific targeting of individual blood vessels. Local controls, discussed later, account for this phenomenon. (Seek additional content for more information on these dynamic aspects of the autonomic nervous system.) Hormones and local chemicals also control blood vessels. Together, these neural and chemical mechanisms reduce or increase blood flow in response to changing body conditions, from exercise to hydration. Regulation of both blood flow and blood pressure is discussed in detail later in this chapter.

The smooth muscle layers of the tunica media are supported by a framework of collagenous fibres that also binds the tunica media to the inner and outer tunics. Along with the collagenous fibres are large numbers of elastic fibres that appear as wavy lines in prepared slides. Separating the tunica media from the outer tunica externa in larger arteries is the external elastic membrane (also called the external elastic lamina), which also appears wavy in slides. This structure is not usually seen in smaller arteries, nor is it seen in veins.

Tunica Externa

The outer tunic, the tunica externa (also called the tunica adventitia), is a substantial sheath of connective tissue composed primarily of collagenous fibres. Some bands of elastic fibres are found here as well. The tunica externa in veins also contains groups of smooth muscle fibres. This is normally the thickest tunic in veins and may be thicker than the tunica media in some larger arteries. The outer layers of the tunica externa are not distinct but rather blend with the surrounding connective tissue outside the vessel, helping to hold the vessel in relative position. If you are able to palpate some of the superficial veins on your upper limbs and try to move them, you will find that the tunica externa prevents this. If the tunica externa did not hold the vessel in place, any movement would likely result in disruption of blood flow.

Arteries

An artery is a blood vessel that conducts blood away from the heart. All arteries have relatively thick walls that can withstand the high pressure of blood ejected from the heart. However, those close to the heart have the thickest walls, containing a high percentage of elastic fibres in all three of their tunics. This type of artery is known as an elastic artery (Figure 6.6.3). Vessels larger than 10 mm in diameter are typically elastic. Their abundant elastic fibres allow them to expand, as blood pumped from the ventricles passes through them, and then to recoil after the surge has passed. If artery walls were rigid and unable to expand and recoil, their resistance to blood flow would greatly increase and blood pressure would rise to even higher levels, which would in turn require the heart to pump harder to increase the volume of blood expelled by each pump (the stroke volume) and maintain adequate pressure and flow. Artery walls would have to become even thicker in response to this increased pressure. The elastic recoil of the vascular wall helps to maintain the pressure gradient that drives the blood through the arterial system. An elastic artery is also known as a conducting artery, because the large diameter of the lumen enables it to accept a large volume of blood from the heart and conduct it to smaller branches.

Farther from the heart, where the surge of blood has dampened, the percentage of elastic fibres in an artery’s tunica intima decreases and the amount of smooth muscle in its tunica media increases. The artery at this point is described as a muscular artery. The diameter of muscular arteries typically ranges from 0.1 mm to 10 mm. Their thick tunica media allows muscular arteries to play a leading role in vasoconstriction. In contrast, their decreased quantity of elastic fibres limits their ability to expand. Fortunately, because the blood pressure has eased by the time it reaches these more distant vessels, elasticity has become less important.

Notice that although the distinctions between elastic and muscular arteries are important, there is no “line of demarcation” where an elastic artery suddenly becomes muscular. Rather, there is a gradual transition as the vascular tree repeatedly branches. In turn, muscular arteries branch to distribute blood to the vast network of arterioles. For this reason, a muscular artery is also known as a distributing artery.

Arterioles

An arteriole is a very small artery that leads to a capillary. Arterioles have the same three tunics as the larger vessels, but the thickness of each is greatly diminished. The critical endothelial lining of the tunica intima is intact. The tunica media is restricted to one or two smooth muscle cell layers in thickness. The tunica externa remains but is very thin (see Figure 6.6.3).

With a lumen averaging 30 micrometres or less in diameter, arterioles are critical in slowing down—or resisting—blood flow and, thus, causing a substantial drop in blood pressure. Because of this, you may see them referred to as resistance vessels. The muscle fibres in arterioles are normally slightly contracted, causing arterioles to maintain a consistent muscle tone—in this case referred to as vascular tone—in a similar manner to the muscular tone of skeletal muscle. In reality, all blood vessels exhibit vascular tone due to the partial contraction of smooth muscle. The importance of the arterioles is that they will be the primary site of both resistance and regulation of blood pressure. The precise diameter of the lumen of an arteriole at any given moment is determined by neural and chemical controls, and vasoconstriction and vasodilation in the arterioles are the primary mechanisms for distribution of blood flow.

Capillaries

A capillary is a microscopic channel that supplies blood to the tissues themselves, a process called perfusion. Exchange of gases and other substances occurs in the capillaries between the blood and the surrounding cells and their tissue fluid (interstitial fluid). The diameter of a capillary lumen ranges from 5–10 micrometres; the smallest are just barely wide enough for an erythrocyte to squeeze through. Flow through capillaries is often described as microcirculation.

The wall of a capillary consists of the endothelial layer surrounded by a basement membrane with occasional smooth muscle fibres. There is some variation in wall structure: In a large capillary, several endothelial cells bordering each other may line the lumen; in a small capillary, there may be only a single cell layer that wraps around to contact itself.

For capillaries to function, their walls must be leaky, allowing substances to pass through. There are three major types of capillaries, which differ according to their degree of “leakiness:” continuous, fenestrated, and sinusoid capillaries (Figure 6.6.4).

Continuous Capillaries

The most common type of capillary, the continuous capillary, is found in almost all vascularised tissues. Continuous capillaries are characterised by a complete endothelial lining with tight junctions between endothelial cells. Although a tight junction is usually impermeable and only allows for the passage of water and ions, they are often incomplete in capillaries, leaving intercellular clefts that allow for exchange of water and other very small molecules between the blood plasma and the interstitial fluid. Substances that can pass between cells include metabolic products, such as glucose, water, and small hydrophobic molecules like gases and hormones, as well as various leukocytes. Continuous capillaries not associated with the brain are rich in transport vesicles, contributing to either endocytosis or exocytosis. Those in the brain are part of the blood-brain barrier. Here, there are tight junctions and no intercellular clefts, plus a thick basement membrane and astrocyte extensions called end feet; these structures combine to prevent the movement of nearly all substances.

Fenestrated Capillaries

A fenestrated capillary is one that has pores (or fenestrations) in addition to tight junctions in the endothelial lining. These make the capillary permeable to larger molecules. The number of fenestrations and their degree of permeability vary, however, according to their location. Fenestrated capillaries are common in the small intestine, which is the primary site of nutrient absorption, as well as in the kidneys, which filter the blood. They are also found in the choroid plexus of the brain and many endocrine structures, including the hypothalamus, pituitary, pineal and thyroid glands.

Sinusoid Capillaries

A sinusoid capillary (or sinusoid) is the least common type of capillary. Sinusoid capillaries are flattened, and they have extensive intercellular gaps and incomplete basement membranes, in addition to intercellular clefts and fenestrations. This gives them an appearance not unlike Swiss cheese. These very large openings allow for the passage of the largest molecules, including plasma proteins and even cells. Blood flow through sinusoids is very slow, allowing more time for exchange of gases, nutrients, and wastes. Sinusoids are found in the liver and spleen, bone marrow, lymph nodes (where they carry lymph, not blood), and many endocrine glands including the pituitary and adrenal glands. Without these specialised capillaries, these organs would not be able to provide their myriad of functions. For example, when bone marrow forms new blood cells, the cells must enter the blood supply and can only do so through the large openings of a sinusoid capillary; they cannot pass through the small openings of continuous or fenestrated capillaries. The liver also requires extensive specialised sinusoid capillaries in order to process the materials brought to it by the hepatic portal vein from both the digestive tract and spleen, and to release plasma proteins into circulation.

Metarterioles and Capillary Beds

A metarteriole is a type of vessel that has structural characteristics of both an arteriole and a capillary. Slightly larger than the typical capillary, the smooth muscle of the tunica media of the metarteriole is not continuous but forms rings of smooth muscle (sphincters) prior to the entrance to the capillaries. Each metarteriole arises from a terminal arteriole and branches to supply blood to a capillary bed that may consist of 10–100 capillaries.

The precapillary sphincters, circular smooth muscle cells that surround the capillary at its origin with the metarteriole, tightly regulate the flow of blood from a metarteriole to the capillaries it supplies. Their function is critical: If all of the capillary beds in the body were to open simultaneously, they would collectively hold every drop of blood in the body and there would be none in the arteries, arterioles, venules, veins, or the heart itself. Normally, the precapillary sphincters are closed. When the surrounding tissues need oxygen and have excess waste products, the precapillary sphincters open, allowing blood to flow through and exchange to occur before closing once more (Figure 6.6.5). If all of the precapillary sphincters in a capillary bed are closed, blood will flow from the metarteriole directly into a thoroughfare channel and then into the venous circulation, bypassing the capillary bed entirely. This creates what is known as a vascular shunt. In addition, an arteriovenous anastomosis may bypass the capillary bed and lead directly to the venous system.

Although you might expect blood flow through a capillary bed to be smooth, in reality, it moves with an irregular, pulsating flow. This pattern is called vasomotion and is regulated by chemical signals that are triggered in response to changes in internal conditions, such as oxygen, carbon dioxide, hydrogen ion, and lactic acid levels. For example, during strenuous exercise when oxygen levels decrease and carbon dioxide, hydrogen ion, and lactic acid levels all increase, the capillary beds in skeletal muscle are open, as they would be in the digestive system when nutrients are present in the digestive tract. During sleep or rest periods, vessels in both areas are largely closed; they open only occasionally to allow oxygen and nutrient supplies to travel to the tissues to maintain basic life processes.

Venules

A venule is an extremely small vein, generally 8–100 micrometres in diameter. Postcapillary venules join multiple capillaries exiting from a capillary bed. Multiple venules join to form veins. The walls of venules consist of endothelium, a thin middle layer with a few muscle cells and elastic fibres, plus an outer layer of connective tissue fibres that constitute a very thin tunica externa (Figure 6.6.6). Venules as well as capillaries are the primary sites of emigration or diapedesis, in which the white blood cells adhere to the endothelial lining of the vessels and then squeeze through adjacent cells to enter the tissue fluid.

Veins

A vein is a blood vessel that conducts blood toward the heart. Compared to arteries, veins are thin-walled vessels with large and irregular lumens (see Figure 6.6.6). Because they are low-pressure vessels, larger veins are commonly equipped with valves that promote the unidirectional flow of blood toward the heart and prevent backflow toward the capillaries caused by the inherent low blood pressure in veins as well as the pull of gravity. Table 2 compares the features of arteries and veins.

Table 6.6.2. Comparison of arteries and veins

Disorders of the Cardiovascular System: Oedema and Varicose Veins

Despite the presence of valves and the contributions of other anatomical and physiological adaptations we will cover shortly, over the course of a day, some blood will inevitably pool, especially in the lower limbs, due to the pull of gravity. Any blood that accumulates in a vein will increase the pressure within it, which can then be reflected back into the smaller veins, venules, and eventually even the capillaries. Increased pressure will promote the flow of fluids out of the capillaries and into the interstitial fluid. The presence of excess tissue fluid around the cells leads to a condition called oedema.

Most people experience a daily accumulation of tissue fluid, especially if they spend much of their work life on their feet (like most health professionals). However, clinical oedema goes beyond normal swelling and requires medical treatment. Oedema has many potential causes, including hypertension and heart failure, severe protein deficiency, renal failure, and many others. In order to treat oedema, which is a sign rather than a discrete disorder, the underlying cause must be diagnosed and alleviated.

Oedema may be accompanied by varicose veins, especially in the superficial veins of the legs (Figure 6.6.7). This disorder arises when defective valves allow blood to accumulate within the veins, causing them to distend, twist, and become visible on the surface of the integument. Varicose veins may occur in both sexes but are more common in women and are often related to pregnancy. More than simple cosmetic blemishes, varicose veins are often painful and sometimes itchy or throbbing. Without treatment, they tend to grow worse over time. The use of support hose, as well as elevating the feet and legs whenever possible, may be helpful in alleviating this condition. Laser surgery and interventional radiologic procedures can reduce the size and severity of varicose veins. Severe cases may require conventional surgery to remove the damaged vessels. As there are typically redundant circulation patterns, that is, anastomoses, for the smaller and more superficial veins, removal does not typically impair the circulation. There is evidence that patients with varicose veins suffer a greater risk of developing a thrombus or clot.

Veins as Blood Reservoirs

In addition to their primary function of returning blood to the heart, veins may be considered blood reservoirs, since systemic veins contain approximately 64 percent of the blood volume at any given time (Figure 6.6.8). Their ability to hold this much blood is due to their high capacitance, that is, their capacity to distend (expand) readily to store a high volume of blood, even at a low pressure. The large lumens and relatively thin walls of veins make them far more distensible than arteries; thus, they are said to be capacitance vessels.

When blood flow needs to be redistributed to other portions of the body, the vasomotor centre located in the medulla oblongata sends sympathetic stimulation to the smooth muscles in the walls of the veins, causing constriction—or in this case, venoconstriction. Less dramatic than the vasoconstriction seen in smaller arteries and arterioles, venoconstriction may be likened to a “stiffening” of the vessel wall. This increases pressure on the blood within the veins, speeding its return to the heart. As you will note in Figure 6.6.8, approximately 21 percent of the venous blood is located in venous networks within the liver, bone marrow, and integument. This volume of blood is referred to as venous reserve. Through venoconstriction, this “reserve” volume of blood can get back to the heart more quickly for redistribution to other parts of the circulation.

Click the drop down below to review the terms learned from this chapter.

Blood flow refers to the movement of blood through a vessel, tissue, or organ, and is usually expressed in terms of volume of blood per unit of time. It is initiated by the contraction of the ventricles of the heart. Ventricular contraction ejects blood into the major arteries, resulting in flow from regions of higher pressure to regions of lower pressure, as blood encounters smaller arteries and arterioles, then capillaries, then the venules and veins of the venous system. This section discusses a number of critical variables that contribute to blood flow throughout the body. It also discusses the factors that impede or slow blood flow, a phenomenon known as resistance.

As noted earlier, hydrostatic pressure is the force exerted by a fluid due to gravitational pull, usually against the wall of the container in which it is located. One form of hydrostatic pressure is blood pressure, the force exerted by blood upon the walls of the blood vessels or the chambers of the heart. Blood pressure may be measured in capillaries and veins, as well as the vessels of the pulmonary circulation; however, the term blood pressure without any specific descriptors typically refers to systemic arterial blood pressure—that is, the pressure of blood flowing in the arteries of the systemic circulation. In clinical practice, this pressure is measured in mm Hg and is usually obtained using the brachial artery of the arm.

Components of Arterial Blood Pressure

Arterial blood pressure in the larger vessels consists of several distinct components (Figure 6.7.1): systolic and diastolic pressures, pulse pressure, and mean arterial pressure.

Systolic and Diastolic Pressure

When systemic arterial blood pressure is measured, it is recorded as a ratio of two numbers (e.g., 120/80 is a normal adult blood pressure), expressed as systolic pressure over diastolic pressure. The systolic pressure is the higher value (typically around 120 mm Hg) and reflects the arterial pressure resulting from the ejection of blood during ventricular contraction, or systole. The diastolic pressure is the lower value (usually about 80 mm Hg) and represents the arterial pressure of blood during ventricular relaxation, or diastole.

Pulse Pressure

As shown in Figure 6.7.1, the difference between the systolic pressure and the diastolic pressure is the pulse pressure. For example, an individual with a systolic pressure of 120 mm Hg and a diastolic pressure of 80 mm Hg would have a pulse pressure of 40 mmHg.

Generally, a pulse pressure should be at least 25 percent of the systolic pressure. A pulse pressure below this level is described as low or narrow. This may occur, for example, in patients with a low stroke volume, which may be seen in congestive heart failure, stenosis of the aortic valve, or significant blood loss following trauma. In contrast, a high or wide pulse pressure is common in healthy people following strenuous exercise, when their resting pulse pressure of 30–40 mm Hg may increase temporarily to 100 mm Hg as stroke volume increases. A persistently high pulse pressure at or above 100 mm Hg may indicate excessive resistance in the arteries and can be caused by a variety of disorders. Chronic high resting pulse pressures can degrade the heart, brain, and kidneys, and warrant medical treatment.

Mean Arterial Pressure

Mean arterial pressure (MAP) represents the “average” pressure of blood in the arteries, that is, the average force driving blood into vessels that serve the tissues. Mean is a statistical concept and is calculated by taking the sum of the values divided by the number of values. Although complicated to measure directly and complicated to calculate, MAP can be approximated by adding the diastolic pressure to one-third of the pulse pressure or systolic pressure minus the diastolic pressure:

MAP = diastolic BP + ((systolic-diastolic BP) / 3)

In Figure 6.7.1, this value is approximately 80 + (120 − 80) / 3, or 93.33. Normally, the MAP falls within the range of 70–110 mm Hg. If the value falls below 60 mm Hg for an extended time, blood pressure will not be high enough to ensure circulation to and through the tissues, which results in ischaemia, or insufficient blood flow. A condition called hypoxia, inadequate oxygenation of tissues, commonly accompanies ischaemia. The term hypoxaemia refers to low levels of oxygen in systemic arterial blood. Neurons are especially sensitive to hypoxia and may die or be damaged if blood flow and oxygen supplies are not quickly restored.

Pulse

After blood is ejected from the heart, elastic fibres in the arteries help maintain a high-pressure gradient as they expand to accommodate the blood, then recoil. This expansion and recoiling effect, known as the pulse, can be palpated manually or measured electronically. Although the effect diminishes over distance from the heart, elements of the systolic and diastolic components of the pulse are still evident down to the level of the arterioles.

Because pulse indicates heart rate, it is measured clinically to provide clues to a patient’s state of health. It is recorded as beats per minute. Both the rate and the strength of the pulse are important clinically. A high or irregular pulse rate can be caused by physical activity or other temporary factors, but it may also indicate a heart condition. The pulse strength indicates the strength of ventricular contraction and cardiac output. If the pulse is strong, then systolic pressure is high. If it is weak, systolic pressure has fallen, and medical intervention may be warranted.

Pulse can be palpated manually by placing the tips of the fingers across an artery that runs close to the body surface and pressing lightly. While this procedure is normally performed using the radial artery in the wrist or the common carotid artery in the neck, any superficial artery that can be palpated may be used (Figure 6.7.2). Common sites to find a pulse include temporal and facial arteries in the head, brachial arteries in the upper arm, femoral arteries in the thigh, popliteal arteries behind the knees, posterior tibial arteries near the medial tarsal regions, and dorsalis pedis arteries in the feet. A variety of commercial electronic devices are also available to measure pulse.

Measurement of Blood Pressure

Blood pressure is one of the critical parameters measured on virtually every patient in every healthcare setting. The technique used today was developed more than 100 years ago by a pioneering Russian physician, Dr. Nikolai Korotkoff. Turbulent blood flow through the vessels can be heard as a soft ticking while measuring blood pressure; these sounds are known as Korotkoff sounds. The technique of measuring blood pressure requires the use of a sphygmomanometer (a blood pressure cuff attached to a measuring device) and a stethoscope. The technique is as follows:

1. The clinician wraps an inflatable cuff tightly around the patient’s arm at about the level of the heart.
2. The clinician squeezes a rubber pump to inject air into the cuff, raising pressure around the artery and temporarily cutting off blood flow into the patient’s arm.
3. The clinician places the stethoscope on the patient’s antecubital region and, while gradually allowing air within the cuff to escape, listens for the Korotkoff sounds.

Although there are five recognised Korotkoff sounds, only two are normally recorded. Initially, no sounds are heard since there is no blood flow through the vessels, but as air pressure drops, the cuff relaxes, and blood flow returns to the arm. As shown in Figure 6.7.3, the first sound heard through the stethoscope—the first Korotkoff sound—indicates systolic pressure. As more air is released from the cuff, blood is able to flow freely through the brachial artery and all sounds disappear. The point at which the last sound is heard is recorded as the patient’s diastolic pressure.

The majority of hospitals and clinics have automated equipment for measuring blood pressure that work on the same principles. An even more recent innovation is a small instrument that wraps around a patient’s wrist. The patient then holds the wrist over the heart while the device measures blood flow and records pressure.

Variables Affecting Blood Flow and Blood Pressure

Five variables influence blood flow and blood pressure:

• Cardiac output
• Compliance
• Volume of the blood
• Viscosity of the blood
• Blood vessel length and diameter

Recall that blood moves from higher pressure to lower pressure. It is pumped from the heart into the arteries at high pressure. If you increase pressure in the arteries (afterload), and cardiac function does not compensate, blood flow will actually decrease. In the venous system, the opposite relationship is true. Increased pressure in the veins does not decrease flow as it does in arteries, but actually increases flow. Since pressure in the veins is normally relatively low, for blood to flow back into the heart, the pressure in the atria during atrial diastole must be even lower. It normally approaches zero, except when the atria contract (see Figure 6.7.1).

Cardiac Output

Cardiac output is the measurement of blood flow from the heart through the ventricles and is usually measured in litres per minute. Any factor that causes cardiac output to increase, by elevating heart rate or stroke volume or both, will elevate blood pressure and promote blood flow. These factors include sympathetic stimulation, the catecholamines adrenaline and noradrenaline, thyroid hormones, and increased calcium ion levels. Conversely, any factor that decreases cardiac output, by decreasing heart rate or stroke volume or both, will decrease arterial pressure and blood flow. These factors include parasympathetic stimulation, elevated or decreased potassium ion levels, decreased calcium levels, anoxia, and acidosis.

Compliance

Compliance is the ability of any compartment to expand to accommodate increased content. A metal pipe, for example, is not compliant, whereas a balloon is. The greater the compliance of an artery, the more effectively it is able to expand to accommodate surges in blood flow without increased resistance or blood pressure. Veins are more compliant than arteries and can expand to hold more blood. When vascular disease causes stiffening of arteries, compliance is reduced and resistance to blood flow is increased. The result is more turbulence, higher pressure within the vessel, and reduced blood flow. This increases the work of the heart.

A Mathematical Approach to Factors Affecting Blood Flow

Jean Louis Marie Poiseuille was a French physician and physiologist who devised a mathematical equation describing blood flow and its relationship to known parameters. The same equation also applies to engineering studies of the flow of fluids. Although understanding the math behind the relationships among the factors affecting blood flow is not necessary to understand blood flow, it can help solidify an understanding of their relationships. Please note that even if the equation looks intimidating, breaking it down into its components and following the relationships will make these relationships clearer, even if you are weak in math. Focus on the three critical variables: radius (r), vessel length (λ), and viscosity (η).

Poiseuille’s equation:

Blood flow = π ΔP r48ηλ

π is the Greek letter pi, used to represent the mathematical constant that is the ratio of a circle’s circumference to its diameter. It may commonly be represented as 3.14, although the actual number extends to infinity.

• ΔP represents the difference in pressure.
• r4 is the radius (one-half of the diameter) of the vessel to the fourth power.
• η is the Greek letter eta and represents the viscosity of the blood.
• λ is the Greek letter lambda and represents the length of a blood vessel.

One of several things this equation allows us to do is calculate the resistance in the vascular system. Normally this value is extremely difficult to measure, but it can be calculated from this known relationship:

• Blood flow = ΔP/Resistance

If we rearrange this slightly,

• Resistance = ΔP/Blood flow

Then by substituting Poiseuille’s equation for blood flow:

• Resistance =8ηλ/πr4

By examining this equation, you can see that there are only three variables: viscosity, vessel length, and radius, since 8 and π are both constants. The important thing to remember is this: Two of these variables, viscosity and vessel length, will change slowly in the body. Only one of these factors, the radius, can be changed rapidly by vasoconstriction and vasodilation, thus dramatically impacting resistance and flow. Further, small changes in the radius will greatly affect flow, since it is raised to the fourth power in the equation.

We have briefly considered how cardiac output and blood volume impact blood flow and pressure; the next step is to see how the other variables (contraction, vessel length, and viscosity) articulate with Poiseuille’s equation and what they can teach us about the impact on blood flow.

Blood Volume

The relationship between blood volume, blood pressure, and blood flow is intuitively obvious. Water may merely trickle along a creek bed in a dry season but rush quickly and under great pressure after a heavy rain. Similarly, as blood volume decreases, pressure and flow decrease. As blood volume increases, pressure and flow increase.

Under normal circumstances, blood volume varies little. Low blood volume, called hypovolaemia, may be caused by bleeding, dehydration, vomiting, severe burns, or some medications used to treat hypertension. It is important to recognise that other regulatory mechanisms in the body are so effective at maintaining blood pressure that an individual may be asymptomatic until 10–20 percent of the blood volume has been lost. Treatment typically includes intravenous fluid replacement.

Hypervolaemia, excessive fluid volume, may be caused by retention of water and sodium, as seen in patients with heart failure, liver cirrhosis, some forms of kidney disease, hyperaldosteronism, and some glucocorticoid steroid treatments. Restoring homeostasis in these patients depends upon reversing the condition that triggered the hypervolaemia.

Blood Viscosity

Viscosity is the thickness of fluids that affects their ability to flow. Clean water, for example, is less viscous than mud. The viscosity of blood is directly proportional to resistance and inversely proportional to flow; therefore, any condition that causes viscosity to increase will also increase resistance and decrease flow. For example, imagine sipping milk, then a milkshake, through the same size straw. You experience more resistance and therefore less flow from the milkshake. Conversely, any condition that causes viscosity to decrease (such as when the milkshake melts) will decrease resistance and increase flow.

Normally the viscosity of blood does not change over short periods of time. The two primary determinants of blood viscosity are the formed elements and plasma proteins. Since most formed elements are erythrocytes, any condition affecting erythropoiesis, such as polycythaemia or anaemia, can alter viscosity. Since most plasma proteins are produced by the liver, any condition affecting liver function can also change the viscosity slightly and therefore decrease blood flow. Liver abnormalities include hepatitis, cirrhosis, alcohol damage, and drug toxicities. While leukocytes and platelets are normally a small component of the formed elements, there are some rare conditions in which severe overproduction can impact viscosity as well.

Vessel Length and Diameter

The length of a vessel is directly proportional to its resistance: the longer the vessel, the greater the resistance and the lower the flow. As with blood volume, this makes intuitive sense, since the increased surface area of the vessel will impede the flow of blood. Likewise, if the vessel is shortened, the resistance will decrease and flow will increase.

The length of our blood vessels increases throughout childhood as we grow, of course, but is unchanging in adults under normal physiological circumstances. Further, the distribution of vessels is not the same in all tissues. Adipose tissue does not have an extensive vascular supply. One pound of adipose tissue contains approximately 200 miles of vessels, whereas skeletal muscle contains more than twice that. Overall, vessels decrease in length only during loss of mass or amputation. An individual weighing 68kg has approximately 96,560km of vessels in the body. Gaining about 4.5km adds from 3218 to 6437 kilometres of vessels, depending upon the nature of the gained tissue. One of the great benefits of weight reduction is the reduced stress to the heart, which does not have to overcome the resistance of as many miles of vessels.

In contrast to length, the diameter of blood vessels changes throughout the body, according to the type of vessel, as we discussed earlier. The diameter of any given vessel may also change frequently throughout the day in response to neural and chemical signals that trigger vasodilation and vasoconstriction. The vascular tone of the vessel is the contractile state of the smooth muscle and the primary determinant of diameter, and thus of resistance and flow. The effect of vessel diameter on resistance is inverse: Given the same volume of blood, an increased diameter means there is less blood contacting the vessel wall, thus lower friction and lower resistance, subsequently increasing flow. A decreased diameter means more of the blood contacts the vessel wall, and resistance increases, subsequently decreasing flow.

The influence of lumen diameter on resistance is dramatic: A slight increase or decrease in diameter causes a huge decrease or increase in resistance. This is because resistance is inversely proportional to the radius of the blood vessel (one-half of the vessel’s diameter) raised to the fourth power (R = 1/r4). This means, for example, that if an artery or arteriole constricts to one-half of its original radius, the resistance to flow will increase 16 times. And if an artery or arteriole dilates to twice its initial radius, then resistance in the vessel will decrease to 1/16 of its original value and flow will increase 16 times.

The Roles of Vessel Diameter and Total Area in Blood Flow and Blood Pressure

Recall that we classified arterioles as resistance vessels, because given their small lumen, they dramatically slow the flow of blood from arteries. In fact, arterioles are the site of greatest resistance in the entire vascular network. This may seem surprising, given that capillaries have a smaller size. How can this phenomenon be explained?

Figure 6.7.4 compares vessel diameter, total cross-sectional area, average blood pressure, and blood velocity through the systemic vessels. Notice in parts (a) and (b) that the total cross-sectional area of the body’s capillary beds is far greater than any other type of vessel. Although the diameter of an individual capillary is significantly smaller than the diameter of an arteriole, there are vastly more capillaries in the body than there are other types of blood vessels. Part (c) shows that blood pressure drops unevenly as blood travels from arteries to arterioles, capillaries, venules, and veins, and encounters greater resistance. However, the site of the most precipitous drop, and the site of greatest resistance, is the arterioles. This explains why vasodilation and vasoconstriction of arterioles play more significant roles in regulating blood pressure than do the vasodilation and vasoconstriction of other vessels.

Part (d) shows that the velocity (speed) of blood flow decreases dramatically as the blood moves from arteries to arterioles to capillaries. This slow flow rate allows more time for exchange processes to occur. As blood flows through the veins, the rate of velocity increases, as blood is returned to the heart.

Disorders of the Cardiovascular System: Arteriosclerosis

Compliance allows an artery to expand when blood is pumped through it from the heart, and then to recoil after the surge has passed. This helps promote blood flow. In arteriosclerosis, compliance is reduced, and pressure and resistance within the vessel increase. This is a leading cause of hypertension and coronary heart disease, as it causes the heart to work harder to generate a pressure great enough to overcome the resistance.

Arteriosclerosis begins with injury to the endothelium of an artery, which may be caused by irritation from high blood glucose, infection, tobacco use, excessive blood lipids, and other factors. Artery walls that are constantly stressed by blood flowing at high pressure are also more likely to be injured—which means that hypertension can promote arteriosclerosis, as well as result from it.

Recall that tissue injury causes inflammation. As inflammation spreads into the artery wall, it weakens and scars it, leaving it stiff (sclerotic). As a result, compliance is reduced. Moreover, circulating triglycerides and cholesterol can seep between the damaged lining cells and become trapped within the artery wall, where they are frequently joined by leukocytes, calcium, and cellular debris. Eventually, this build-up, called plaque, can narrow arteries enough to impair blood flow. The term for this condition, atherosclerosis (athero- = “porridge”) describes the mealy deposits (Figure 6.7.5).

Sometimes a plaque can rupture, causing microscopic tears in the artery wall that allow blood to leak into the tissue on the other side. When this happens, platelets rush to the site to clot the blood. This clot can further obstruct the artery and—if it occurs in a coronary or cerebral artery—cause a sudden heart attack or stroke. Alternatively, plaque can break off and travel through the bloodstream as an embolus until it blocks a more distant, smaller artery.

Even without total blockage, vessel narrowing leads to ischaemia—reduced blood flow—to the tissue region “downstream” of the narrowed vessel. Ischaemia in turn leads to hypoxia—decreased supply of oxygen to the tissues. Hypoxia involving cardiac muscle or brain tissue can lead to cell death and severe impairment of brain or heart function.

A major risk factor for both arteriosclerosis and atherosclerosis is advanced age, as the conditions tend to progress over time. Arteriosclerosis is normally defined as the more generalised loss of compliance, “hardening of the arteries,” whereas atherosclerosis is a more specific term for the build-up of plaque in the walls of the vessel and is a specific type of arteriosclerosis. There is also a distinct genetic component, and pre-existing hypertension and/or diabetes also greatly increase the risk. However, obesity, poor nutrition, lack of physical activity, and tobacco use all are major risk factors.

Treatment includes lifestyle changes, such as weight loss, smoking cessation, regular exercise, and adoption of a diet low in sodium and saturated fats. Medications to reduce cholesterol and blood pressure may be prescribed. For blocked coronary arteries, surgery is warranted. In angioplasty, a catheter is inserted into the vessel at the point of narrowing, and a second catheter with a balloon-like tip is inflated to widen the opening. To prevent subsequent collapse of the vessel, a small mesh tube called a stent is often inserted. In an endarterectomy, plaque is surgically removed from the walls of a vessel. This operation is typically performed on the carotid arteries of the neck, which are a prime source of oxygenated blood for the brain. In a coronary bypass procedure, a non-vital superficial vessel from another part of the body (often the great saphenous vein) or a synthetic vessel is inserted to create a path around the blocked area of a coronary artery.

Venous System

The pumping action of the heart propels the blood into the arteries, from an area of higher pressure toward an area of lower pressure. If blood is to flow from the veins back into the heart, the pressure in the veins must be greater than the pressure in the atria of the heart. Two factors help maintain this pressure gradient between the veins and the heart. First, the pressure in the atria during diastole is very low, often approaching zero when the atria are relaxed (atrial diastole). Second, two physiologic “pumps” increase pressure in the venous system. The use of the term “pump” implies a physical device that speeds flow. These physiological pumps are less obvious.

Skeletal Muscle Pump

In many body regions, the pressure within the veins can be increased by the contraction of the surrounding skeletal muscle. This mechanism, known as the skeletal muscle pump (Figure 6.7.6), helps the lower-pressure veins counteract the force of gravity, increasing pressure to move blood back to the heart. As leg muscles contract, for example during walking or running, they exert pressure on nearby veins with their numerous one-way valves. This increased pressure causes blood to flow upward, opening valves superior to the contracting muscles so blood flows through. Simultaneously, valves inferior to the contracting muscles close; thus, blood should not seep back downward toward the feet. Military recruits are trained to flex their legs slightly while standing at attention for prolonged periods. Failure to do so may allow blood to pool in the lower limbs rather than returning to the heart. Consequently, the brain will not receive enough oxygenated blood, and the individual may lose consciousness.

Respiratory Pump

The respiratory pump aids blood flow through the veins of the thorax and abdomen. During inhalation, the volume of the thorax increases, largely through the contraction of the diaphragm, which moves downward and compresses the abdominal cavity. The elevation of the chest caused by the contraction of the external intercostal muscles also contributes to the increased volume of the thorax. The volume increase causes air pressure within the thorax to decrease, allowing us to inhale. Additionally, as air pressure within the thorax drops, blood pressure in the thoracic veins also decreases, falling below the pressure in the abdominal veins. This causes blood to flow along its pressure gradient from veins outside the thorax, where pressure is higher, into the thoracic region, where pressure is now lower. This in turn promotes the return of blood from the thoracic veins to the atria. During exhalation, when air pressure increases within the thoracic cavity, pressure in the thoracic veins increases, speeding blood flow into the heart while valves in the veins prevent blood from flowing backward from the thoracic and abdominal veins.

Pressure Relationship in the Venous System

Although vessel diameter increases from the smaller venules to the larger veins and eventually to the venae cavae (singular = vena cava), the total cross-sectional area actually decreases (see Figure 6.7.4a and 6.7.4b). The individual veins are larger in diameter than the venules, but their total number is much lower, so their total cross-sectional area is also lower.

Also notice that, as blood moves from venules to veins, the average blood pressure drops (see Figure 6.7.4c), but the blood velocity actually increases (see Figure 6.7.4d). This pressure gradient drives blood back toward the heart. Again, the presence of one-way valves and the skeletal muscle and respiratory pumps contribute to this increased flow. Since approximately 64 percent of the total blood volume resides in systemic veins, any action that increases the flow of blood through the veins will increase venous return to the heart. Maintaining vascular tone within the veins prevents the veins from merely distending, dampening the flow of blood, and as you will see, vasoconstriction actually enhances the flow.

The Role of Venoconstriction in Resistance, Blood Pressure and Flow

As previously discussed, vasoconstriction of an artery or arteriole decreases the radius, increasing resistance and pressure, but decreasing flow. Venoconstriction, on the other hand, has a very different outcome. The walls of veins are thin but irregular; thus, when the smooth muscle in those walls constricts, the lumen becomes more rounded. The more rounded the lumen, the less surface area the blood encounters, and the less resistance the vessel offers. Vasoconstriction increases pressure within a vein as it does in an artery, but in veins, the increased pressure increases flow. Recall that the pressure in the atria, into which the venous blood will flow, is very low, approaching zero for at least part of the relaxation phase of the cardiac cycle. Thus, venoconstriction increases the return of blood to the heart. Another way of stating this is that venoconstriction increases the preload or stretch of the cardiac muscle and increases contraction.

Click the drop down below to review the terms learned from this chapter.

The primary purpose of the cardiovascular system is to circulate gases, nutrients, wastes, and other substances to and from the cells of the body. Small molecules, such as gases, lipids, and lipid-soluble molecules, can diffuse directly through the membranes of the endothelial cells of the capillary wall. Glucose, amino acids, and ions—including sodium, potassium, calcium, and chloride—use transporters to move through specific channels in the membrane by facilitated diffusion. Glucose, ions, and larger molecules may also leave the blood through intercellular clefts. Larger molecules can pass through the pores of fenestrated capillaries, and even large plasma proteins can pass through the great gaps in the sinusoids. Some large proteins in blood plasma can move into and out of the endothelial cells packaged within vesicles by endocytosis and exocytosis. Water moves by osmosis.

Bulk Flow

The mass movement of fluids into and out of capillary beds requires a transport mechanism far more efficient than mere diffusion. This movement, often referred to as bulk flow, involves two pressure-driven mechanisms: Volumes of fluid move from an area of higher pressure in a capillary bed to an area of lower pressure in the tissues via filtration. In contrast, the movement of fluid from an area of higher pressure in the tissues into an area of lower pressure in the capillaries is reabsorption. Two types of pressure interact to drive each of these movements: hydrostatic pressure and osmotic pressure.

Hydrostatic Pressure

The primary force driving fluid transport between the capillaries and tissues is hydrostatic pressure, which can be defined as the pressure of any fluid enclosed in a space. Blood hydrostatic pressure is the force exerted by the blood confined within blood vessels or heart chambers. Even more specifically, the pressure exerted by blood against the wall of a capillary is called capillary hydrostatic pressure (CHP), and is the same as capillary blood pressure. CHP is the force that drives fluid out of capillaries and into the tissues.

As fluid exits a capillary and moves into tissues, the hydrostatic pressure in the interstitial fluid correspondingly rises. This opposing hydrostatic pressure is called the interstitial fluid hydrostatic pressure (IFHP). Generally, the CHP originating from the arterial pathways is considerably higher than the IFHP, because lymphatic vessels are continually absorbing excess fluid from the tissues. Thus, fluid generally moves out of the capillary and into the interstitial fluid. This process is called filtration.

Osmotic Pressure

The net pressure that drives reabsorption—the movement of fluid from the interstitial fluid back into the capillaries—is called osmotic pressure (sometimes referred to as oncotic pressure). Whereas hydrostatic pressure forces fluid out of the capillary, osmotic pressure draws fluid back in. Osmotic pressure is determined by osmotic concentration gradients, that is, the difference in the solute-to-water concentrations in the blood and tissue fluid. A region higher in solute concentration (and lower in water concentration) draws water across a semipermeable membrane from a region higher in water concentration (and lower in solute concentration).

As we discuss osmotic pressure in blood and tissue fluid, it is important to recognise that the formed elements of blood do not contribute to osmotic concentration gradients. Rather, it is the plasma proteins that play the key role. Solutes also move across the capillary wall according to their concentration gradient, but overall, the concentrations should be similar and not have a significant impact on osmosis. Because of their large size and chemical structure, plasma proteins are not truly solutes, that is, they do not dissolve but are dispersed or suspended in their fluid medium, forming a colloid rather than a solution.

The pressure created by the concentration of colloidal proteins in the blood is called the blood colloidal osmotic pressure (BCOP). Its effect on capillary exchange accounts for the reabsorption of water. The plasma proteins suspended in blood cannot move across the semipermeable capillary cell membrane, and so they remain in the plasma. As a result, blood has a higher colloidal concentration and lower water concentration than tissue fluid. It therefore attracts water. We can also say that the BCOP is higher than the interstitial fluid colloidal osmotic pressure (IFCOP), which is always very low because interstitial fluid contains few proteins. Thus, water is drawn from the tissue fluid back into the capillary, carrying dissolved molecules with it. This difference in colloidal osmotic pressure accounts for reabsorption.

Interaction of Hydrostatic and Osmotic Pressures

The normal unit used to express pressures within the cardiovascular system is millimetres of mercury (mm Hg). When blood leaving an arteriole first enters a capillary bed, the CHP is quite high—about 35 mm Hg. Gradually, this initial CHP declines as the blood moves through the capillary so that by the time the blood has reached the venous end, the CHP has dropped to approximately 18 mm Hg. In comparison, the plasma proteins remain suspended in the blood, so the BCOP remains fairly constant at about 25 mm Hg throughout the length of the capillary and considerably below the osmotic pressure in the interstitial fluid.

The net filtration pressure (NFP) represents the interaction of the hydrostatic and osmotic pressures, driving fluid out of the capillary. It is equal to the difference between the CHP and the BCOP. Since filtration is, by definition, the movement of fluid out of the capillary, when reabsorption is occurring, the NFP is a negative number.

NFP changes at different points in a capillary bed (Figure 6.8.1). Close to the arterial end of the capillary, it is approximately 10 mm Hg, because the CHP of 35 mm Hg minus the BCOP of 25 mm Hg equals 10 mm Hg. Recall that the hydrostatic and osmotic pressures of the interstitial fluid are essentially negligible. Thus, the NFP of 10 mm Hg drives a net movement of fluid out of the capillary at the arterial end. At approximately the middle of the capillary, the CHP is about the same as the BCOP of 25 mm Hg, so the NFP drops to zero. At this point, there is no net change of volume: Fluid moves out of the capillary at the same rate as it moves into the capillary. Near the venous end of the capillary, the CHP has dwindled to about 18 mm Hg due to loss of fluid. Because the BCOP remains steady at 25 mm Hg, water is drawn into the capillary, that is, reabsorption occurs. Another way of expressing this is to say that at the venous end of the capillary, there is an NFP of −7 mm Hg.

The Role of Lymphatic Capillaries

Since overall CHP is higher than BCOP, it is inevitable that more net fluid will exit the capillary through filtration at the arterial end than enters through reabsorption at the venous end. Considering all capillaries over the course of a day, this can be quite a substantial amount of fluid: Approximately 24 litres per day are filtered, whereas 20.4 litres are reabsorbed. This excess fluid is picked up by capillaries of the lymphatic system. These extremely thin-walled vessels have copious numbers of valves that ensure unidirectional flow through ever-larger lymphatic vessels that eventually drain into the subclavian veins in the neck. An important function of the lymphatic system is to return the fluid (lymph) to the blood. Lymph may be thought of as recycled blood plasma.

Click the drop down below to review the terms learned from this chapter.

In order to maintain homeostasis in the cardiovascular system and provide adequate blood to the tissues, blood flow must be redirected continually to the tissues as they become more active. In a very real sense, the cardiovascular system engages in resource allocation, because there is not enough blood flow to distribute blood equally to all tissues simultaneously. For example, when an individual is exercising, more blood will be directed to skeletal muscles, the heart, and the lungs. Following a meal, more blood is directed to the digestive system. Only the brain receives a more or less constant supply of blood whether you are active, resting, thinking, or engaged in any other activity.

Table 6.9.1 provides the distribution of systemic blood at rest and during exercise. Although most of the data appears logical, the values for the distribution of blood to the integument may seem surprising. During exercise, the body distributes more blood to the body surface where it can dissipate the excess heat generated by increased activity into the environment.

Table 6.9.1 Systemic blood flow during rest, mild exercise, and maximal exercise in a healthy young individual.

Three homeostatic mechanisms ensure adequate blood flow, blood pressure, distribution, and ultimately perfusion: neural, endocrine, and autoregulatory mechanisms. They are summarised in Figure 6.9.1.

Neural Regulation

The nervous system plays a critical role in the regulation of vascular homeostasis. The primary regulatory sites include the cardiovascular centres in the brain that control both cardiac and vascular functions. In addition, more generalised neural responses from the limbic system and the autonomic nervous system are factors.

The Cardiovascular Centres in the Brain

Neurological regulation of blood pressure and flow depends on the cardiovascular centres located in the medulla oblongata. This cluster of neurons responds to changes in blood pressure as well as blood concentrations of oxygen, carbon dioxide, and hydrogen ions. The cardiovascular centre contains three distinct paired components:

1. The cardioaccelerator centres stimulate cardiac function by regulating heart rate and stroke volume via sympathetic stimulation from the cardiac accelerator nerve.
2. The cardioinhibitor centre slow cardiac function by decreasing heart rate and stroke volume via parasympathetic stimulation from the vagus nerve.
3. The vasomotor centre control vessel tone or contraction of the smooth muscle in the tunica media. Changes in diameter affect peripheral resistance, pressure, and flow, which affect cardiac output. The majority of these neurons act via the release of the neurotransmitter noradrenaline from sympathetic neurons.

Although each centre functions independently, they are not anatomically distinct.

There is also a small population of neurons that control vasodilation in the vessels of the brain and skeletal muscles by relaxing the smooth muscle fibres in the vessel tunics. Many of these are cholinergic neurons, that is, they release acetylcholine, which in turn stimulates the vessels’ endothelial cells to release nitric oxide (NO), which causes vasodilation. Others release noradrenaline that binds to β2 receptors. A few neurons release NO directly as a neurotransmitter.

Recall that mild stimulation of the skeletal muscles maintains muscle tone. A similar phenomenon occurs with vascular tone in vessels. As noted earlier, arterioles are normally partially constricted: With maximal stimulation, their radius may be reduced to one-half of the resting state. Full dilation of most arterioles requires that this sympathetic stimulation be suppressed. When it is, an arteriole can expand by as much as 150 percent. Such a significant increase can dramatically affect resistance, pressure, and flow.

Baroreceptor Reflexes

Baroreceptors are specialised stretch receptors located within thin areas of blood vessels and heart chambers that respond to the degree of stretch caused by the presence of blood. They send impulses to the cardiovascular centre to regulate blood pressure. Vascular baroreceptors are found primarily in sinuses (small cavities) within the aorta and carotid arteries: The aortic sinuses are found in the walls of the ascending aorta just superior to the aortic valve, whereas the carotid sinuses are in the base of the internal carotid arteries. There are also low-pressure baroreceptors located in the walls of the venae cavae and right atrium.

When blood pressure increases, the baroreceptors are stretched more tightly and initiate action potentials at a higher rate. At lower blood pressures, the degree of stretch is lower and the rate of firing is slower. When the cardiovascular centre in the medulla oblongata receives this input, it triggers a reflex that maintains homeostasis (Figure 6.9.2).

When blood pressure rises too high, the baroreceptors fire at a higher rate and trigger parasympathetic stimulation of the heart. As a result, cardiac output falls. Sympathetic stimulation of the peripheral arterioles will also decrease, resulting in vasodilation. Combined, these activities cause blood pressure to fall.

When blood pressure drops too low, the rate of baroreceptor firing decreases. This will trigger an increase in sympathetic stimulation of the heart, causing cardiac output to increase. It will also trigger sympathetic stimulation of the peripheral vessels, resulting in vasoconstriction. Combined, these activities cause blood pressure to rise.

The baroreceptors in the venae cavae and right atrium monitor blood pressure as the blood returns to the heart from the systemic circulation. Normally, blood flow into the aorta is the same as blood flow back into the right atrium. If blood is returning to the right atrium more rapidly than it is being ejected from the left ventricle, the atrial receptors will stimulate the cardiovascular centres to increase sympathetic firing and increase cardiac output until homeostasis is achieved. The opposite is also true. This mechanism is referred to as the atrial reflex.

Chemoreceptor Reflexes

In addition to the baroreceptors are chemoreceptors that monitor levels of oxygen, carbon dioxide, and hydrogen ions (pH), and thereby contribute to vascular homeostasis. Chemoreceptors monitoring the blood are located in close proximity to the baroreceptors in the aortic and carotid sinuses. They signal the cardiovascular centre as well as the respiratory centres in the medulla oblongata.

Since tissues consume oxygen and produce carbon dioxide and acids as waste products, when the body is more active, oxygen levels fall and carbon dioxide levels rise as cells undergo cellular respiration to meet the energy needs of activities. This causes more hydrogen ions to be produced, causing the blood pH to drop. When the body is resting, oxygen levels are higher, carbon dioxide levels are lower, more hydrogen is bound, and pH rises. (Seek additional content for more detail about pH.)

The chemoreceptors respond to increasing carbon dioxide and hydrogen ion levels (falling pH) by stimulating the cardioaccelerator and vasomotor centres, increasing cardiac output and constricting peripheral vessels. The cardioinhibitor centres are suppressed. With falling carbon dioxide and hydrogen ion levels (increasing pH), the cardioinhibitor centres are stimulated, and the cardioaccelerator and vasomotor centres are suppressed, decreasing cardiac output and causing peripheral vasodilation. In order to maintain adequate supplies of oxygen to the cells and remove waste products such as carbon dioxide, it is essential that the respiratory system respond to changing metabolic demands. In turn, the cardiovascular system will transport these gases to the lungs for exchange, again in accordance with metabolic demands. This interrelationship of cardiovascular and respiratory control cannot be overemphasised.

Other neural mechanisms can also have a significant impact on cardiovascular function. These include the limbic system that links physiological responses to psychological stimuli, as well as generalised sympathetic and parasympathetic stimulation.

Endocrine Regulation

Endocrine control over the cardiovascular system involves the catecholamines, adrenaline and noradrenaline, as well as several hormones that interact with the kidneys in the regulation of blood volume.

Adrenaline and Noradrenaline

The catecholamines adrenaline and noradrenaline are released by the adrenal medulla, and enhance and extend the body’s sympathetic or “fight-or-flight” response (see Figure 6.9.3). They increase heart rate and force of contraction, while temporarily constricting blood vessels to organs not essential for flight-or-fight responses and redirecting blood flow to the liver, muscles, and heart.

Antidiuretic Hormone (ADH)

Antidiuretic hormone (ADH), also known as vasopressin, is secreted by the cells in the hypothalamus and transported via the hypothalamic-hypophyseal tracts to the posterior pituitary where it is stored until released upon nervous stimulation. The primary trigger prompting the hypothalamus to release ADH is increasing osmolarity of tissue fluid, usually in response to significant loss of blood volume. ADH signals its target cells in the kidneys to reabsorb more water, thus preventing the loss of additional fluid in the urine. This will increase overall fluid levels and help restore blood volume and pressure. In addition, ADH constricts peripheral vessels.

Renin-Angiotensin-Aldosterone System (RAAS)

The renin-angiotensin-aldosterone mechanism has a major effect upon the cardiovascular system (Figure 6.9.3). Renin is an enzyme, although because of its importance in the renin-angiotensin-aldosterone pathway, some sources identify it as a hormone. Specialised cells in the kidneys found in the juxtaglomerular apparatus respond to decreased blood flow by secreting renin into the blood. Renin converts the plasma protein angiotensinogen, which is produced by the liver, into its active form—angiotensin I. Angiotensin I circulates in the blood and is then converted into angiotensin II in the lungs. This reaction is catalysed by the enzyme angiotensin-converting enzyme (ACE).

Angiotensin II is a powerful vasoconstrictor, greatly increasing blood pressure. It also stimulates the release of ADH and aldosterone, a hormone produced by the adrenal cortex. Aldosterone increases the reabsorption of sodium into the blood by the kidneys. Since water follows sodium, this increases the reabsorption of water. This in turn increases blood volume, raising blood pressure. Angiotensin II also stimulates the thirst centre in the hypothalamus, so an individual will likely consume more fluids, again increasing blood volume and pressure.

Erythropoietin (EPO)

Erythropoietin (EPO) is released by the kidneys when blood flow and/or oxygen levels decrease. EPO stimulates the production of erythrocytes within the bone marrow. Erythrocytes are the major formed element of the blood and may contribute 40 percent or more to blood volume, a significant factor of viscosity, resistance, pressure, and flow. In addition, EPO is a vasoconstrictor. Overproduction of EPO or excessive intake of synthetic EPO, often to enhance athletic performance, will increase viscosity, resistance, and pressure, and decrease flow in addition to its contribution as a vasoconstrictor.

Atrial Natriuretic Peptide (ANP)

Secreted by cells in the atria of the heart, atrial natriuretic hormone (ANH) or also known as atrial natriuretic peptide, is secreted when blood volume is high enough to cause extreme stretching of the cardiac cells. Cells in the ventricle produce a hormone with similar effects, called B-type natriuretic hormone. Natriuretic hormones are antagonists to angiotensin II. They promote loss of sodium and water from the kidneys, and suppress renin, aldosterone and ADH production and release. All of these actions promote loss of fluid from the body, so blood volume and blood pressure drop.

Autoregulation of Perfusion

As the name would suggest, autoregulation mechanisms require neither specialised nervous stimulation nor endocrine control. Rather, these are local, self-regulatory mechanisms that allow each region of tissue to adjust its blood flow—and thus its perfusion. These local mechanisms include chemical signals and myogenic controls.

Chemical Signals Involved in Autoregulation

Chemical signals work at the level of the precapillary sphincters to trigger either constriction or relaxation. As you know, opening a precapillary sphincter allows blood to flow into that particular capillary, whereas constricting a precapillary sphincter temporarily shuts off blood flow to that region. The factors involved in regulating the precapillary sphincters include the following:

Opening of the sphincter is triggered in response to decreased oxygen concentrations; increased carbon dioxide concentrations; increasing levels of lactic acid or other by-products of cellular metabolism; increasing concentrations of potassium ions or hydrogen ions (falling pH); inflammatory chemicals such as histamines; and increased body temperature. These conditions in turn stimulate the release of NO, a powerful vasodilator, from endothelial cells.

Contraction of the precapillary sphincter is triggered by the opposite levels of the regulators, which prompt the release of endothelins, powerful vasoconstricting peptides secreted by endothelial cells. Platelet secretions and certain prostaglandins may also trigger constriction.

Again, these factors alter tissue perfusion via their effects on the precapillary sphincter mechanism, which regulates blood flow to capillaries. Since the amount of blood is limited, not all capillaries can fill at once, so blood flow is allocated based upon the needs and metabolic state of the tissues as reflected in these parameters. Bear in mind, however, that dilation and constriction of the arterioles feeding the capillary beds is the primary control mechanism.

The Myogenic Response

The myogenic response is a reaction to the stretching of the smooth muscle in the walls of arterioles as changes in blood flow occur through the vessel. This may be viewed as a largely protective function against dramatic fluctuations in blood pressure and blood flow to maintain homeostasis. If perfusion of an organ is too low (ischaemia), the tissue will experience low levels of oxygen (hypoxia). In contrast, excessive perfusion could damage the organ’s smaller and more fragile vessels. The myogenic response is a localised process that serves to stabilise blood flow in the capillary network that follows that arteriole.

When blood flow is low, the vessel’s smooth muscle will be only minimally stretched. In response, it relaxes, allowing the vessel to dilate and thereby increase the movement of blood into the tissue. When blood flow is too high, the smooth muscle will contract in response to the increased stretch, prompting vasoconstriction that reduces blood flow.

Table 6.9.2 Summary of the effects of nervous, endocrine and local controls on arterioles.

Effect of Exercise on Vascular Homeostasis

The heart is a muscle and, like any muscle, it responds dramatically to exercise. For a healthy young adult, cardiac output (heart rate × stroke volume) increases in the nonathlete from approximately 5.0 litres per minute to a maximum of about 20 litres per minute. Accompanying this will be an increase in blood pressure from about 120/80 to 185/75. However, well-trained aerobic athletes can increase these values substantially. For these individuals, cardiac output soars from approximately 5.3 litres per minute resting to more than 30 litres per minute during maximal exercise. Along with this increase in cardiac output, blood pressure increases from 120/80 at rest to 200/90 at maximum values.

In addition to improved cardiac function, exercise increases the size and mass of the heart. The average weight of the heart for the nonathlete is about 300 g, whereas in an athlete it can increase to 500 g. This increase in size generally makes the heart stronger and more efficient at pumping blood, increasing both stroke volume and cardiac output.

Tissue perfusion also increases as the body transitions from a resting state to light exercise and eventually to heavy exercise. These changes result in selective vasodilation in the skeletal muscles, heart, lungs, liver, and integument. Simultaneously, vasoconstriction occurs in the vessels leading to the kidneys and most of the digestive and reproductive organs. The flow of blood to the brain remains largely unchanged whether at rest or exercising, since the vessels in the brain largely do not respond to regulatory stimuli, in most cases, because they lack the appropriate receptors.

As vasodilation occurs in selected vessels, resistance drops and more blood rushes into the organs they supply. This blood eventually returns to the venous system. Venous return is further enhanced by both the skeletal muscle and respiratory pumps. As blood returns to the heart more quickly, preload rises and the Frank-Starling principle tells us that contraction of the cardiac muscle in the atria and ventricles will be more forceful. Eventually, even the best-trained athletes will fatigue and must undergo a period of rest following exercise. Cardiac output and distribution of blood then return to normal.

Regular exercise promotes cardiovascular health in a variety of ways. Because an athlete’s heart is larger than a nonathlete’s, stroke volume increases, so the athletic heart can deliver the same amount of blood as the nonathletic heart but with a lower heart rate. This increased efficiency allows the athlete to exercise for longer periods of time before muscles fatigue and places less stress on the heart. Exercise also lowers overall cholesterol levels by removing from the circulation a complex form of cholesterol, triglycerides, and proteins known as low-density lipoproteins (LDLs), which are widely associated with increased risk of cardiovascular disease. Although there is no way to remove deposits of plaque from the walls of arteries other than specialised surgery, exercise does promote the health of vessels by decreasing the rate of plaque formation and reducing blood pressure, so the heart does not have to generate as much force to overcome resistance.

Generally as little as 30 minutes of noncontinuous exercise over the course of each day has beneficial effects and has been shown to lower the rate of heart attack by nearly 50 percent. While it is always advisable to follow a healthy diet, stop smoking, and lose weight, studies have clearly shown that fit, overweight people may actually be healthier overall than sedentary slender people. Thus, the benefits of moderate exercise are undeniable.

Clinical Considerations in Vascular Homeostasis

Any disorder that affects blood volume, vascular tone, or any other aspect of vascular functioning is likely to affect vascular homeostasis as well. That includes hypertension, haemorrhage, and shock.

Hypertension and Hypotension

Chronically elevated blood pressure is known clinically as hypertension. It is defined as chronic and persistent blood pressure measurements of 140/90 mm Hg or above. Pressures between 120/80 and 140/90 mm Hg are defined as prehypertension. The Australian Bureau of Statistics report that between 2017-2018, one in three Australian adults had high blood pressure, with hypertension making up over five percent of the total burden of disease in Australia. It has been estimated that over one billion people worldwide have hypertension, most of whom live in lower-income countries. Unfortunately, hypertension is typically a silent disorder; therefore, hypertensive patients may fail to recognise the seriousness of their condition and fail to follow their treatment plan. The result is often a heart attack or stroke. Hypertension may also lead to an aneurism (ballooning of a blood vessel caused by a weakening of the wall), peripheral arterial disease (obstruction of vessels in peripheral regions of the body), chronic kidney disease, or heart failure.

Haemorrhage

Minor blood loss is managed by haemostasis and repair. Haemorrhage is a loss of blood that cannot be controlled by haemostatic mechanisms. Initially, the body responds to haemorrhage by initiating mechanisms aimed at increasing blood pressure and maintaining blood flow. Ultimately, however, blood volume will need to be restored, either through physiological processes or through medical intervention.

In response to blood loss, stimuli from the baroreceptors trigger the cardiovascular centres to stimulate sympathetic responses to increase cardiac output and vasoconstriction. This typically prompts the heart rate to increase to about 180–200 contractions per minute, restoring cardiac output to normal levels. Vasoconstriction of the arterioles increases vascular resistance, whereas constriction of the veins increases venous return to the heart. Both of these steps will help increase blood pressure. Sympathetic stimulation also triggers the release of adrenaline and noradrenaline, which enhance both cardiac output and vasoconstriction. If blood loss were less than 20 percent of total blood volume, these responses together would usually return blood pressure to normal and redirect the remaining blood to the tissues.

Additional endocrine involvement is necessary, however, to restore the lost blood volume. The angiotensin-renin-aldosterone mechanism stimulates the thirst centre in the hypothalamus, which increases fluid consumption to help restore the lost blood. More importantly, it increases renal reabsorption of sodium and water, reducing water loss in urine output. The kidneys also increase the production of EPO, stimulating the formation of erythrocytes that not only deliver oxygen to the tissues but also increase overall blood volume. Figure 6.9.5 summarises the responses to loss of blood volume.

Circulatory Shock

The loss of too much blood may lead to circulatory shock, a life-threatening condition in which the circulatory system is unable to maintain blood flow to adequately supply sufficient oxygen and other nutrients to the tissues to maintain cellular metabolism. It should not be confused with emotional or psychological shock. Typically, the patient in circulatory shock will demonstrate an increased heart rate but decreased blood pressure, but there are cases in which blood pressure will remain normal. Urine output will fall dramatically, and the patient may appear confused or lose consciousness. Urine output less than 1 mL/kg body weight/hour is cause for concern. Unfortunately, shock is an example of a positive-feedback loop that, if uncorrected, may lead to the death of the patient.

There are several recognised forms of shock:

Hypovolaemic shock in adults is typically caused by haemorrhage, although in children it may be caused by fluid losses related to severe vomiting or diarrhoea. Other causes for hypovolaemic shock include extensive burns, exposure to some toxins, and excessive urine loss related to diabetes insipidus or ketoacidosis. Typically, patients present with a rapid, almost tachycardic heart rate; a weak pulse often described as “thread;” cool, clammy skin, particularly in the extremities, due to restricted peripheral blood flow; rapid, shallow breathing; hypothermia; thirst; and dry mouth. Treatments generally involve providing intravenous fluids to restore the patient to normal function and various drugs such as dopamine, adrenaline, and noradrenaline to raise blood pressure.

Cardiogenic shock results from the inability of the heart to maintain cardiac output. Most often, it results from a myocardial infarction (heart attack), but it may also be caused by arrhythmias, valve disorders, cardiomyopathies, cardiac failure, or simply insufficient flow of blood through the cardiac vessels. Treatment involves repairing the damage to the heart or its vessels to resolve the underlying cause, rather than treating cardiogenic shock directly.

Vascular shock occurs when arterioles lose their normal muscular tone and dilate dramatically. It may arise from a variety of causes, and treatments almost always involve fluid replacement and medications, called inotropic or pressor agents, which restore tone to the muscles of the vessels. In addition, eliminating or at least alleviating the underlying cause of the condition is required. This might include antibiotics and antihistamines, or select steroids, which may aid in the repair of nerve damage. A common cause is sepsis (or septicaemia), also called “blood poisoning,” which is a widespread bacterial infection that results in an organismal-level inflammatory response known as septic shock. Neurogenic shock is a form of vascular shock that occurs with cranial or spinal injuries that damage the cardiovascular centres in the medulla oblongata or the nervous fibres originating from this region. Anaphylactic shock is a severe allergic response that causes the widespread release of histamines, triggering vasodilation throughout the body.

Obstructive shock, as the name would suggest, occurs when a significant portion of the vascular system is blocked. It is not always recognised as a distinct condition and may be grouped with cardiogenic shock, including pulmonary embolism and cardiac tamponade. Treatments depend upon the underlying cause and, in addition to administering fluids intravenously, often include the administration of anticoagulants, removal of fluid from the pericardial cavity, or air from the thoracic cavity, and surgery as required. The most common cause is a pulmonary embolism, a clot that lodges in the pulmonary vessels and interrupts blood flow. Other causes include stenosis of the aortic valve; cardiac tamponade, in which excess fluid in the pericardial cavity interferes with the ability of the heart to fully relax and fill with blood (resulting in decreased preload); and a pneumothorax, in which an excessive amount of air is present in the thoracic cavity, outside of the lungs, which interferes with venous return, pulmonary function, and delivery of oxygen to the tissues.

Click the drop down below to review the terms learned from this chapter.

Virtually every cell, tissue, organ, and system in the body is impacted by the circulatory system. This includes the generalised and more specialised functions of transport of materials, capillary exchange, maintaining health by transporting white blood cells and various immunoglobulins (antibodies), haemostasis, regulation of body temperature, and helping to maintain acid-base balance. In addition to these shared functions, many systems enjoy a unique relationship with the circulatory system. Figure 6.10.1 summarises these relationships.

As you learn about the vessels of the systemic and pulmonary circuits, notice that many arteries and veins share the same names, parallel one another throughout the body, and are very similar on the right and left sides of the body. These pairs of vessels will be traced through only one side of the body. Where differences occur in branching patterns or when vessels are singular, this will be indicated. For example, you will find a pair of femoral arteries and a pair of femoral veins, with one vessel on each side of the body. In contrast, some vessels closer to the midline of the body, such as the aorta, are unique. Moreover, some superficial veins, such as the great saphenous vein in the femoral region, have no arterial counterpart. Another phenomenon that can make the study of vessels challenging is that names of vessels can change with location. Like a street that changes name as it passes through an intersection, an artery or vein can change names as it passes an anatomical landmark. For example, the left subclavian artery becomes the axillary artery as it passes through the body wall and into the axillary region, and then becomes the brachial artery as it flows from the axillary region into the upper arm (or brachium). You will also find examples of anastomoses where two blood vessels that previously branched reconnect. Anastomoses are especially common in veins, where they help maintain blood flow even when one vessel is blocked or narrowed, although there are some important ones in the arteries supplying the brain.

As you read about circular pathways, notice that there is an occasional, very large artery referred to as a trunk, a term indicating that the vessel gives rise to several smaller arteries. For example, the celiac trunk gives rise to the left gastric, common hepatic, and splenic arteries.

As you study this section, imagine you are on a “Voyage of Discovery” similar to Lewis and Clark’s expedition in 1804–1806, which followed rivers and streams through unfamiliar territory, seeking a water route from the Atlantic to the Pacific Ocean. You might envision being inside a miniature boat, exploring the various branches of the circulatory system. This simple approach has proven effective for many students in mastering these major circulatory patterns. Another approach that works well for many students is to create simple line drawings similar to the ones provided, labelling each of the major vessels. It is beyond the scope of this text to name every vessel in the body. However, we will attempt to discuss the major pathways for blood and acquaint you with the major named arteries and veins in the body. Also, please keep in mind that individual variations in circulation patterns are not uncommon.

Pulmonary Circulation

Recall that blood returning from the systemic circuit enters the right atrium (Figure 6.10.2) via the superior and inferior venae cavae and the coronary sinus, which drains the blood supply of the heart muscle. These vessels will be described more fully later in this section. This blood is relatively low in oxygen and relatively high in carbon dioxide, since much of the oxygen has been extracted for use by the tissues and the waste gas carbon dioxide was picked up to be transported to the lungs for elimination. From the right atrium, blood moves into the right ventricle, which pumps it to the lungs for gas exchange. This system of vessels is referred to as the pulmonary circuit.

The single vessel exiting the right ventricle is the pulmonary trunk. At the base of the pulmonary trunk is the pulmonary semilunar valve, which prevents backflow of blood into the right ventricle during ventricular diastole. As the pulmonary trunk reaches the superior surface of the heart, it curves posteriorly and rapidly bifurcates (divides) into two branches, a left and a right pulmonary artery. To prevent confusion between these vessels, it is important to refer to the vessel exiting the heart as the pulmonary trunk, rather than also calling it a pulmonary artery. The pulmonary arteries in turn branch many times within the lung, forming a series of smaller arteries and arterioles that eventually lead to the pulmonary capillaries. The pulmonary capillaries surround lung structures known as alveoli that are the sites of oxygen and carbon dioxide exchange.

Once gas exchange is completed, oxygenated blood flows from the pulmonary capillaries into a series of pulmonary venules that eventually lead to a series of larger pulmonary veins. Four pulmonary veins, two on the left and two on the right, return blood to the left atrium. At this point, the pulmonary circuit is complete. Table 6.10.1 defines the major arteries and veins of the pulmonary circuit discussed in the text.

Table 6.10.1. Pulmonary arteries and veins

Overview of Systemic Arteries

Blood relatively high in oxygen concentration is returned from the pulmonary circuit to the left atrium via the four pulmonary veins. From the left atrium, blood moves into the left ventricle, which pumps blood into the aorta. The aorta and its branches—the systemic arteries—send blood to virtually every organ of the body (Figure 6.10.3).

The Aorta

The aorta is the largest artery in the body (Figure 6.10.4). It arises from the left ventricle and eventually descends to the abdominal region, where it bifurcates at the level of the fourth lumbar vertebra into the two common iliac arteries. The aorta consists of the ascending aorta, the aortic arch, and the descending aorta, which passes through the diaphragm and a landmark that divides into the superior thoracic and inferior abdominal components. Arteries originating from the aorta ultimately distribute blood to virtually all tissues of the body. At the base of the aorta is the aortic semilunar valve that prevents backflow of blood into the left ventricle while the heart is relaxing. After exiting the heart, the ascending aorta moves in a superior direction for approximately 5 cm and ends at the sternal angle. Following this ascent, it reverses direction, forming a graceful arc to the left, called the aortic arch. The aortic arch descends toward the inferior portions of the body and ends at the level of the intervertebral disk between the fourth and fifth thoracic vertebrae. Beyond this point, the descending aorta continues close to the bodies of the vertebrae and passes through an opening in the diaphragm known as the aortic hiatus. Superior to the diaphragm, the aorta is called the thoracic aorta, and inferior to the diaphragm, it is called the abdominal aorta. The abdominal aorta terminates when it bifurcates into the two common iliac arteries at the level of the fourth lumbar vertebra. See Figure 6.10.4 for an illustration of the ascending aorta, the aortic arch, and the initial segment of the descending aorta plus major branches; Table 6.10.2 summarises the structures of the aorta.

Table 6.10.2. Components of the aorta

Coronary Circulation

The first vessels that branch from the ascending aorta are the paired coronary arteries (see Figure 6.10.4), which arise from two of the three sinuses in the ascending aorta just superior to the aortic semilunar valve. These sinuses contain the aortic baroreceptors and chemoreceptors critical to maintain cardiac function. The left coronary artery arises from the left posterior aortic sinus. The right coronary artery arises from the anterior aortic sinus. Normally, the right posterior aortic sinus does not give rise to a vessel.

The coronary arteries encircle the heart, forming a ring-like structure that divides into the next level of branches that supplies blood to the heart tissues.

Aortic Arch Branches

There are three major branches of the aortic arch: the brachiocephalic artery, the left common carotid artery, and the left subclavian (literally “under the clavicle”) artery. As you would expect based upon proximity to the heart, each of these vessels is classified as an elastic artery.

The brachiocephalic artery is located only on the right side of the body; there is no corresponding artery on the left. The brachiocephalic artery branches into the right subclavian artery and the right common carotid artery. The left subclavian and left common carotid arteries arise independently from the aortic arch but otherwise follow a similar pattern and distribution to the corresponding arteries on the right side (see Figure 6.10.2).

Each subclavian artery supplies blood to the arms, chest, shoulders, back, and central nervous system. It then gives rise to three major branches: the internal thoracic artery, the vertebral artery, and the thyrocervical artery. The internal thoracic artery, or mammary artery, supplies blood to the thymus, the pericardium of the heart, and the anterior chest wall. The vertebral artery passes through the vertebral foramen in the cervical vertebrae and then through the foramen magnum into the cranial cavity to supply blood to the brain and spinal cord. The paired vertebral arteries join together to form the large basilar artery at the base of the medulla oblongata. This is an example of an anastomosis. The subclavian artery also gives rise to the thyrocervical artery that provides blood to the thyroid, the cervical region of the neck, and the upper back and shoulder.

The common carotid artery divides into internal and external carotid arteries. The right common carotid artery arises from the brachiocephalic artery and the left common carotid artery arises directly from the aortic arch. The external carotid artery supplies blood to numerous structures within the face, lower jaw, neck, oesophagus, and larynx. These branches include the lingual, facial, occipital, maxillary, and superficial temporal arteries. The internal carotid artery initially forms an expansion known as the carotid sinus, containing the carotid baroreceptors and chemoreceptors. Like their counterparts in the aortic sinuses, the information provided by these receptors is critical to maintaining cardiovascular homeostasis (see Figure 6.10.2).

The internal carotid arteries along with the vertebral arteries are the two primary suppliers of blood to the human brain. Given the central role and vital importance of the brain to life, it is critical that blood supply to this organ remains uninterrupted. Recall that blood flow to the brain is remarkably constant, with approximately 20 percent of blood flow directed to this organ at any given time. When blood flow is interrupted, even for just a few seconds, a transient ischemic attack (TIA), or mini-stroke, may occur, resulting in loss of consciousness or temporary loss of neurological function. In some cases, the damage may be permanent. Loss of blood flow for longer periods, typically between 3 and 4 minutes, will likely produce irreversible brain damage or a stroke, also called a cerebrovascular accident (CVA). The locations of the arteries in the brain not only provide blood flow to the brain tissue but also prevent interruption in the flow of blood. Both the carotid and vertebral arteries branch once they enter the cranial cavity, and some of these branches form a structure known as the arterial circle (or circle of Willis), an anastomosis that is remarkably like a traffic circle that sends off branches (in this case, arterial branches to the brain). As a rule, branches to the anterior portion of the cerebrum are normally fed by the internal carotid arteries; the remainder of the brain receives blood flow from branches associated with the vertebral arteries.

The internal carotid artery continues through the carotid canal of the temporal bone and enters the base of the brain through the carotid foramen where it gives rise to several branches (Figure 6.10.5 and Figure 6.10.6). One of these branches is the anterior cerebral artery that supplies blood to the frontal lobe of the cerebrum. Another branch, the middle cerebral artery, supplies blood to the temporal and parietal lobes, which are the most common sites of CVAs. The ophthalmic artery, the third major branch, provides blood to the eyes.

The right and left anterior cerebral arteries join together to form an anastomosis called the anterior communicating artery. The initial segments of the anterior cerebral arteries and the anterior communicating artery form the anterior portion of the arterial circle. The posterior portion of the arterial circle is formed by a left and a right posterior communicating artery that branches from the posterior cerebral artery, which arises from the basilar artery. It provides blood to the posterior portion of the cerebrum and brain stem. The basilar artery is an anastomosis that begins at the junction of the two vertebral arteries and sends branches to the cerebellum and brain stem. It flows into the posterior cerebral arteries. Table 6.10.3 summarises the aortic arch branches, including the major branches supplying the brain.

Table 6.10.3. Aortic arch branches and brain circulation

Thoracic Aorta and Major Branches

The thoracic aorta begins at the level of vertebra T5 and continues through to the diaphragm at the level of T12, initially traveling within the mediastinum to the left of the vertebral column. As it passes through the thoracic region, the thoracic aorta gives rise to several branches, which are collectively referred to as visceral branches and parietal branches (Figure 6.10.7). Those branches that supply blood primarily to visceral organs are known as the visceral branches and include the bronchial arteries, pericardial arteries, oesophageal arteries, and the mediastinal arteries, each named after the tissues it supplies. Each bronchial artery (typically two on the left and one on the right) supplies systemic blood to the lungs and visceral pleura, in addition to the blood pumped to the lungs for oxygenation via the pulmonary circuit. The bronchial arteries follow the same path as the respiratory branches, beginning with the bronchi and ending with the bronchioles. There is considerable, but not total, intermingling of the systemic and pulmonary blood at anastomoses in the smaller branches of the lungs. This may sound incongruous—that is, the mixing of systemic arterial blood high in oxygen with the pulmonary arterial blood lower in oxygen—but the systemic vessels also deliver nutrients to the lung tissue just as they do elsewhere in the body. The mixed blood drains into typical pulmonary veins, whereas the bronchial artery branches remain separate and drain into bronchial veins described later. Each pericardial artery supplies blood to the pericardium, the oesophageal artery provides blood to the oesophagus, and the mediastinal artery provides blood to the mediastinum. The remaining thoracic aorta branches are collectively referred to as parietal branches or somatic branches and include the intercostal and superior phrenic arteries. Each intercostal artery provides blood to the muscles of the thoracic cavity and vertebral column. The superior phrenic artery provides blood to the superior surface of the diaphragm. Table 6.10.4 lists the arteries of the thoracic region.

Table 6.10.4. Arteries of the thoracic region

Abdominal Aorta and Major Branches

After crossing through the diaphragm at the aortic hiatus, the thoracic aorta is called the abdominal aorta (see Figure 6.10.7). This vessel remains to the left of the vertebral column and is embedded in adipose tissue behind the peritoneal cavity. It formally ends at approximately the level of vertebra L4, where it bifurcates to form the common iliac arteries. Before this division, the abdominal aorta gives rise to several important branches. A single celiac trunk (artery) emerges and divides into the left gastric artery to supply blood to the stomach and oesophagus, the splenic artery to supply blood to the spleen, and the common hepatic artery, which in turn gives rise to the hepatic artery proper to supply blood to the liver, the right gastric artery to supply blood to the stomach, the cystic artery to supply blood to the gall bladder, and several branches, one to supply blood to the duodenum and another to supply blood to the pancreas. Two additional single vessels arise from the abdominal aorta. These are the superior and inferior mesenteric arteries. The superior mesenteric artery arises approximately 2.5 cm after the celiac trunk and branches into several major vessels that supply blood to the small intestine (duodenum, jejunum, and ileum), the pancreas, and a majority of the large intestine. The inferior mesenteric artery supplies blood to the distal segment of the large intestine, including the rectum. It arises approximately 5 cm superior to the common iliac arteries.

In addition to these single branches, the abdominal aorta gives rise to several significant paired arteries along the way. These include the inferior phrenic arteries, the adrenal arteries, the renal arteries, the gonadal arteries, and the lumbar arteries. Each inferior phrenic artery is a counterpart of a superior phrenic artery and supplies blood to the inferior surface of the diaphragm. The adrenal artery supplies blood to the adrenal (suprarenal) glands and arises near the superior mesenteric artery. Each renal artery branches approximately 2.5 cm inferior to the superior mesenteric arteries and supplies a kidney. The right renal artery is longer than the left since the aorta lies to the left of the vertebral column and the vessel must travel a greater distance to reach its target. Renal arteries branch repeatedly to supply blood to the kidneys. Each gonadal artery supplies blood to the gonads, or reproductive organs, and is also described as either an ovarian artery or a testicular artery (internal spermatic), depending upon the sex of the individual. An ovarian artery supplies blood to an ovary, uterine (Fallopian) tube, and the uterus, and is located within the suspensory ligament of the uterus. It is considerably shorter than a testicular artery, which ultimately travels outside the body cavity to the testes, forming one component of the spermatic cord. The gonadal arteries arise inferior to the renal arteries and are generally retroperitoneal. The ovarian artery continues to the uterus where it forms an anastomosis with the uterine artery that supplies blood to the uterus. Both the uterine arteries and vaginal arteries, which distribute blood to the vagina, are branches of the internal iliac artery. The four paired lumbar arteries are the counterparts of the intercostal arteries and supply blood to the lumbar region, the abdominal wall, and the spinal cord. In some instances, a fifth pair of lumbar arteries emerges from the median sacral artery.

The aorta divides at approximately the level of vertebra L4 into a left and a right common iliac artery but continues as a small vessel, the median sacral artery, into the sacrum. The common iliac arteries provide blood to the pelvic region and ultimately to the lower limbs. They split into external and internal iliac arteries approximately at the level of the lumbar-sacral articulation. Each internal iliac artery sends branches to the urinary bladder, the walls of the pelvis, the external genitalia, and the medial portion of the femoral region. In females, they also provide blood to the uterus and vagina. The much larger external iliac artery supplies blood to each of the lower limbs. Figure 6.10.8 shows the distribution of the major branches of the aorta into the thoracic and abdominal regions. Figure 6.10.9 shows the distribution of the major branches of the common iliac arteries. Table 6.10.5 summarises the major branches of the abdominal aorta.

Major Branches of the Iliac Arteries

The flow chart summarises the distribution of the major branches of the common iliac arteries into the pelvis and lower limbs. The left side follows a similar pattern to the right.

Table 6.10.5. Vessels of the abdominal aorta

Arteries Serving the Upper Limbs

As the subclavian artery exits the thorax into the axillary region, it is renamed the axillary artery. Although it does branch and supply blood to the region near the head of the humerus (via the humeral circumflex arteries), the majority of the vessel continues into the upper arm, or brachium, and becomes the brachial artery (Figure 6.10.10). The brachial artery supplies blood to much of the brachial region and divides at the elbow into several smaller branches, including the deep brachial arteries, which provide blood to the posterior surface of the arm, and the ulnar collateral arteries, which supply blood to the region of the elbow. As the brachial artery approaches the coronoid fossa, it bifurcates into the radial and ulnar arteries, which continue into the forearm, or antebrachium. The radial artery and ulnar artery parallel their namesake bones, giving off smaller branches until they reach the wrist, or carpal region. At this level, they fuse to form the superficial and deep palmar arches that supply blood to the hand, as well as the digital arteries that supply blood to the digits. Figure 6.10.11 shows the distribution of systemic arteries from the heart into the upper limb. Table 6.10.6 summarises the arteries serving the upper limbs.

Table 6.10.6. Arteries serving the upper limbs

Arteries Serving the Lower Limbs

The external iliac artery exits the body cavity and enters the femoral region of the lower leg (Figure 6.10.12). As it passes through the body wall, it is renamed the femoral artery. It gives off several smaller branches as well as the lateral deep femoral artery that in turn gives rise to a lateral circumflex artery. These arteries supply blood to the deep muscles of the thigh as well as ventral and lateral regions of the integument. The femoral artery also gives rise to the genicular artery, which provides blood to the region of the knee. As the femoral artery passes posterior to the knee near the popliteal fossa, it is called the popliteal artery. The popliteal artery branches into the anterior and posterior tibial arteries.

The anterior tibial artery is located between the tibia and fibula and supplies blood to the muscles and integument of the anterior tibial region. Upon reaching the tarsal region, it becomes the dorsalis pedis artery, which branches repeatedly and provides blood to the tarsal and dorsal regions of the foot. The posterior tibial artery provides blood to the muscles and integument on the posterior surface of the tibial region. The fibular or peroneal artery branches from the posterior tibial artery. It bifurcates and becomes the medial plantar artery and lateral plantar artery, providing blood to the plantar surfaces. There is an anastomosis with the dorsalis pedis artery, and the medial and lateral plantar arteries form two arches called the dorsal arch (also called the arcuate arch) and the plantar arch, which provide blood to the remainder of the foot and toes. Figure 6.10.13 shows the distribution of the major systemic arteries in the lower limb. Table 6.10.7 summarises the major systemic arteries discussed in the text.

Table 6.10.7. Arteries serving the lower limbs

Overview of Systemic Veins

Systemic veins return blood to the right atrium. Since the blood has already passed through the systemic capillaries, it will be relatively low in oxygen concentration. In many cases, there will be veins draining organs and regions of the body with the same name as the arteries that supplied these regions and the two often parallel one another. This is often described as a “complementary” pattern. However, there is a great deal more variability in the venous circulation than normally occurs in the arteries. For the sake of brevity and clarity, this text will discuss only the most commonly encountered patterns. However, keep this variation in mind when you move from the classroom to clinical practice.

In both the neck and limb regions, there are often both superficial and deeper levels of veins. The deeper veins generally correspond to the complementary arteries. The superficial veins do not normally have direct arterial counterparts, but in addition to returning blood, they also make contributions to the maintenance of body temperature. When the ambient temperature is warm, more blood is diverted to the superficial veins where heat can be more easily dissipated to the environment. In colder weather, there is more constriction of the superficial veins and blood is diverted deeper where the body can retain more of the heat.

The “Voyage of Discovery” analogy and stick drawings mentioned earlier remain valid techniques for the study of systemic veins, but veins present a more difficult challenge because there are numerous anastomoses and multiple branches. It is like following a river with many tributaries and channels, several of which interconnect. Tracing blood flow through arteries follows the current in the direction of blood flow, so that we move from the heart through the large arteries and into the smaller arteries to the capillaries. From the capillaries, we move into the smallest veins and follow the direction of blood flow into larger veins and back to the heart. Figure 6.10.14 outlines the path of the major systemic veins.

The right atrium receives all the systemic venous return. Most of the blood flows into either the superior vena cava or inferior vena cava. If you draw an imaginary line at the level of the diaphragm, systemic venous circulation from above that line will generally flow into the superior vena cava; this includes blood from the head, neck, chest, shoulders, and upper limbs. The exception to this is that most venous blood flow from the coronary veins flows directly into the coronary sinus and from there directly into the right atrium. Beneath the diaphragm, systemic venous flow enters the inferior vena cava, that is, blood from the abdominal and pelvic regions and the lower limbs.

The Superior Vena Cava

The superior vena cava drains most of the body superior to the diaphragm (Figure 6.10.15). On both the left and right sides, the subclavian vein forms when the axillary vein passes through the body wall from the axillary region. It fuses with the external and internal jugular veins from the head and neck to form the brachiocephalic vein. Each vertebral vein also flows into the brachiocephalic vein close to this fusion. These veins arise from the base of the brain and the cervical region of the spinal cord, and flow largely through the intervertebral foramina in the cervical vertebrae. They are the counterparts of the vertebral arteries. Each internal thoracic vein, also known as an internal mammary vein, drains the anterior surface of the chest wall and flows into the brachiocephalic vein.

The remainder of the blood supply from the thorax drains into the azygos vein. Each intercostal vein drains muscles of the thoracic wall, each oesophageal vein delivers blood from the inferior portions of the oesophagus, each bronchial vein drains the systemic circulation from the lungs, and several smaller veins drain the mediastinal region. Bronchial veins carry approximately 13 percent of the blood that flows into the bronchial arteries; the remainder intermingles with the pulmonary circulation and returns to the heart via the pulmonary veins. These veins flow into the azygos vein, and with the smaller hemiazygos vein (hemi- = “half”) on the left of the vertebral column, drain blood from the thoracic region. The hemiazygos vein does not drain directly into the superior vena cava but enters the brachiocephalic vein via the superior intercostal vein.

The azygos vein passes through the diaphragm from the thoracic cavity on the right side of the vertebral column and begins in the lumbar region of the thoracic cavity. It flows into the superior vena cava at approximately the level of T2, making a significant contribution to the flow of blood. It combines with the two large left and right brachiocephalic veins to form the superior vena cava.

Table 6.10.8 summarises the veins of the thoracic region that flow into the superior vena cava.

Table 6.10.8. Veins of the thoracic region

Veins of the Head and Neck

Blood from the brain and the superficial facial vein flow into each internal jugular vein (Figure 6.10.16). Blood from the more superficial portions of the head, scalp, and cranial regions, including the temporal vein and maxillary vein, flow into each external jugular vein. Although the external and internal jugular veins are separate vessels, there are anastomoses between them close to the thoracic region. Blood from the external jugular vein empties into the subclavian vein. Table 6.10.9 summarises the major veins of the head and neck.

Table 6.10.9. Major veins of the head and neck

Venous Drainage of the Brain

Circulation to the brain is both critical and complex (see Table 6.10.13). Many smaller veins of the brain stem and the superficial veins of the cerebrum lead to larger vessels referred to as intracranial sinuses. These include the superior and inferior sagittal sinuses, straight sinus, cavernous sinuses, left and right sinuses, the petrosal sinuses, and the occipital sinuses. Ultimately, sinuses will lead back to either the inferior jugular vein or vertebral vein.

Most of the veins on the superior surface of the cerebrum flow into the largest of the sinuses, the superior sagittal sinus. It is located midsagittally between the meningeal and periosteal layers of the dura mater within the falx cerebri and, at first glance in images or models, can be mistaken for the subarachnoid space. Most reabsorption of cerebrospinal fluid occurs via the chorionic villi (arachnoid granulations) into the superior sagittal sinus. Blood from most of the smaller vessels originating from the inferior cerebral veins flows into the great cerebral vein and into the straight sinus. Other cerebral veins and those from the eye socket flow into the cavernous sinus, which flows into the petrosal sinus and then into the internal jugular vein. The occipital sinus, sagittal sinus, and straight sinuses all flow into the left and right transverse sinuses near the lambdoid suture. The transverse sinuses in turn flow into the sigmoid sinuses that pass through the jugular foramen and into the internal jugular vein. The internal jugular vein flows parallel to the common carotid artery and is more or less its counterpart. It empties into the brachiocephalic vein. The veins draining the cervical vertebrae and the posterior surface of the skull, including some blood from the occipital sinus, flow into the vertebral veins. These parallel the vertebral arteries and travel through the transverse foramina of the cervical vertebrae. The vertebral veins also flow into the brachiocephalic veins. Table 6.10.10 summarises the major veins of the brain.

Table 6.10.10. Major veins of the brain

Veins Draining the Upper Limbs

The digital veins in the fingers come together in the hand to form the palmar venous arches (Figure 6.10.17). From here, the veins come together to form the radial vein, the ulnar vein, and the median antebrachial vein. The radial vein and the ulnar vein parallel the bones of the forearm and join together at the antebrachium to form the brachial vein, a deep vein that flows into the axillary vein in the brachium.

The median antebrachial vein parallels the ulnar vein, is more medial in location, and joins the basilic vein in the forearm. As the basilic vein reaches the antecubital region, it gives off a branch called the median cubital vein that crosses at an angle to join the cephalic vein. The median cubital vein is the most common site for drawing venous blood in humans. The basilic vein continues through the arm medially and superficially to the axillary vein.

The cephalic vein begins in the antebrachium and drains blood from the superficial surface of the arm into the axillary vein. It is extremely superficial and easily seen along the surface of the biceps brachii muscle in individuals with good muscle tone and in those without excessive subcutaneous adipose tissue in the arms.

The subscapular vein drains blood from the subscapular region and joins the cephalic vein to form the axillary vein. As it passes through the body wall and enters the thorax, the axillary vein becomes the subclavian vein.

Many of the larger veins of the thoracic and abdominal region and upper limb are further represented in the flow chart in Figure 6.10.18. Table 6.10.11 summarises the veins of the upper limbs.

Table 6.10.11. Veins of the upper limbs

The Inferior Vena Cava

Other than the small amount of blood drained by the azygos and hemiazygos veins, most of the blood inferior to the diaphragm drains into the inferior vena cava before it is returned to the heart (see Figure 6.10.15). Lying just beneath the parietal peritoneum in the abdominal cavity, the inferior vena cava parallels the abdominal aorta, where it can receive blood from abdominal veins. The lumbar portions of the abdominal wall and spinal cord are drained by a series of lumbar veins, usually four on each side. The ascending lumbar veins drain into either the azygos vein on the right or the hemiazygos vein on the left and return to the superior vena cava. The remaining lumbar veins drain directly into the inferior vena cava.

Blood supply from the kidneys flows into each renal vein, normally the largest veins entering the inferior vena cava. A number of other, smaller veins empty into the left renal vein. Each adrenal vein drains the adrenal or suprarenal glands located immediately superior to the kidneys. The right adrenal vein enters the inferior vena cava directly, whereas the left adrenal vein enters the left renal vein.

From the male reproductive organs, each testicular vein flows from the scrotum, forming a portion of the spermatic cord. Each ovarian vein drains an ovary in females. Each of these veins is generically called a gonadal vein. The right gonadal vein empties directly into the inferior vena cava, and the left gonadal vein empties into the left renal vein.

Each side of the diaphragm drains into a phrenic vein; the right phrenic vein empties directly into the inferior vena cava, whereas the left phrenic vein empties into the left renal vein. Blood supply from the liver drains into each hepatic vein and directly into the inferior vena cava. Since the inferior vena cava lies primarily to the right of the vertebral column and aorta, the left renal vein is longer, as are the left phrenic, adrenal, and gonadal veins. The longer length of the left renal vein makes the left kidney the primary target of surgeons removing this organ for donation. Figure 6.10.19 provides a flow chart of the veins flowing into the inferior vena cava. Table 6.10.12 summarises the major veins of the abdominal region.

Table 6.10.12. Major veins of the abdominal region

Veins Draining the Lower Limbs

The superior surface of the foot drains into the digital veins, and the inferior surface drains into the plantar veins, which flow into a complex series of anastomoses in the feet and ankles, including the dorsal venous arch and the plantar venous arch (Figure 6.10.20). From the dorsal venous arch, blood supply drains into the anterior and posterior tibial veins. The anterior tibial vein drains the area near the tibialis anterior muscle and combines with the posterior tibial vein and the fibular vein to form the popliteal vein. The posterior tibial vein drains the posterior surface of the tibia and joins the popliteal vein. The fibular vein drains the muscles and integument in proximity to the fibula and also joins the popliteal vein. The small saphenous vein located on the lateral surface of the leg drains blood from the superficial regions of the lower leg and foot and flows into to the popliteal vein. As the popliteal vein passes behind the knee in the popliteal region, it becomes the femoral vein. It is palpable in patients without excessive adipose tissue.

Close to the body wall, the great saphenous vein, the deep femoral vein, and the femoral circumflex vein drain into the femoral vein. The great saphenous vein is a prominent surface vessel located on the medial surface of the leg and thigh that collects blood from the superficial portions of these areas. The deep femoral vein, as the name suggests, drains blood from the deeper portions of the thigh. The femoral circumflex vein forms a loop around the femur just inferior to the trochanters and drains blood from the areas in proximity to the head and neck of the femur.

As the femoral vein penetrates the body wall from the femoral portion of the upper limb, it becomes the external iliac vein, a large vein that drains blood from the leg to the common iliac vein. The pelvic organs and integument drain into the internal iliac vein, which forms from several smaller veins in the region, including the umbilical veins that run on either side of the bladder. The external and internal iliac veins combine near the inferior portion of the sacroiliac joint to form the common iliac vein. In addition to blood supply from the external and internal iliac veins, the middle sacral vein drains the sacral region into the common iliac vein. Similar to the common iliac arteries, the common iliac veins come together at the level of L5 to form the inferior vena cava.

Figure 6.10.21 is a flow chart of veins flowing into the lower limb. Table 6.10.13 summarises the major veins of the lower limbs.

Table 6.10.13. Veins of the lower limbs

Hepatic Portal System

The liver is a complex biochemical processing plant. It packages nutrients absorbed by the digestive system; produces plasma proteins, clotting factors, and bile; and disposes of worn-out cell components and waste products. Instead of entering the circulation directly, absorbed nutrients and certain wastes (for example, materials produced by the spleen) travel to the liver for processing. They do so via the hepatic portal system (Figure 6.10.22). Portal systems begin and end in capillaries. In this case, the initial capillaries from the stomach, small intestine, large intestine, and spleen lead to the hepatic portal vein and end in specialised capillaries within the liver, the hepatic sinusoids. You saw the only other portal system with the hypothalamic-hypophyseal portal vessel in the endocrine chapter.

The hepatic portal system consists of the hepatic portal vein and the veins that drain into it. The hepatic portal vein itself is relatively short, beginning at the level of L2 with the confluence of the superior mesenteric and splenic veins. It also receives branches from the inferior mesenteric vein, plus the splenic veins and all their tributaries. The superior mesenteric vein receives blood from the small intestine, two-thirds of the large intestine, and the stomach. The inferior mesenteric vein drains the distal third of the large intestine, including the descending colon, the sigmoid colon, and the rectum. The splenic vein is formed from branches from the spleen, pancreas, and portions of the stomach, and the inferior mesenteric vein. After its formation, the hepatic portal vein also receives branches from the gastric veins of the stomach and cystic veins from the gall bladder. The hepatic portal vein delivers materials from these digestive and circulatory organs directly to the liver for processing.

Because of the hepatic portal system, the liver receives its blood supply from two different sources: from normal systemic circulation via the hepatic artery and from the hepatic portal vein. The liver processes the blood from the portal system to remove certain wastes and excess nutrients, which are stored for later use. This processed blood, as well as the systemic blood that came from the hepatic artery, exits the liver via the right, left, and middle hepatic veins, and flows into the inferior vena cava. Overall systemic blood composition remains relatively stable, since the liver is able to metabolise the absorbed digestive components.

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In a developing embryo, the heart has developed enough by day 21 post-fertilisation to begin beating. Circulation patterns are clearly established by the fourth week of embryonic life. It is critical to the survival of the developing human that the circulatory system forms early to supply the growing tissue with nutrients and gases, and to remove waste products. Blood cells and vessel production in structures outside the embryo proper called the yolk sac, chorion, and connecting stalk begin about 15 to 16 days following fertilisation. Development of these circulatory elements within the embryo itself begins approximately 2 days later. You will learn more about the formation and function of these early structures when you study the chapter on development. During those first few weeks, blood vessels begin to form from the embryonic mesoderm. The precursor cells are known as haemangioblasts. These in turn differentiate into angioblasts, which give rise to the blood vessels and pluripotent stem cells, which differentiate into the formed elements of blood. (Seek additional content for more detail on foetal development and circulation.) Together, these cells form masses known as blood islands scattered throughout the embryonic disc. Spaces appear on the blood islands that develop into vessel lumens. The endothelial lining of the vessels arise from the angioblasts within these islands. Surrounding mesenchymal cells give rise to the smooth muscle and connective tissue layers of the vessels. While the vessels are developing, the pluripotent stem cells begin to form the blood.

Vascular tubes also develop on the blood islands, and they eventually connect to one another as well as to the developing, tubular heart. Thus, the developmental pattern, rather than beginning from the formation of one central vessel and spreading outward, occurs in many regions simultaneously with vessels later joining together. This angiogenesis—the creation of new blood vessels from existing ones—continues as needed throughout life as we grow and develop.

Blood vessel development often follows the same pattern as nerve development and travels to the same target tissues and organs. This occurs because the many factors directing growth of nerves also stimulate blood vessels to follow a similar pattern. Whether a given vessel develops into an artery or a vein is dependent upon local concentrations of signalling proteins.

As the embryo grows within the mother’s uterus, its requirements for nutrients and gas exchange also grow. The placenta—a circulatory organ unique to pregnancy—develops jointly from the embryo and uterine wall structures to fill this need. Emerging from the placenta is the umbilical vein, which carries oxygen-rich blood from the mother to the foetal inferior vena cava via the ductus venosus to the heart that pumps it into foetal circulation. Two umbilical arteries carry oxygen-depleted foetal blood, including wastes and carbon dioxide, to the placenta. Remnants of the umbilical arteries remain in the adult.

There are three major shunts—alternate paths for blood flow—found in the circulatory system of the foetus. Two of these shunts divert blood from the pulmonary to the systemic circuit, whereas the third connects the umbilical vein to the inferior vena cava. The first two shunts are critical during foetal life, when the lungs are compressed, filled with amniotic fluid, and non-functional, and gas exchange is provided by the placenta. These shunts close shortly after birth, however, when the newborn begins to breathe. The third shunt persists a bit longer but becomes non-functional once the umbilical cord is severed. The three shunts are as follows (Figure 6.11.1).

The foramen ovale is an opening in the interatrial septum that allows blood to flow from the right atrium to the left atrium. A valve associated with this opening prevents backflow of blood during the foetal period. As the newborn begins to breathe and blood pressure in the atria increases, this shunt closes. The fossa ovalis remains in the interatrial septum after birth, marking the location of the former foramen ovale.

The ductus arteriosus is a short, muscular vessel that connects the pulmonary trunk to the aorta. Most of the blood pumped from the right ventricle into the pulmonary trunk is thereby diverted into the aorta. Only enough blood reaches the foetal lungs to maintain the developing lung tissue. When the newborn takes the first breath, pressure within the lungs drops dramatically, and both the lungs and the pulmonary vessels expand. As the amount of oxygen increases, the smooth muscles in the wall of the ductus arteriosus constrict, sealing off the passage. Eventually, the muscular and endothelial components of the ductus arteriosus degenerate, leaving only the connective tissue component of the ligamentum arteriosum.

The ductus venosus is a temporary blood vessel that branches from the umbilical vein, allowing much of the freshly oxygenated blood from the placenta—the organ of gas exchange between the mother and foetus—to bypass the foetal liver and go directly to the foetal heart. The ductus venosus closes slowly during the first weeks of infancy and degenerates to become the ligamentum venosum.

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The immune system is the complex collection of cells and organs that destroys or neutralises pathogens that would otherwise cause disease or death. The lymphatic system, for most people, is associated with the immune system to such a degree that the two systems are virtually indistinguishable. The lymphatic system is the system of vessels, cells, and organs that carries excess fluids to the bloodstream and filters pathogens from the blood. The swelling of lymph nodes during an infection and the transport of lymphocytes via the lymphatic vessels are just two examples of the many connections between these critical organ systems.

Functions of the Lymphatic System

A major function of the lymphatic system is to drain body fluids and return them to the bloodstream. Blood pressure causes leakage of fluid from the capillaries, resulting in the accumulation of fluid in the interstitial space—that is, spaces between individual cells in the tissues. In humans, 20 litres of plasma is released into the interstitial space of the tissues each day due to capillary filtration. Once this filtrate is out of the bloodstream and in the tissue spaces, it is referred to as interstitial fluid. Of this, 17 litres is reabsorbed directly by the blood vessels. But what happens to the remaining three litres? This is where the lymphatic system comes into play. It drains the excess fluid and empties it back into the bloodstream via a series of vessels, trunks, and ducts. Lymph is the term used to describe interstitial fluid once it has entered the lymphatic system. When the lymphatic system is damaged in some way, such as by being blocked by cancer cells or destroyed by injury, protein-rich interstitial fluid accumulates (sometimes “backs up” from the lymph vessels) in the tissue spaces. This inappropriate accumulation of fluid referred to as lymphedema may lead to serious medical consequences.

As the vertebrate immune system evolved, the network of lymphatic vessels became convenient avenues for transporting the cells of the immune system. Additionally, the transport of dietary lipids and fat-soluble vitamins absorbed in the gut uses this system.

Cells of the immune system not only use lymphatic vessels to make their way from interstitial spaces back into the circulation, but they also use lymph nodes as major staging areas for the development of critical immune responses. A lymph node is one of the small, bean-shaped organs located throughout the lymphatic system.

Structure of the Lymphatic System

The lymphatic vessels begin as open-ended capillaries, which feed into larger and larger lymphatic vessels, and eventually empty into the bloodstream by a series of ducts. Along the way, the lymph travels through the lymph nodes, which are commonly found near the groin, armpits, neck, chest, and abdomen. Humans have about 500–600 lymph nodes throughout the body (Figure 7.1.1).

A major distinction between the lymphatic and cardiovascular systems in humans is that lymph is not actively pumped by the heart, but is forced through the vessels by the movements of the body, the contraction of skeletal muscles during body movements, and breathing. One-way valves (semi-lunar valves) in lymphatic vessels keep the lymph moving toward the heart. Lymph flows from the lymphatic capillaries, through lymphatic vessels, and then is dumped into the circulatory system via the lymphatic ducts located at the junction of the jugular and subclavian veins in the neck.

Lymphatic Capillaries

Lymphatic capillaries, also called the terminal lymphatics, are vessels where interstitial fluid enters the lymphatic system to become lymph fluid. Located in almost every tissue in the body, these vessels are interlaced among the arterioles and venules of the circulatory system in the soft connective tissues of the body (Figure 7.1.2). Exceptions are the central nervous system, bone marrow, bones, teeth and the cornea of the eye, which do not contain lymph vessels.

Lymphatic capillaries are formed by a one cell-thick layer of endothelial cells and represent the open end of the system, allowing interstitial fluid to flow into them via overlapping cells (see Figure 7.1.2). When interstitial pressure is low, the endothelial flaps close to prevent “backflow.” As interstitial pressure increases, the spaces between the cells open up, allowing the fluid to enter. Entry of fluid into lymphatic capillaries is also enabled by the collagen filaments that anchor the capillaries to surrounding structures. As interstitial pressure increases, the filaments pull on the endothelial cell flaps, opening up them even further to allow easy entry of fluid.

In the small intestine, lymphatic capillaries called lacteals are critical for the transport of dietary lipids and lipid-soluble vitamins to the bloodstream. In the small intestine, dietary triglycerides combine with other lipids and proteins, and enter the lacteals to form a milky fluid called chyle. The chyle then travels through the lymphatic system, eventually entering the liver and then the bloodstream.

Larger Lymphatic Vessels, Trunks and Ducts

The lymphatic capillaries empty into larger lymphatic vessels, which are similar to veins in terms of their three-tunic structure and the presence of valves. These one-way valves are located fairly close to one another, and each one causes a bulge in the lymphatic vessel, giving the vessels a beaded appearance (see Figure 7.1.2).

The superficial and deep lymphatics eventually merge to form larger lymphatic vessels known as lymphatic trunks. On the right side of the body, the right sides of the head, thorax, and right upper limb drain lymph fluid into the right subclavian vein via the right lymphatic duct (Figure 7.1.3). On the left side of the body, the remaining portions of the body drain into the larger thoracic duct, which drains into the left subclavian vein. The thoracic duct itself begins just beneath the diaphragm in the cisterna chyli, a sac-like chamber that receives lymph from the lower abdomen, pelvis, and lower limbs by way of the left and right lumbar trunks and the intestinal trunk.

The overall drainage system of the body is asymmetrical (see Figure 7.1.3). The right lymphatic duct receives lymph from only the upper right side of the body. The lymph from the rest of the body enters the bloodstream through the thoracic duct via all the remaining lymphatic trunks. In general, lymphatic vessels of the subcutaneous tissues of the skin, that is, the superficial lymphatics, follow the same routes as veins, whereas the deep lymphatic vessels of the viscera generally follow the paths of arteries.

The Organisation of Immune Function

The immune system is a collection of barriers, cells, and soluble proteins that interact and communicate with each other in extraordinarily complex ways. The modern model of immune function is organised into three phases based on the timing of their effects. The three temporal phases consist of the following:

Barrier defences such as the skin and mucous membranes, which act instantaneously to prevent pathogenic invasion into the body tissues

The rapid but nonspecific innate immune response, which consists of a variety of specialised cells and soluble factors

The slower but more specific and effective adaptive immune response, which involves many cell types and soluble factors, but is primarily controlled by white blood cells (leukocytes) known as lymphocytes, which help control immune responses

The cells of the blood, including all those involved in the immune response, arise in the bone marrow via various differentiation pathways from hematopoietic stem cells (Figure 7.1.4). In contrast with embryonic stem cells, hematopoietic stem cells are present throughout adulthood and allow for the continuous differentiation of blood cells to replace those lost to age or function. These cells can be divided into three classes based on function:

• Phagocytic cells, which ingest pathogens to destroy them
• Lymphocytes, which specifically coordinate the activities of adaptive immunity
• Cells containing cytoplasmic granules, which help mediate immune responses against parasites and intracellular pathogens such as viruses

Lymphocytes: B Cells, T cells, Plasma Cells and Natural Killer Cells

As stated above, lymphocytes are the primary cells of adaptive immune responses (Table 7.1.1). The two basic types of lymphocytes, B cells and T cells, are identical morphologically with a large central nucleus surrounded by a thin layer of cytoplasm. They are distinguished from each other by their surface protein markers as well as by the molecules they secrete. While B cells mature in red bone marrow and T cells mature in the thymus, they both initially develop from bone marrow. T cells migrate from bone marrow to the thymus gland where they further mature. B cells and T cells are found in many parts of the body, circulating in the bloodstream and lymph, and residing in secondary lymphoid organs, including the spleen and lymph nodes, which will be described later in this section. The human body contains approximately 2×10¹² lymphocytes.

B Cells

B cells are immune cells that function primarily by producing antibodies. An antibody is any of the group of proteins that binds specifically to pathogen-associated molecules known as antigens. An antigen is a chemical structure on the surface of a pathogen that binds to T or B lymphocyte antigen receptors. Once activated by binding to antigen, B cells differentiate into cells that secrete a soluble form of their surface antibodies. These activated B cells are known as plasma cells.

T Cells

The T cell, on the other hand, does not secrete antibody but performs a variety of functions in the adaptive immune response. Different T cell types have the ability to either secrete soluble factors that communicate with other cells of the adaptive immune response or destroy cells infected with intracellular pathogens. The roles of T and B lymphocytes in the adaptive immune response will be discussed further in this chapter.

Plasma Cells

Another type of lymphocyte of importance is the plasma cell. A plasma cell is a B cell that has differentiated in response to antigen binding and has thereby gained the ability to secrete soluble antibodies. These cells differ in morphology from standard B and T cells in that they contain a large amount of cytoplasm packed with the protein-synthesising machinery known as rough endoplasmic reticulum.

Natural Killer (NK) Cells

A fourth important lymphocyte is the natural killer cell, a participant in the innate immune response. A natural killer cell (NK) is a circulating blood cell that contains cytotoxic (cell-killing) granules in its extensive cytoplasm. It shares this mechanism with the cytotoxic T cells of the adaptive immune response. NK cells are among the body’s first lines of defence against viruses and certain types of cancer.

Table 7.1.1. Lymphocytes

Primary Lymphoid Organs and Lymphocyte Development

Understanding the differentiation and development of B and T cells is critical to the understanding of the adaptive immune response. It is through this process that the body (ideally) learns to destroy only pathogens and leaves the body’s own cells relatively intact. The primary lymphoid organs are the bone marrow and thymus gland. The lymphoid organs are where lymphocytes mature, proliferate, and are selected, which enables them to attack pathogens without harming the cells of the body.

Bone Marrow

In the embryo, blood cells are made in the yolk sac. As development proceeds, this function is taken over by the spleen, lymph nodes, and liver. Later, the bone marrow takes over most haematopoietic functions, although the final stages of the differentiation of some cells may take place in other organs. The red bone marrow is a loose collection of cells where haematopoiesis occurs, and the yellow bone marrow is a site of energy storage, which consists largely of fat cells (Figure 7.1.5). The B cell undergoes nearly all of its development in the red bone marrow, whereas the immature T cell, called a thymocyte, leaves the bone marrow and matures largely in the thymus gland.

Thymus

The thymus gland is a bilobed organ found in the space between the sternum and the aorta of the heart (Figure 7.1.6). Connective tissue holds the lobes closely together but also separates them and forms a capsule.

The connective tissue capsule further divides the thymus into lobules via extensions called trabeculae. The outer region of the organ is known as the cortex and contains large numbers of thymocytes with some epithelial cells, macrophages, and dendritic cells (two types of phagocytic cells that are derived from monocytes). The cortex is densely packed so it stains more intensely than the rest of the thymus (see Figure 7.1.6). The medulla, where thymocytes migrate before leaving the thymus, contains a less dense collection of thymocytes, epithelial cells, and dendritic cells.

Ageing and the Immune System

By the year 2050, the number of adults between 65 and 85 years is estimated to double, while number of adults aged above 85 is estimated to quadruple.  Although the aging population shows the greatest burden of chronic conditions related to immune deficiencies, younger population is also affected. This loss of immune function with age is called immunosenescence. To treat this growing population, medical professionals must better understand the ageing process. One major cause of age-related immune deficiencies is thymic involution, the shrinking of the thymus gland that begins at birth, at a rate of about three percent tissue loss per year, and continues until 35–45 years of age, when the rate declines to about one percent loss per year for the rest of one’s life. At that pace, the total loss of thymic epithelial tissue and thymocytes would occur at about 120 years of age. Thus, this age is a theoretical limit to a healthy human lifespan.

Thymic involution has been observed in all vertebrate species that have a thymus gland. Animal studies have shown that transplanted thymic grafts between inbred strains of mice involuted according to the age of the donor and not of the recipient, implying the process is genetically programmed. There is evidence that the thymic microenvironment, so vital to the development of naïve T cells, loses thymic epithelial cells according to the decreasing expression of the FOXN1 gene with age.

It is also known that thymic involution can be altered by hormone levels. Sex hormones such as estrogen and testosterone enhance involution, and the hormonal changes in pregnant women cause a temporary thymic involution that reverses itself, when the size of the thymus and its hormone levels return to normal, usually after lactation ceases. What does all this tell us? Can we reverse immunosenescence, or at least slow it down? The potential is there for using thymic transplants from younger donors to keep thymic output of naïve T cells high. Gene therapies that target gene expression are also seen as future possibilities. The more we learn through immunosenescence research, the more opportunities there will be to develop therapies, even though these therapies will likely take decades to develop. The ultimate goal is for everyone to live and be healthy longer, but there may be limits to immortality imposed by our genes and hormones.

Secondary Lymphoid Organs and Their Roles in Active Immune Responses

Lymphocytes develop and mature in the primary lymphoid organs, but they mount immune responses from the secondary lymphoid organs. A naïve lymphocyte is one that has left the primary organ and entered a secondary lymphoid organ. Naïve lymphocytes are fully functional immunologically but have yet to encounter an antigen to respond to. In addition to circulating in the blood and lymph, lymphocytes concentrate in secondary lymphoid organs, which include the lymph nodes, spleen, and lymphoid nodules. All of these tissues have many features in common, including the following:

1. The presence of lymphoid follicles, the sites of the formation of lymphocytes, with specific B cell-rich and T cell-rich areas
2. An internal structure of reticular fibres with associated fixed macrophages
3. Germinal centres, which are the sites of rapidly dividing B lymphocytes and plasma cells, with the exception of the spleen
4. Specialised post-capillary vessels known as high endothelial venules; the cells lining these venules are thicker and more columnar than normal endothelial cells, which allow cells from the blood to directly enter these tissues

Lymph Nodes

Lymph nodes function to remove debris and pathogens from the lymph, and are thus sometimes referred to as the “filters of the lymph” (Figure 7.1.7). Any bacteria that infect the interstitial fluid are taken up by the lymphatic capillaries and transported to a regional lymph node. Dendritic cells and macrophages within this organ internalise and kill many of the pathogens that pass through, thereby removing them from the body. The lymph node is also the site of adaptive immune responses mediated by T cells, B cells, and accessory cells of the adaptive immune system. Like the thymus, the bean-shaped lymph nodes are surrounded by a tough capsule of connective tissue and are separated into compartments by trabeculae, the extensions of the capsule. In addition to the structure provided by the capsule and trabeculae, the structural support of the lymph node is provided by a series of reticular fibres laid down by fibroblasts.

The major routes into the lymph node are via afferent lymphatic vessels. Cells and lymph fluid that leave the lymph node may do so by another set of vessels known as the efferent lymphatic vessels. Lymph enters the lymph node via the subcapsular sinus, which is occupied by dendritic cells, macrophages, and reticular fibres. Within the cortex of the lymph node are lymphoid follicles, which consist of germinal centres of rapidly dividing B cells surrounded by a layer of T cells and other accessory cells. As the lymph continues to flow through the node, it enters the medulla, which consists of medullary cords of B cells and plasma cells, and the medullary sinuses where the lymph collects before leaving the node via the efferent lymphatic vessels.

Spleen

In addition to the lymph nodes, the spleen is a major secondary lymphoid organ (Figure 7.1.8). It is about 12 cm (5 in) long and is attached to the lateral border of the stomach via the gastrosplenic ligament. The spleen is a fragile organ without a strong capsule and is dark red due to its extensive vascularisation. The spleen is sometimes called the “filter of the blood” because of its extensive vascularisation and the presence of macrophages and dendritic cells that remove microbes and other materials from the blood, including dying red blood cells. The spleen also functions as the location of immune responses to blood-borne pathogens.

The spleen is also divided by trabeculae of connective tissue, and within each splenic nodule is an area of red pulp, consisting of mostly red blood cells, and white pulp, which resembles the lymphoid follicles of the lymph nodes. Upon entering the spleen, the splenic artery splits into several arterioles (surrounded by white pulp) and eventually into sinusoids. Blood from the capillaries subsequently collects in the venous sinuses and leaves via the splenic vein. The red pulp consists of reticular fibres with fixed macrophages attached, free macrophages, and all of the other cells typical of the blood, including some lymphocytes. The white pulp surrounds a central arteriole and consists of germinal centres of dividing B cells surrounded by T cells and accessory cells, including macrophages and dendritic cells. Thus, the red pulp primarily functions as a filtration system of the blood, using cells of the relatively nonspecific immune response, and white pulp is where adaptive T and B cell responses are mounted.

Lymphoid Nodules

The other lymphoid tissues, the lymphoid nodules, have a simpler architecture than the spleen and lymph nodes in that they consist of a dense cluster of lymphocytes without a surrounding fibrous capsule. These nodules are located in the respiratory and digestive tracts, areas routinely exposed to environmental pathogens.

Tonsils are lymphoid nodules located along the inner surface of the pharynx and are important in developing immunity to oral pathogens (Figure 7.1.9). The tonsil located at the back of the throat, the pharyngeal tonsil, is sometimes referred to as the adenoid when swollen. Such swelling is an indication of an active immune response to infection. Histologically, tonsils do not contain a complete capsule, and the epithelial layer invaginates deeply into the interior of the tonsil to form tonsillar crypts. These structures, which accumulate all sorts of materials taken into the body through eating and breathing, actually “encourage” pathogens to penetrate deep into the tonsillar tissues where they are acted upon by numerous lymphoid follicles and eliminated. This seems to be the major function of tonsils—to help children’s bodies recognise, destroy, and develop immunity to common environmental pathogens so that they will be protected in their later lives. Tonsils are often removed in those children who have recurring throat infections, especially those involving the palatine tonsils on either side of the throat, whose swelling may interfere with their breathing and/or swallowing.

Mucosa-associated lymphoid tissue (MALT) consists of an aggregate of lymphoid follicles directly associated with the mucous membrane epithelia. MALT makes up dome-shaped structures found underlying the mucosa of the gastrointestinal tract, breast tissue, lungs, and eyes. Peyer’s patches, a type of MALT in the small intestine, are especially important for immune responses against ingested substances (Figure 7.1.10). Peyer’s patches contain specialised endothelial cells called M (or microfold) cells that sample material from the intestinal lumen and transport it to nearby follicles so that adaptive immune responses to potential pathogens can be mounted.

Bronchus-associated lymphoid tissue (BALT) consists of lymphoid follicular structures with an overlying epithelial layer found along the bifurcations of the bronchi, and between bronchi and arteries. They also have the typically less-organised structure of other lymphoid nodules. These tissues, in addition to the tonsils, are effective against inhaled pathogens.

Click the drop down below to review the terms learned from this chapter.

The immune system can be divided into two overlapping mechanisms to destroy pathogens: the innate immune response, which is relatively rapid but nonspecific and thus not always effective, and the adaptive immune response, which is slower in its development during an initial infection with a pathogen, but is highly specific and effective at attacking a wide variety of pathogens (Figure 7.2.1).

Any discussion of the innate immune response usually begins with the physical barriers that prevent pathogens from entering the body, destroy them after they enter, or flush them out before they can establish themselves in the hospitable environment of the body’s soft tissues. Barrier defences are part of the body’s most basic defence mechanisms. The barrier defences are not a response to infections, but they are continuously working to protect against a broad range of pathogens.

The different modes of barrier defences are associated with the external surfaces of the body, where pathogens may try to enter (Table 7.2.1). The primary barrier to the entrance of microorganisms into the body is the skin. Not only is the skin covered with a layer of dead, keratinised epithelium that is too dry for bacteria in which to grow, but as these cells are continuously sloughed off from the skin, they carry bacteria and other pathogens with them. Additionally, sweat and other skin secretions may lower pH, contain toxic lipids, and physically wash microbes away.

Table 7.2.1. Barrier defences

Another barrier is the saliva in the mouth, which is rich in lysozyme—an enzyme that destroys bacteria by digesting their cell walls. The acidic environment of the stomach, which is fatal to many pathogens, is also a barrier. Additionally, the mucus layer of the gastrointestinal tract, respiratory tract, reproductive tract, eyes, ears, and nose traps both microbes and debris, and facilitates their removal. In the case of the upper respiratory tract, ciliated epithelial cells move potentially contaminated mucus upwards to the mouth, where it is then swallowed into the digestive tract, ending up in the harsh acidic environment of the stomach. Considering how often you breathe compared to how often you eat or perform other activities that expose you to pathogens, it is not surprising that multiple barrier mechanisms have evolved to work in concert to protect this vital area.

Cells of the Innate Immune Response

A phagocyte is a cell that is able to surround and engulf a particle or cell, a process called phagocytosis. The phagocytes of the immune system engulf other particles or cells, either to clean an area of debris, old cells, or to kill pathogenic organisms such as bacteria. The phagocytes are the body’s fast acting, first line of immunological defence against organisms that have breached barrier defences and have entered the vulnerable tissues of the body.

Phagocytes: Macrophages and Neutrophils

Many of the cells of the immune system have a phagocytic ability, at least at some point during their life cycles. Phagocytosis is an important and effective mechanism of destroying pathogens during innate immune responses. The phagocyte takes the organism inside itself as a phagosome, which subsequently fuses with a lysosome and its digestive enzymes, effectively killing many pathogens. On the other hand, some bacteria including Mycobacteria tuberculosis, the cause of tuberculosis, may be resistant to these enzymes and are therefore much more difficult to clear from the body. Macrophages, neutrophils, and dendritic cells are the major phagocytes of the immune system.

A macrophage is an irregularly shaped phagocyte that is amoeboid in nature and is the most versatile of the phagocytes in the body. Macrophages move through tissues and squeeze through capillary walls using pseudopodia. They not only participate in innate immune responses but have also evolved to cooperate with lymphocytes as part of the adaptive immune response. Macrophages exist in many tissues of the body, either freely roaming through connective tissues or fixed to reticular fibres within specific tissues such as lymph nodes. When pathogens breach the body’s barrier defences, macrophages are the first line of defence (Table 7.2.2). They are called different names, depending on the tissue: Kupffer cells in the liver, histiocytes in connective tissue, and alveolar macrophages in the lungs.

A neutrophil is a phagocytic cell that is attracted via chemotaxis from the bloodstream to infected tissues. These spherical cells are granulocytes. A granulocyte contains cytoplasmic granules, which in turn contain a variety of vasoactive mediators such as histamine. In contrast, macrophages are agranulocytes. An agranulocyte has few or no cytoplasmic granules. Whereas macrophages act like sentries, always on guard against infection, neutrophils can be thought of as military reinforcements that are called into a battle to hasten the destruction of the enemy. Although, usually thought of as the primary pathogen-killing cell of the inflammatory process of the innate immune response, new research has suggested that neutrophils play a role in the adaptive immune response as well, just as macrophages do.

A monocyte is a circulating precursor cell that differentiates into either a macrophage or dendritic cell, which can be rapidly attracted to areas of infection by signal molecules of inflammation.

Table 7.2.2. Phagocytic cells of the innate immune system

Natural Killer Cells

NK cells are a type of lymphocyte that have the ability to induce apoptosis, that is, programmed cell death, in cells infected with intracellular pathogens such as obligate intracellular bacteria and viruses. NK cells recognise these cells by mechanisms that are still not well understood, but that presumably involve their surface receptors. NK cells can induce apoptosis, in which a cascade of events inside the cell causes its own death by either of two mechanisms:

1. NK cells are able to respond to chemical signals and express the fas ligand. The fas ligand is a surface molecule that binds to the fas molecule on the surface of the infected cell, sending it apoptotic signals, thus killing the cell and the pathogen within it; or
2. The granules of the NK cells release perforins and granzymes. A perforin is a protein that forms pores in the membranes of infected cells. A granzyme is a protein-digesting enzyme that enters the cell via the perforin pores and triggers apoptosis intracellularly.

Both mechanisms are especially effective against virally infected cells. If apoptosis is induced before the virus has the ability to synthesise and assemble all its components, no infectious virus will be released from the cell, thus preventing further infection.

Recognition of Pathogens

Cells of the innate immune response, the phagocytic cells, and the cytotoxic NK cells recognise patterns of pathogen-specific molecules, such as bacterial cell wall components or bacterial flagellar proteins, using pattern recognition receptors. A pattern recognition receptor (PRR) is a membrane-bound receptor that recognises characteristic features of a pathogen and molecules released by stressed or damaged cells.

These receptors, which are thought to have evolved prior to the adaptive immune response, are present on the cell surface whether they are needed or not. Their variety, however, is limited by two factors. First, the fact that each receptor type must be encoded by a specific gene requires the cell to allocate most or all its DNA to make receptors able to recognise all pathogens. Secondly, the variety of receptors is limited by the finite surface area of the cell membrane. Thus, the innate immune system must “get by” using only a limited number of receptors that are active against as wide a variety of pathogens as possible. This strategy is in stark contrast to the approach used by the adaptive immune system, which uses large numbers of different receptors, each highly specific to a particular pathogen.

Should the cells of the innate immune system come into contact with a species of pathogen they recognise, the cell will bind to the pathogen and initiate phagocytosis (or cellular apoptosis in the case of an intracellular pathogen) in an effort to destroy the offending microbe. Receptors vary somewhat according to cell type, but they usually include receptors for bacterial components and for complement, discussed below.

Soluble Mediators of the Innate Immune Response

The previous discussions have alluded to chemical signals that can induce cells to change various physiological characteristics, such as the expression of a particular receptor. These soluble factors are secreted during innate or early induced responses, and later during adaptive immune responses.

Cytokines and Chemokines

A cytokine is signalling molecule that allows cells to communicate with each other over short distances. Cytokines are secreted into the intercellular space, and the action of the cytokine induces the receiving cell to change its physiology. A chemokine is a soluble chemical mediator similar to cytokines except that its function is to attract cells (chemotaxis) from longer distances.

Early Induced Proteins

Early induced proteins are those that are not constitutively present in the body, but are made as they are needed early during the innate immune response. Interferons are an example of early induced proteins. Cells infected with viruses secrete interferons that travel to adjacent cells and induce them to make antiviral proteins. Thus, even though the initial cell is sacrificed, the surrounding cells are protected. Other early induced proteins specific for bacterial cell wall components are mannose-binding protein and C-reactive protein, made in the liver, which bind specifically to polysaccharide components of the bacterial cell wall. Phagocytes such as macrophages have receptors for these proteins, and they are thus able to recognise them as they are bound to the bacteria. This brings the phagocyte and bacterium into close proximity and enhances the phagocytosis of the bacterium by the process known as opsonisation. Opsonisation is the tagging of a pathogen for phagocytosis by the binding of an antibody or an antimicrobial protein.

Complement System

The complement system is a series of proteins constitutively found in the blood plasma. As such, these proteins are not considered part of the early induced immune response, even though they share features with some of the antibacterial proteins of this class. Made in the liver, they have a variety of functions in the innate immune response, using what is known as the “alternate pathway” of complement activation. Additionally, complement functions in the adaptive immune response as well, in what is called the classical pathway. The complement system consists of several proteins that enzymatically alter and fragment later proteins in a series, which is why it is termed cascade. Once activated, the series of reactions is irreversible, and releases fragments that have the following actions:

• Bind to the cell membrane of the pathogen that activates it, labelling it for phagocytosis (opsonisation)
• Diffuse away from the pathogen and act as chemotactic agents to attract phagocytic cells to the site of inflammation
• Form damaging pores in the plasma membrane of the pathogen

Figure 7.2.2 shows the classical pathway, which requires antibodies of the adaptive immune response. The alternate pathway does not require an antibody to become activated.

The splitting of the C3 protein is the common step to both pathways. In the alternate pathway, C3 is activated spontaneously and, after reacting with the molecules factor P, factor B, and factor D, splits apart. The larger fragment, C3b, binds to the surface of the pathogen and C3a, the smaller fragment, diffuses outward from the site of activation and attracts phagocytes to the site of infection. Surface-bound C3b then activates the rest of the cascade, with the last five proteins, C5–C9, forming the membrane-attack complex (MAC). The MAC can kill certain pathogens by disrupting their osmotic balance. The MAC is especially effective against a broad range of bacteria. The classical pathway is similar, except the early stages of activation require the presence of antibody bound to antigen, and thus is dependent on the adaptive immune response. The earlier fragments of the cascade also have important functions. Phagocytic cells such as macrophages and neutrophils are attracted to an infection site by chemotactic attraction to smaller complement fragments. Additionally, once they arrive, their receptors for surface-bound C3b opsonise the pathogen for phagocytosis and destruction.

Inflammatory Response

The hallmark of the innate immune response is inflammation. Inflammation is something everyone has experienced. Stub a toe, cut a finger, or do any activity that causes tissue damage and inflammation will result, with its four characteristics: heat, redness, pain, and swelling (“loss of function” is sometimes mentioned as a fifth characteristic). It is important to note that inflammation does not have to be initiated by an infection but can also be caused by tissue injuries. The release of damaged cellular contents into the site of injury is enough to stimulate the response, even in the absence of breaks in physical barriers that would allow pathogens to enter (by hitting your thumb with a hammer, for example). The inflammatory reaction brings in phagocytic cells to the damaged area to clear cellular debris and to set the stage for wound repair (Figure 7.2.3).

This reaction also brings in the cells of the innate immune system, allowing them to get rid of the sources of a possible infection. Inflammation is part of a very basic form of immune response. The process not only brings fluid and cells into the site to destroy the pathogen and remove it and debris from the site, but also helps to isolate the site, limiting the spread of the pathogen. Acute inflammation is a short-term inflammatory response to an insult to the body. If the cause of the inflammation is not resolved, however, it can lead to chronic inflammation, which is associated with major tissue destruction and fibrosis. Chronic inflammation is ongoing inflammation. It can be caused by foreign bodies, persistent pathogens, and autoimmune diseases such as rheumatoid arthritis.

There are four important parts to the inflammatory response:

Tissue Injury. The released contents of injured cells stimulate the release of mast cell granules and their potent inflammatory mediators such as histamine, leukotrienes, and prostaglandins. Histamine increases the diameter of local blood vessels (vasodilation), causing an increase in blood flow. Histamine also increases the permeability of local capillaries, causing plasma to leak out and form interstitial fluid. This causes the swelling associated with inflammation.

Additionally, injured cells, phagocytes, and basophils are sources of inflammatory mediators, including prostaglandins and leukotrienes. Leukotrienes attract neutrophils from the blood by chemotaxis and increase vascular permeability. Prostaglandins cause vasodilation by relaxing vascular smooth muscle and are a major cause of the pain associated with inflammation. Nonsteroidal anti-inflammatory drugs such as aspirin and ibuprofen relieve pain by inhibiting prostaglandin production.

Vasodilation. Many inflammatory mediators such as histamine are vasodilators that increase the diameters of local capillaries. This causes increased blood flow and is responsible for the heat and redness of inflamed tissue. It allows greater access of the blood to the site of inflammation.

Increased Vascular Permeability. At the same time, inflammatory mediators increase the permeability of the local vasculature, causing leakage of fluid into the interstitial space, resulting in the swelling, or oedema, associated with inflammation.

Recruitment of Phagocytes. Leukotrienes are particularly good at attracting neutrophils from the blood to the site of infection by chemotaxis. Following an early neutrophil infiltrate stimulated by macrophage cytokines, more macrophages are recruited to clean up the debris left over at the site. When local infections are severe, neutrophils are attracted to the sites of infections in large numbers, and as they phagocytose the pathogens and subsequently die, their accumulated cellular remains are visible as pus at the infection site.

Overall, inflammation is valuable for many reasons. Not only are the pathogens killed and debris removed, but the increase in vascular permeability encourages the entry of clotting factors, the first step towards wound repair. Inflammation also facilitates the transport of antigen to lymph nodes by dendritic cells for the development of the adaptive immune response.

Click the drop down below to review the terms learned from this chapter.

Innate immune responses (and early induced responses) are in many cases ineffective at completely controlling pathogen growth. However, they slow pathogen growth and allow time for the adaptive immune response to strengthen and either control or eliminate the pathogen. The innate immune system also sends signals to the cells of the adaptive immune system, guiding them in how to attack the pathogen. Thus, these are the two important arms of the immune response.

The Benefits of the Adaptive Immune Response

The specificity of the adaptive immune response—its ability to specifically recognise and make a response against a wide variety of pathogens—is its great strength. Antigens, the small chemical groups often associated with pathogens, are recognised by receptors on the surface of B and T lymphocytes. The adaptive immune response to these antigens is so versatile that it can respond to nearly any pathogen. This increase in specificity comes because the adaptive immune response has a unique way to develop as many as 1011, or 100 trillion, different receptors to recognise nearly every conceivable pathogen. How could so many different types of antibodies be encoded? And what about the many specificities of T cells? There is not nearly enough DNA in a cell to have a separate gene for each specificity. The mechanism was finally worked out in the 1970s and 1980s using the new tools of molecular genetics

Primary Disease and Immunological Memory

The immune system’s first exposure to a pathogen is called a primary adaptive response. Symptoms of a first infection, called primary disease, are always relatively severe because it takes time for an initial adaptive immune response to a pathogen to become effective.

Upon re-exposure to the same pathogen, a secondary adaptive immune response is generated, which is stronger and faster that the primary response. The secondary adaptive response often eliminates a pathogen before it can cause significant tissue damage or any symptoms. Without symptoms, there is no disease, and the individual is not even aware of the infection. This secondary response is the basis of immunological memory, which protects us from getting diseases repeatedly from the same pathogen. By this mechanism, an individual’s exposure to pathogens early in life spares the person from these diseases later in life.

Self Recognition

A third important feature of the adaptive immune response is its ability to distinguish between self-antigens, those that are normally present in the body, and foreign antigens, those that might be on a potential pathogen. As T and B cells mature, there are mechanisms in place that prevent them from recognising self-antigen, preventing a damaging immune response against the body. These mechanisms are not 100 percent effective, however, and their breakdown leads to autoimmune diseases, which will be discussed later in this section.

T Cell-Mediated Immune Responses

The primary cells that control the adaptive immune response are the lymphocytes, the T and B cells. T cells are particularly important, as they not only control a multitude of immune responses directly, but also control B cell immune responses in many cases as well. Thus, many of the decisions about how to attack a pathogen are made at the T cell level, and knowledge of their functional types is crucial to understanding the functioning and regulation of adaptive immune responses as a whole.

T lymphocytes recognise antigens based on a two-chain protein receptor. The most common and important of these are the alpha-beta T cell receptors (Figure 7.3.1).

There are two chains in the T cell receptor, and each chain consists of two domains. The variable region domain is furthest away from the T cell membrane and is so named because its amino acid sequence varies between receptors. In contrast, the constant region domain has less variation. The differences in the amino acid sequences of the variable domains are the molecular basis of the diversity of antigens the receptor can recognise. Thus, the antigen-binding site of the receptor consists of the terminal ends of both receptor chains, and the amino acid sequences of those two areas combine to determine its antigenic specificity. Each T cell produces only one type of receptor and thus is specific for a single particular antigen.

Antigens

Antigens on pathogens are usually large and complex and consist of many antigenic determinants. An antigenic determinant (epitope) is one of the small regions within an antigen to which a receptor can bind, and antigenic determinants are limited by the size of the receptor itself. They usually consist of six or fewer amino acid residues in a protein, or one or two sugar moieties in a carbohydrate antigen. Antigenic determinants on a carbohydrate antigen are usually less diverse than on a protein antigen. Carbohydrate antigens are found on bacterial cell walls and on red blood cells (the ABO blood group antigens). Protein antigens are complex because of the variety of three-dimensional shapes that proteins can assume and are especially important for the immune responses to viruses and worm parasites. It is the interaction of the shape of the antigen and the complementary shape of the amino acids of the antigen-binding site that accounts for the chemical basis of specificity (Figure 7.3.2).

Antigen Processing and Presentation

Although Figure 7.3.12 shows T cell receptors interacting with antigenic determinants directly, the mechanism that T cells use to recognise antigens is, in reality, much more complex. T cells do not recognise free-floating or cell-bound antigens as they appear on the surface of the pathogen. They only recognise antigen on the surface of specialised cells called antigen-presenting cells. Antigens are internalised by these cells. Antigen processing is a mechanism that enzymatically cleaves the antigen into smaller pieces. The antigen fragments are then brought to the cell’s surface and associated with a specialised type of antigen-presenting protein known as a major histocompatibility complex (MHC) molecule. The MHC is the cluster of genes that encode these antigen-presenting molecules. The association of the antigen fragments with an MHC molecule on the surface of a cell is known as antigen presentation and results in the recognition of antigen by a T cell. This association of antigen and MHC occurs inside the cell, and it is the complex of the two that is brought to the surface. The peptide-binding cleft is a small indentation at the end of the MHC molecule that is furthest away from the cell membrane; it is here that the processed fragment of antigen sits. MHC molecules can present a variety of antigens, depending on the amino acid sequence, in their peptide-binding clefts. It is the combination of the MHC molecule and the fragment of the original peptide or carbohydrate that is actually physically recognised by the T cell receptor (Figure 7.3.3).

Two distinct types of MHC molecules, MHC class I and MHC class II, play roles in antigen presentation. Although produced from different genes, they both have similar functions. They bring processed antigen to the surface of the cell via a transport vesicle and present the antigen to the T cell and its receptor. Antigens from different classes of pathogens, however, use different MHC classes and take different routes through the cell to get to the surface for presentation. The basic mechanism, though, is the same. Antigens are processed by digestion, are brought into the endomembrane system of the cell, and then are expressed on the surface of the antigen-presenting cell for antigen recognition by a T cell. Intracellular antigens are typical of viruses, which replicate inside the cell, and certain other intracellular parasites and bacteria. These antigens are processed in the cytosol by an enzyme complex known as the proteasome and are then brought into the endoplasmic reticulum by the transporter associated with antigen processing (TAP) system, where they interact with class I MHC molecules and are eventually transported to the cell surface by a transport vesicle.

Extracellular antigens, characteristic of many bacteria, parasites, and fungi that do not replicate inside the cell’s cytoplasm, are brought into the endomembrane system of the cell by receptor-mediated endocytosis. The resulting vesicle fuses with vesicles from the Golgi complex, which contain pre-formed MHC class II molecules. After fusion of these two vesicles and the association of antigen and MHC, the new vesicle makes its way to the cell surface.

Antigen-Presenting Cells (APC)

Many cell types express class I molecules for the presentation of intracellular antigens. These MHC molecules may then stimulate a cytotoxic T cell immune response, eventually destroying the cell and the pathogen within. This is especially important when it comes to the most common class of intracellular pathogens, the virus. Viruses infect nearly every tissue of the body, so all these tissues must necessarily be able to express class I MHC or no T cell response can be made.

On the other hand, class II MHC molecules are expressed only on the cells of the immune system, specifically cells that affect other arms of the immune response. Thus, these cells are called “professional” antigen-presenting cells to distinguish them from those that bear class I MHC. The three types of professional antigen presenters are macrophages, dendritic cells, and B cells (Table 7.3.1).

Macrophages stimulate T cells to release cytokines that enhance phagocytosis. Dendritic cells also kill pathogens by phagocytosis, but their major function is to bring antigens to regional draining lymph nodes. The lymph nodes are the locations in which most T cell responses against pathogens of the interstitial tissues are mounted. Macrophages are found in the skin and in the lining of mucosal surfaces, such as the nasopharynx, stomach, lungs, and intestines. B cells may also present antigens to T cells, which are necessary for certain types of antibody responses, to be covered later in this chapter.

Table 7.3.1. Classes of antigen-presenting cells

T Cell Development and Differentiation

The process of eliminating T cells that might attack the cells of one’s own body is referred to as T cell tolerance. While thymocytes are in the cortex of the thymus, they are referred to as “double negatives,” meaning that they do not bear the CD4 or CD8 molecules that you can use to follow their pathways of differentiation (Figure 7.3.4). In the cortex of the thymus, they are exposed to cortical epithelial cells. In a process known as positive selection, double-negative thymocytes bind to the MHC molecules they observe on the thymic epithelia, and the MHC molecules of “self” are selected. This mechanism kills many thymocytes during T cell differentiation. In fact, only two percent of the thymocytes that enter the thymus leave it as mature, functional T cells.

Later, the cells become double positives that express both CD4 and CD8 markers and move from the cortex to the junction between the cortex and medulla. It is here that negative selection takes place. In negative selection, self-antigens are brought into the thymus from other parts of the body by professional antigen-presenting cells. The T cells that bind to these self-antigens are selected for negatively and are killed by apoptosis. In summary, the only T cells left are those that can bind to MHC molecules of the body with foreign antigens presented on their binding clefts, preventing an attack on one’s own body tissues, at least under normal circumstances. Tolerance can be broken, however, by the development of an autoimmune response, to be discussed later in this chapter.

The cells that leave the thymus become single positives, expressing either CD4 or CD8, but not both (see Figure 7.3.14). The CD4+ T cells will bind to class II MHC and the CD8+ cells will bind to class I MHC. The discussion that follows explains the functions of these molecules and how they can be used to differentiate between the different T cell functional types.

Mechanisms of T Cell-Mediated Immune Responses

Mature T cells become activated by recognising processed foreign antigen in association with a self-MHC molecule and begin dividing rapidly by mitosis. This proliferation of T cells is called clonal expansion and is necessary to make the immune response strong enough to effectively control a pathogen. How does the body select only those T cells that are needed against a specific pathogen? Again, the specificity of a T cell is based on the amino acid sequence and the three-dimensional shape of the antigen-binding site formed by the variable regions of the two chains of the T cell receptor (Figure 7.3.5). Clonal selection is the process of antigen binding only to those T cells that have receptors specific to that antigen. Each T cell that is activated has a specific receptor “hard-wired” into its DNA, and all of its progeny will have identical DNA and T cell receptors, forming clones of the original T cell.

Clonal Selection and Expansion

The clonal selection theory was proposed by Frank Burnet in the 1950s. However, the term clonal selection is not a complete description of the theory, as clonal expansion goes hand in glove with the selection process. The main tenet of the theory is that a typical individual has a multitude (~4 x 1011) of different types of T cell clones based on their receptors. In this use, a clone is a group of lymphocytes that share the same antigen receptor. Each clone is necessarily present in the body in low numbers. Otherwise, the body would not have room for lymphocytes with so many specificities.

Only those clones of lymphocytes whose receptors are activated by the antigen are stimulated to proliferate. Keep in mind that most antigens have multiple antigenic determinants, so a T cell response to a typical antigen involves a polyclonal response. A polyclonal response is the stimulation of multiple T cell clones. Once activated, the selected clones increase in number and make many copies of each cell type, each clone with its unique receptor. By the time this process is complete, the body will have large numbers of specific lymphocytes available to fight the infection (see Figure 7.3.5).

The Cellular Basis of Immunological Memory

As already discussed, one of the major features of an adaptive immune response is the development of immunological memory.

During a primary adaptive immune response, both memory T cells and effector T cells are generated. Memory T cells are long-lived and can even persist for a lifetime. Memory cells are primed to act rapidly. Thus, any subsequent exposure to the pathogen will elicit a very rapid T cell response. This rapid, secondary adaptive response generates large numbers of effector T cells so fast that the pathogen is often overwhelmed before it can cause any symptoms of disease. This is what is meant by immunity to a disease. The same pattern of primary and secondary immune responses occurs in B cells and the antibody response, as will be discussed later in the chapter.

T Cell Types and Their Functions

In the discussion of T cell development, you saw that mature T cells express either the CD4 marker or the CD8 marker, but not both. These markers are cell adhesion molecules that keep the T cell in close contact with the antigen-presenting cell by directly binding to the MHC molecule (to a different part of the molecule than does the antigen). Thus, T cells and antigen-presenting cells are held together in two ways: by CD4 or CD8 attaching to MHC and by the T cell receptor binding to antigen (Figure 7.3.6).

Although the correlation is not 100 percent, CD4-bearing T cells are associated with helper functions and CD8-bearing T cells are associated with cytotoxicity. These functional distinctions based on CD4 and CD8 markers are useful in defining the function of each type.

Helper T Cells and Their Cytokines

Helper T cells (Th), bearing the CD4 molecule, function by secreting cytokines that act to enhance other immune responses. There are two classes of Th cells, and they act on different components of the immune response. These cells are not distinguished by their surface molecules but by the characteristic set of cytokines they secrete (Table 7.3.2).

Th1 cells are a type of helper T cell that secretes cytokines that regulate the immunological activity and development of a variety of cells, including macrophages and other types of T cells.

Th2 cells, on the other hand, are cytokine-secreting cells that act on B cells to drive their differentiation into plasma cells that make antibody. In fact, T cell help is required for antibody responses to most protein antigens, and these are called T cell-dependent antigens.

Cytotoxic T Cells

Cytotoxic T cells (Tc) are T cells that kill target cells by inducing apoptosis using the same mechanism as NK cells. They either express Fas ligand, which binds to the fas molecule on the target cell, or act by using perforins and granzymes contained in their cytoplasmic granules. As was discussed earlier with NK cells, killing a virally infected cell before the virus can complete its replication cycle results in the production of no infectious particles. As more Tc cells are developed during an immune response, they overwhelm the ability of the virus to cause disease. In addition, each Tc cell can kill more than one target cell, making them especially effective. Tc cells are so important in the antiviral immune response that some speculate that this was the main reason the adaptive immune response evolved in the first place.

Regulatory T Cells

Regulatory T cells (Treg), or suppressor T cells, are the most recently discovered of the types listed here, so less is understood about them. In addition to CD4, they bear the molecules CD25 and FOXP3. Exactly how they function is still under investigation, but it is known that they suppress other T cell immune responses. This is an important feature of the immune response, because if clonal expansion during immune responses could continue uncontrolled, these responses could lead to autoimmune diseases and other medical issues.

Not only do T cells directly destroy pathogens, but they regulate nearly all other types of the adaptive immune response as well, as evidenced by the functions of the T cell types, their surface markers, the cells they work on, and the types of pathogens they work against (see Table 5).

Table 7.3.2. Functions of T cell types and their cytokines

Click the drop down below to review the terms learned from this chapter.

Antibodies were the first component of the adaptive immune response to be characterised by scientists working on the immune system. It was already known that individuals who survived a bacterial infection were immune to re-infection with the same pathogen. Early microbiologists took serum from an immune patient and mixed it with a fresh culture of the same type of bacteria, then observed the bacteria under a microscope. The bacteria became clumped in a process called agglutination. When a different bacterial species was used, the agglutination did not happen. Thus, there was something in the serum of immune individuals that could specifically bind to and agglutinate bacteria.

Scientists now know the cause of the agglutination is an antibody molecule, also called an immunoglobulin. What is an antibody? An antibody protein is essentially a secreted form of a B cell receptor. (In fact, surface immunoglobulin is another name for the B cell receptor.) Not surprisingly, the same genes encode both the secreted antibodies and the surface immunoglobulins. One minor difference in the way these proteins are synthesised distinguishes a naïve B cell with antibody on its surface from an antibody-secreting plasma cell with no antibodies on its surface. The antibodies of the plasma cell have the exact same antigen-binding site and specificity as their B cell precursors.

There are five different classes of antibody found in humans: IgM, IgD, IgG, IgA, and IgE. Each of these has specific functions in the immune response, so by learning about them, researchers can learn about the great variety of antibody functions critical to many adaptive immune responses.

B cells do not recognise antigen in the complex fashion of T cells. B cells can recognise native, unprocessed antigen and do not require the participation of MHC molecules and antigen-presenting cells.

B Cell Differentiation and Activation

B cells differentiate in the bone marrow. During the process of maturation, up to 100 trillion different clones of B cells are generated, which is similar to the diversity of antigen receptors seen in T cells.

B cell differentiation and the development of tolerance are not quite as well understood as it is in T cells. Central tolerance is the destruction or inactivation of B cells that recognise self-antigens in the bone marrow, and its role is critical and well established. In the process of clonal deletion, immature B cells that bind strongly to self-antigens expressed on tissues are signalled to commit suicide by apoptosis, removing them from the population. In the process of clonal anergy, however, B cells exposed to soluble antigen in the bone marrow are not physically deleted but become unable to function.

Another mechanism called peripheral tolerance is a direct result of T cell tolerance. In peripheral tolerance, functional, mature B cells leave the bone marrow but have yet to be exposed to self-antigen. Most protein antigens require signals from helper T cells (Th2) to proceed to make antibody. When a B cell binds to a self-antigen but receives no signals from a nearby Th2 cell to produce antibody, the cell is signalled to undergo apoptosis and is destroyed. This is yet another example of the control that T cells have over the adaptive immune response.

After B cells are activated by their binding to antigen, they differentiate into plasma cells. Plasma cells often leave the secondary lymphoid organs, where the response is generated, and migrate back to the bone marrow, where the whole differentiation process started. After secreting antibodies for a specific period, they die, as most of their energy is devoted to making antibodies and not to maintaining themselves. Thus, plasma cells are said to be terminally differentiated.

The final B cell of interest is the memory B cell, which results from the clonal expansion of an activated B cell. Memory B cells function in a way similar to memory T cells. They lead to a stronger and faster secondary response when compared to the primary response, as illustrated below.

Antibody Structure

Antibodies are glycoproteins consisting of two types of polypeptide chains with attached carbohydrates. The heavy chain and the light chain are the two polypeptides that form the antibody. The main differences between the classes of antibodies are in the differences between their heavy chains, but as you shall see, the light chains have an important role, forming part of the antigen-binding site on the antibody molecules.

Four-Chain Models of Antibody Structures

All antibody molecules have two identical heavy chains and two identical light chains. (Some antibodies contain multiple units of this four-chain structure.) The Fc region of the antibody is formed by the two heavy chains coming together, usually linked by disulphide bonds (Figure 7.4.1). The Fc portion of the antibody is important in that many effector cells of the immune system have Fc receptors. Cells having these receptors can then bind to antibody-coated pathogens, greatly increasing the specificity of the effector cells. At the other end of the molecule are two identical antigen-binding sites.

Five Classes of Antibodies and their Functions

In general, antibodies have two basic functions. They can act as the B cell antigen receptor or they can be secreted, circulate, and bind to a pathogen, often labelling it for identification by other forms of the immune response. Of the five antibody classes, notice that only two can function as the antigen receptor for naïve B cells: IgM and IgD (Figure 7.4.2). Mature B cells that leave the bone marrow express both IgM and IgD, but both antibodies have the same antigen specificity. Only IgM is secreted, however, and no other nonreceptor function for IgD has been discovered.

IgM consists of five four-chain structures (20 total chains with 10 identical antigen-binding sites) and is thus the largest of the antibody molecules. IgM is usually the first antibody made during a primary response. Its 10 antigen-binding sites and large shape allow it to bind well to many bacterial surfaces. It is excellent at binding complement proteins and activating the complement cascade, consistent with its role in promoting chemotaxis, opsonisation, and cell lysis. Thus, it is a very effective antibody against bacteria at early stages of a primary antibody response. As the primary response proceeds, the antibody produced in a B cell can change to IgG, IgA, or IgE by the process known as class switching. Class switching is the change of one antibody class to another. While the class of antibody changes, the specificity and the antigen-binding sites do not. Thus, the antibodies made are still specific to the pathogen that stimulated the initial IgM response.

IgG is a major antibody of late primary responses and the main antibody of secondary responses in the blood. This is because class switching occurs during primary responses. IgG is a monomeric antibody that clears pathogens from the blood and can activate complement proteins (although not as well as IgM), taking advantage of its antibacterial activities. Furthermore, this class of antibody is the one that crosses the placenta to protect the developing foetus from disease exits the blood to the interstitial fluid to fight extracellular pathogens.

IgA exists in two forms, a four-chain monomer in the blood and an eight-chain structure, or dimer, in exocrine gland secretions of the mucous membranes, including mucus, saliva and tears. Thus, dimeric IgA is the only antibody to leave the interior of the body to protect body surfaces. IgA is also of importance to newborns, because this antibody is present in mother’s breast milk (colostrum), which serves to protect the infant from disease.

IgE is usually associated with allergies and anaphylaxis. It is present in the lowest concentration in the blood, because its Fc region binds strongly to an IgE-specific Fc receptor on the surfaces of mast cells. IgE makes mast cell degranulation very specific, such that if a person is allergic to peanuts, there will be peanut-specific IgE bound to his or her mast cells. In this person, eating peanuts will cause the mast cells to degranulate, sometimes causing severe allergic reactions, including anaphylaxis, a severe, systemic allergic response that can cause death.

Clonal Selection of B Cells

Clonal selection and expansion work much the same way in B cells as in T cells. Only B cells with appropriate antigen specificity are selected for and expanded (Figure 7.4.3). Eventually, the plasma cells secrete antibodies with antigenic specificity identical to those that were on the surfaces of the selected B cells. Notice in the figure that both plasma cells and memory B cells are generated simultaneously.

Primary Versus Secondary B Cell Reponses

Primary and secondary responses as they relate to T cells were discussed earlier. This section will look at these responses with B cells and antibody production. Because antibodies are easily obtained from blood samples, they are easy to follow and graph (Figure 7.4.4). As you will see from the figure, the primary response to an antigen (representing a pathogen) is delayed by several days. This is the time it takes for the B cell clones to expand and differentiate into plasma cells. The level of antibody produced is low, but it is sufficient for immune protection. The second time a person encounters the same antigen, there is no time delay, and the amount of antibody made is much higher. Thus, the secondary antibody response overwhelms the pathogens quickly and, in most situations, no symptoms are felt. When a different antigen is used, another primary response is made with its low antibody levels and time delay.

Active Versus Passive Immunity

Immunity to pathogens, and the ability to control pathogen growth so that damage to the tissues of the body is limited, can be acquired by (1) the active development of an immune response in the infected individual or (2) the passive transfer of immune components from an immune individual to a nonimmune one. Both active and passive immunity have examples in the natural world and as part of medicine.

Active immunity is the resistance to pathogens acquired during an adaptive immune response within an individual (Table 7.4.1). Naturally acquired active immunity, the response to a pathogen, is the focus of this chapter. Artificially acquired active immunity involves the use of vaccines. A vaccine is a killed or weakened pathogen or its components that, when administered to a healthy individual, leads to the development of immunological memory (a weakened primary immune response) without causing much in the way of symptoms. Thus, with the use of vaccines, one can avoid the damage from disease that results from the first exposure to the pathogen yet reap the benefits of protection from immunological memory. The advent of vaccines was one of the major medical advances of the twentieth century and led to the eradication of smallpox and the control of many infectious diseases, including polio, measles, and whooping cough.

Table 7.4.1. Active versus passive immunity

Passive immunity arises from the transfer of antibodies to an individual without requiring them to mount their own active immune response. Naturally acquired passive immunity is seen during foetal development. IgG is transferred from the maternal circulation to the foetus via the placenta, protecting the foetus from infection and protecting the newborn for the first few months of its life. As already stated, a newborn benefits from the IgA antibodies it obtains from milk during breastfeeding. The foetus and newborn thus benefit from the immunological memory of the mother to the pathogens to which she has been exposed. In medicine, artificially acquired passive immunity usually involves injections of immunoglobulins, taken from animals previously exposed to a specific pathogen. This treatment is a fast-acting method of temporarily protecting an individual who was possibly exposed to a pathogen. The downside to both types of passive immunity is the lack of the development of immunological memory. Once the antibodies are transferred, they are effective for only a limited time before they degrade.

T Cell-Development versus T Cell-Independent Antigens

As discussed previously, Th2 cells secrete cytokines that drive the production of antibodies in a B cell, responding to complex antigens such as those made by proteins. On the other hand, some antigens are T cell independent. A T cell-independent antigen usually is in the form of repeated carbohydrate moieties found on the cell walls of bacteria. Each antibody on the B cell surface has two binding sites, and the repeated nature of T cell-independent antigen leads to crosslinking of the surface antibodies on the B cell. The crosslinking is enough to activate it in the absence of T cell cytokines.

A T cell-dependent antigen, on the other hand, usually is not repeated to the same degree on the pathogen and thus does not crosslink surface antibody with the same efficiency. To elicit a response to such antigens, the B and T cells must come close together (Figure 7.4.5). The B cell must receive two signals to become activated. Its surface immunoglobulin must recognise native antigen. Some of this antigen is internalised, processed, and presented to the Th2 cells on a class II MHC molecule. The T cell then binds using its antigen receptor and is activated to secrete cytokines that diffuse to the B cell, finally activating it completely. Thus, the B cell receives signals from both its surface antibody and the T cell via its cytokines and acts as a professional antigen-presenting cell in the process.

Click the drop down below to review the terms learned from this chapter.

Now that you understand the development of mature, naïve B cells and T cells, and some of their major functions, how do all of these various cells, proteins, and cytokines come together to actually resolve an infection? Ideally, the immune response will rid the body of a pathogen entirely. The adaptive immune response, with its rapid clonal expansion, is well suited to this purpose. Think of a primary infection as a race between the pathogen and the immune system. The pathogen bypasses barrier defences and starts multiplying in the host’s body. During the first 4 to 5 days, the innate immune response will partially control, but not stop, pathogen growth. As the adaptive immune response gears up, however, it will begin to clear the pathogen from the body, while at the same time becoming stronger and stronger. When following antibody responses in patients with a particular disease such as a virus, this clearance is referred to as seroconversion (sero- = “serum”). Seroconversion is the reciprocal relationship between virus levels in the blood and antibody levels. As the antibody levels rise, the virus levels decline, and this is a sign that the immune response is being at least partially effective (partially, because in many diseases, seroconversion does not necessarily mean a patient is getting well).

An excellent example of this is seroconversion during HIV disease (Figure 7.5.1). Notice that antibodies are made early in this disease, and the increase in anti-HIV antibodies correlates with a decrease in detectable virus in the blood. Although these antibodies are an important marker for diagnosing the disease, they are not sufficient to completely clear the virus. Several years later, the vast majority of these individuals, if untreated, will lose their entire adaptive immune response, including the ability to make antibodies, during the final stages of AIDS.

Everyday Connection Disinfectants: Fighting the Good Fight?

“Wash your hands!” Parents have been telling their children this for generations. Dirty hands can spread disease. But is it possible to get rid of enough pathogens that children will never get sick? Are children who avoid exposure to pathogens better off? The answers to both these questions appears to be no.

Antibacterial wipes, soaps, gels, and even toys with antibacterial substances embedded in their plastic are ubiquitous in our society. Still, these products do not rid the skin and gastrointestinal tract of bacteria, and it would be harmful to our health if they did. We need these non-pathogenic bacteria on and within our bodies to keep the pathogenic ones from growing. The urge to keep children perfectly clean is thus probably misguided. Children will get sick anyway, and the later benefits of immunological memory far outweigh the minor discomforts of most childhood diseases. In fact, getting diseases such as chickenpox or measles later in life is much harder on the adult and are associated with symptoms significantly worse than those seen in the childhood illnesses. Of course, vaccinations help children avoid some illnesses, but there are so many pathogens, we will never be immune to them all.

Could over-cleanliness be the reason that allergies are increasing in more developed countries? Some scientists think so. Allergies are based on an IgE antibody response. Many scientists think the system evolved to help the body rid itself of worm parasites. The hygiene theory is the idea that the immune system is geared to respond to antigens, and if pathogens are not present, it will respond instead to inappropriate antigens such as allergens and self-antigens. This is one explanation for the rising incidence of allergies in developed countries, where the response to nonpathogens like pollen, shrimp, and cat dander cause allergic responses while not serving any protective function.

The Mucosal Immune Response

Mucosal tissues are major barriers to the entry of pathogens into the body. The IgA (and sometimes IgM) antibodies in mucus and other secretions can bind to the pathogen, and in the cases of many viruses and bacteria, neutralise them. Neutralisation is the process of coating a pathogen with antibodies, making it physically impossible for the pathogen to bind to receptors. Neutralisation, which occurs in the blood, lymph, and other body fluids and secretions, protects the body constantly. Neutralising antibodies are the basis for the disease protection offered by vaccines. Vaccinations for diseases that commonly enter the body via mucous membranes, such as influenza, are usually formulated to enhance IgA production.

Immune responses in some mucosal tissues such as the Peyer’s patches in the small intestine take up particulate antigens by specialised cells known as microfold or M cells (Figure 7.5.2). These cells allow the body to sample potential pathogens from the intestinal lumen. Dendritic cells then take the antigen to the regional lymph nodes, where an immune response is mounted.

Defences Against Bacteria and Fungi

The body fights bacterial pathogens with a wide variety of immunological mechanisms, essentially trying to find one that is effective. Bacteria such as Mycobacterium leprae, the cause of leprosy, are resistant to lysosomal enzymes and can persist in macrophage organelles or escape into the cytosol. In such situations, infected macrophages receiving cytokine signals from Th1 cells turn on special metabolic pathways. Macrophage oxidative metabolism is hostile to intracellular bacteria, often relying on the production of nitric oxide to kill the bacteria inside the macrophage.

Fungal infections, such as those from Aspergillus, Candida, and Pneumocystis, are largely opportunistic infections that take advantage of suppressed immune responses. Most of the same immune mechanisms effective against bacteria have similar effects on fungi, both of which have characteristic cell wall structures that protect their cells.

Defences Against Parasites

Worm parasites such as helminths are the primary reason why the mucosal immune response, IgE-mediated allergy and asthma, and eosinophils evolved. These parasites were at one time very common in human society. When infecting a human, often via contaminated food, some worms take up residence in the gastrointestinal tract. Eosinophils are attracted to the site by T cell cytokines, which release their granule contents upon their arrival. Mast cell degranulation also occurs, and the fluid leakage caused by the increase in local vascular permeability is thought to have a flushing action on the parasite, expelling its larvae from the body. Furthermore, if IgE labels the parasite, the eosinophils can bind to it by its Fc receptor.

Defences Against Viruses

The primary mechanisms against viruses are NK cells, interferons, and cytotoxic T cells. Antibodies are effective against viruses mostly during protection, where an immune individual can neutralise them based on a previous exposure. Antibodies have no effect on viruses or other intracellular pathogens once they enter the cell, since antibodies are not able to penetrate the plasma membrane of the cell. Many cells respond to viral infections by downregulating their expression of MHC class I molecules. This is to the advantage of the virus, because without class I expression, cytotoxic T cells have no activity. NK cells, however, can recognise virally infected class I-negative cells and destroy them. Thus, NK and cytotoxic T cells have complementary activities against virally infected cells.

Interferons have activity in slowing viral replication and are used in the treatment of certain viral diseases, such as hepatitis B and C, but their ability to eliminate the virus completely is limited. The cytotoxic T cell response, though, is key, as it eventually overwhelms the virus and kills infected cells before the virus can complete its replicative cycle. Clonal expansion and the ability of cytotoxic T cells to kill more than one target cell make these cells especially effective against viruses. In fact, without cytotoxic T cells, it is likely that humans would all die at some point from a viral infection (if no vaccine were available).

Evasion of the Immune System by Pathogens

It is important to keep in mind that although the immune system has evolved to be able to control many pathogens, pathogens themselves have evolved ways to evade the immune response. An example already mentioned is in Mycobacterium tuberculosis, which has evolved a complex cell wall that is resistant to the digestive enzymes of the macrophages that ingest them, and thus persists in the host, causing the chronic disease tuberculosis. This section briefly summarises other ways in which pathogens can “outwit” immune responses. But keep in mind, although it seems as if pathogens have a will of their own, they do not. All of these evasive “strategies” arose strictly by evolution, driven by selection.

Bacteria sometimes evade immune responses because they exist in multiple strains, such as different groups of Staphylococcus aureus. S. aureus is commonly found in minor skin infections, such as boils, and some healthy people harbour it in their nose. One small group of strains of this bacterium, however, called methicillin-resistant Staphylococcus aureus (MRSA), has become resistant to multiple antibiotics and is essentially untreatable. Different bacterial strains differ in the antigens on their surfaces. The immune response against one strain (antigen) does not affect the other; thus, the species survives.

Another method of immune evasion is mutation. Because viruses’ surface molecules mutate continuously, viruses like influenza change enough each year that the flu vaccine for one year may not protect against the flu common to the next. New vaccine formulations must be derived for each flu season.

Genetic recombination—the combining of gene segments from two different pathogens—is an efficient form of immune evasion. For example, the influenza virus contains gene segments that can recombine when two different viruses infect the same cell. Recombination between human and pig influenza viruses led to the 2010 H1N1 swine flu outbreak.

Pathogens can produce immunosuppressive molecules that impair immune function, and there are several different types. Viruses are especially good at evading the immune response in this way, and many types of viruses have been shown to suppress the host immune response in ways much more subtle than the wholesale destruction caused by HIV.

Click the drop down below to review the terms learned from this chapter.

This section is about how the immune system goes wrong. When it goes haywire, and becomes too weak or too strong, it leads to a state of disease. The factors that maintain immunological homeostasis are complex and incompletely understood.

Immunodeficiencies

As you have seen, the immune system is quite complex. It has many pathways using many cell types and signals. Because it is so complex, there are many ways for it to go wrong. Inherited immunodeficiencies arise from gene mutations that affect specific components of the immune response. There are also acquired immunodeficiencies with potentially devastating effects on the immune system, such as HIV.

Inherited Immunodeficiencies

A list of all inherited immunodeficiencies is well beyond the scope of this chapter. The list is almost as long as the list of cells, proteins, and signalling molecules of the immune system itself. Some deficiencies, such as those for complement, cause only a higher susceptibility to some Gram-negative bacteria. Others are more severe in their consequences. Certainly, the most serious of the inherited immunodeficiencies is severe combined immunodeficiency disease (SCID). This disease is complex because it is caused by many different genetic defects. What groups them together is the fact that both the B cell and T cell arms of the adaptive immune response are affected.

Children with this disease usually die of opportunistic infections within their first year of life unless they receive a bone marrow transplant. Such a procedure had not yet been perfected for David Vetter, the “boy in the bubble,” who was treated for SCID by having to live almost his entire life in a sterile plastic cocoon for the 12 years before his death from infection in 1984. One of the features that make bone marrow transplants work as well as they do is the proliferative capability of haematopoietic stem cells of the bone marrow. Only a small amount of bone marrow from a healthy donor is given intravenously to the recipient. It finds its own way to the bone where it populates it, eventually reconstituting the patient’s immune system, which is usually destroyed beforehand by treatment with radiation or chemotherapeutic drugs.

New treatments for SCID using gene therapy, inserting non-defective genes into cells taken from the patient and giving them back, have the advantage of not needing the tissue match required for standard transplants. Although not a standard treatment, this approach holds promise, especially for those in whom standard bone marrow transplantation has failed.

Human Immunodeficiency Viruses/AIDS

Although many viruses cause suppression of the immune system, only one wipes it out completely, and that is the previously mentioned HIV. It is worth discussing the biology of this virus, which can lead to the well-known AIDS, so that its full effects on the immune system can be understood. The virus is transmitted through semen, vaginal fluids, and blood, and can be caught by risky sexual behaviours and the sharing of needles by intravenous drug users. There are sometimes, but not always, flu-like symptoms in the first one to two weeks after infection. This is later followed by seroconversion. The anti-HIV antibodies formed during seroconversion are the basis for most initial HIV screening done in Australia, and many other countries such as United States and England. Because seroconversion takes different lengths of time in different individuals, multiple AIDS tests are given months apart to confirm or eliminate the possibility of infection.

After seroconversion, the amount of virus circulating in the blood drops and stays at a low level for several years. During this time, the levels of CD4+ cells, especially helper T cells, decline steadily, until at some point, the immune response is so weak that opportunistic disease and eventually death result. CD4 is the receptor that HIV uses to get inside T cells and reproduce. Given that CD4+ helper T cells play an important role in other in T cell immune responses and antibody responses, it should be no surprise that both types of immune responses are eventually seriously compromised.

Treatment for the disease consists of drugs that target virally encoded proteins that are necessary for viral replication but are absent from normal human cells. By targeting the virus itself and sparing the cells, this approach has been successful in significantly prolonging the lives of HIV-positive individuals. On the other hand, an HIV vaccine has been 30 years in development and is still years away. Because the virus mutates rapidly to evade the immune system, scientists have been looking for parts of the virus that do not change and thus would be good targets for a vaccine candidate.

Hypersensitivities

The word “hypersensitivity” simply means sensitive beyond normal levels of activation. Allergies and inflammatory responses to non-pathogenic environmental substances have been observed since the dawn of history. Hypersensitivity is a medical term describing symptoms that are now known to be caused by unrelated mechanisms of immunity. Still, it is useful for this discussion to use the four types of hypersensitivities as a guide to understand these mechanisms (Figure 7.6.1).

Immediate (Type I) Hypersensitivity

Antigens that cause allergic responses are often referred to as allergens. The specificity of the immediate hypersensitivity response is predicated on the binding of allergen-specific IgE to the mast cell surface. The process of producing allergen-specific IgE is called sensitisation, and is a necessary prerequisite for the symptoms of immediate hypersensitivity to occur. Allergies and allergic asthma are mediated by mast cell degranulation that is caused by the crosslinking of the antigen-specific IgE molecules on the mast cell surface. The mediators released have various vasoactive effects already discussed, but the major symptoms of inhaled allergens are the nasal oedema and runny nose caused by the increased vascular permeability and increased blood flow of nasal blood vessels. As these mediators are released with mast cell degranulation, type I hypersensitivity reactions are usually rapid and occur within just a few minutes, hence the term immediate hypersensitivity.

Most allergens are in themselves non-pathogenic and therefore innocuous. Some individuals develop mild allergies, which are usually treated with antihistamines. Others develop severe allergies that may cause anaphylactic shock, which can potentially be fatal within 20 to 30 minutes if untreated. This drop in blood pressure (shock) with accompanying contractions of bronchial smooth muscle is caused by systemic mast cell degranulation when an allergen is eaten (for example, shellfish and peanuts), injected (by a bee sting or being administered penicillin), or inhaled (asthma). Because adrenaline raises blood pressure and relaxes bronchial smooth muscle, it is routinely used to counteract the effects of anaphylaxis and can be lifesaving. Patients with known severe allergies are encouraged to keep automatic adrenaline injectors with them at all times, especially when away from easy access to hospitals.

Allergists use skin testing to identify allergens in type I hypersensitivity. In skin testing, allergen extracts are injected into the epidermis, and a positive result of a soft, pale swelling at the site surrounded by a red zone (called the wheal and flare response), caused by the release of histamine and the granule mediators, usually occurs within 30 minutes. The soft centre is due to fluid leaking from the blood vessels and the redness is caused by the increased blood flow to the area that results from the dilation of local blood vessels at the site.

Type II and Type III Hypersensitivities

Type II hypersensitivity, which involves IgG-mediated lysis of cells by complement proteins, occurs during mismatched blood transfusions and blood compatibility diseases such as erythroblastosis fetalis (see section on transplantation). Type III hypersensitivity occurs with diseases such as systemic lupus erythematosus, where soluble antigens, mostly DNA and other material from the nucleus, and antibodies accumulate in the blood to the point that the antigen and antibody precipitate along blood vessel linings. These immune complexes often lodge in the kidneys, joints, and other organs where they can activate complement proteins and cause inflammation.

Delayed (Type IV) Hypersensitivity

Delayed hypersensitivity, or type IV hypersensitivity, is basically a standard cellular immune response. In delayed hypersensitivity, the first exposure to an antigen is called sensitisation, such that on re-exposure, a secondary cellular response results, secreting cytokines that recruit macrophages and other phagocytes to the site. These sensitised T cells, of the Th1 class, will also activate cytotoxic T cells. The time it takes for this reaction to occur accounts for the 24- to 72-hour delay in development.

The classical test for delayed hypersensitivity is the tuberculin test for tuberculosis, where bacterial proteins from M. tuberculosis are injected into the skin. A couple of days later, a positive test is indicated by a raised red area that is hard to the touch, called an induration, which is a consequence of the cellular infiltrate, an accumulation of activated macrophages. A positive tuberculin test means that the patient has been exposed to the bacteria and exhibits a cellular immune response to it.

Another type of delayed hypersensitivity is contact sensitivity, where substances such as the metal nickel cause a red and swollen area upon contact with the skin. The individual must have been previously sensitised to the metal. A much more severe case of contact sensitivity is poison ivy (uncommon in Australia) but many of the harshest symptoms of the reaction are associated with the toxicity of its oils and are not T cell mediated.

Autoimmune Responses

The worst cases of the immune system over-reacting are autoimmune diseases. Somehow, tolerance breaks down and the immune systems in individuals with these diseases begin to attack their own bodies, causing significant damage. The trigger for these diseases is, more often than not, unknown, and the treatments are usually based on resolving the symptoms using immunosuppressive and anti-inflammatory drugs such as steroids. These diseases can be localised and crippling, as in rheumatoid arthritis, or diffuse in the body with multiple symptoms that differ in different individuals, as is the case with systemic lupus erythematosus (Figure 7.6.2).

Environmental triggers seem to play large roles in autoimmune responses. One explanation for the breakdown of tolerance is that, after certain bacterial infections, an immune response to a component of the bacterium cross-reacts with a self-antigen. This mechanism is seen in rheumatic fever, a result of infection with Streptococcus bacteria, which causes strep throat. The antibodies to this pathogen’s M protein cross-react with an antigenic component of heart myosin, a major contractile protein of the heart that is critical to its normal function. The antibody binds to these molecules and activates complement proteins, causing damage to the heart, especially to the heart valves. On the other hand, some theories propose that having multiple common infectious diseases prevents autoimmune responses. The fact that autoimmune diseases are rare in countries that have a high incidence of infectious diseases supports this idea, another example of the hygiene hypothesis discussed earlier in this chapter.

There are genetic factors in autoimmune diseases as well. Some diseases are associated with the MHC genes that an individual expresses. The reason for this association is likely because if one’s MHC molecules are not able to present a certain self-antigen, then that particular autoimmune disease cannot occur. Overall, there are more than 80 different autoimmune diseases, which are a significant health problem in the elderly. Table 7.6.1 lists several of the most common autoimmune diseases, the antigens that are targeted, and the segment of the adaptive immune response that causes the damage.

Table 7.6.1. Autoimmune diseases

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The immune responses to transplanted organs and to cancer cells are both important medical issues. With the use of tissue typing and anti-rejection drugs, transplantation of organs and the control of the anti-transplant immune response have made huge strides in the past 50 years. Today, these procedures are commonplace. Tissue typing is the determination of MHC molecules in the tissue to be transplanted to better match the donor to the recipient. The immune response to cancer, on the other hand, has been more difficult to understand and control. Although the immune system can recognise some cancers and control them, others seem to be resistant to immune mechanisms.

The Rh Factor

Red blood cells can be typed based on their surface antigens. ABO blood type, in which individuals are type A, B, AB, or O according to their genetics, is one example. A separate antigen system seen on red blood cells is the Rh antigen. When someone is “A positive” for example, the positive refers to the presence of the Rh antigen, whereas someone who is “A negative” would lack this molecule.

An interesting consequence of Rh factor expression is seen in erythroblastosis foetalis, a haemolytic disease of the newborn (Figure 7.7.1). This disease occurs when mothers negative for Rh antigen have multiple Rh-positive children. During the birth of a first Rh-positive child, the mother makes a primary anti-Rh antibody response to the foetal blood cells that enter the maternal bloodstream. If the mother has a second Rh-positive child, IgG antibodies against Rh-positive blood mounted during this secondary response cross the placenta and attack the foetal blood, causing anaemia. This is a consequence of the fact that the foetus is not genetically identical to the mother, and thus the mother can mount an immune response against it. This disease is treated with antibodies specific for Rh factor. These are given to the mother during the subsequent births, destroying any foetal blood that might enter her system and preventing the immune response.

Tissue Transplantation

Tissue transplantation is more complicated than blood transfusions because of two characteristics of MHC molecules. These molecules are the major cause of transplant rejection (hence the name “histocompatibility”). MHC polygeny refers to the multiple MHC proteins on cells, and MHC polymorphism refers to the multiple alleles for each individual MHC locus. Thus, there are many alleles in the human population that can be expressed (Table 7.7.1 and Table 7.7.2). When a donor organ expresses MHC molecules that are different from the recipient, the latter will often mount a cytotoxic T cell response to the organ and reject it. Histologically, if a biopsy of a transplanted organ exhibits massive infiltration of T lymphocytes within the first weeks after transplant, it is a sign that the transplant is likely to fail. The response is a classical, and very specific, primary T cell immune response. As far as medicine is concerned, the immune response in this scenario does the patient no good at all and causes significant harm.

Table 7.7.1. Partial table of alleles of the human MHC (Class I)

Table 7.7.2. Partial table of alleles of the human MHC (Class II)

Immunosuppressive drugs such as cyclosporine A have made transplants more successful but matching the MHC molecules is still key. In humans, there are six MHC molecules that show the most polymorphisms, three class I molecules (A, B, and C) and three class II molecules called DP, DQ, and DR. A successful transplant usually requires a match between at least 3–4 of these molecules, with more matches associated with greater success. Family members, since they share a similar genetic background, are much more likely to share MHC molecules than unrelated individuals do. In fact, due to the extensive polymorphisms in these MHC molecules, unrelated donors are found only through a worldwide database. The system is not foolproof however, as there are not enough individuals in the system to provide the organs necessary to treat all patients needing them.

One disease of transplantation occurs with bone marrow transplants, which are used to treat various diseases, including SCID and leukaemia. Because the bone marrow cells being transplanted contain lymphocytes capable of mounting an immune response, and because the recipient’s immune response has been destroyed before receiving the transplant, the donor cells may attack the recipient tissues, causing graft-versus-host disease. Symptoms of this disease, which usually include a rash and damage to the liver and mucosa, are variable, and attempts have been made to moderate the disease by first removing mature T cells from the donor bone marrow before transplanting it.

Immune Responses Against Cancer

It is clear that with some cancers, for example Kaposi’s sarcoma, a healthy immune system does a good job at controlling them (Figure 7.7.2). This disease, which is caused by the human herpesvirus, is almost never observed in individuals with strong immune systems, such as the young and immunocompetent. Other examples of cancers caused by viruses include liver cancer caused by the hepatitis B virus and cervical cancer caused by the human papilloma virus. As these last two viruses have vaccines available for them, getting vaccinated can help prevent these two types of cancer by stimulating the immune response.

On the other hand, as cancer cells are often able to divide and mutate rapidly, they may escape the immune response, just as certain pathogens such as HIV do. There are three stages in the immune response to many cancers: elimination, equilibrium, and escape. Elimination occurs when the immune response first develops toward tumour-specific antigens specific to the cancer and actively kills most cancer cells, followed by a period of controlled equilibrium during which the remaining cancer cells are held in check. Unfortunately, many cancers mutate, so they no longer express any specific antigens for the immune system to respond to, and a subpopulation of cancer cells escapes the immune response, continuing the disease process.

This fact has led to extensive research in trying to develop ways to enhance the early immune response to eliminate the early cancer and thus prevent a later escape. One method that has shown some success is the use of cancer vaccines, which differ from viral and bacterial vaccines in that they are directed against the cells of one’s own body. Treated cancer cells are injected into cancer patients to enhance their anti-cancer immune response and thereby prolong survival. The immune system has the capability to detect these cancer cells and proliferate faster than the cancer cells do, overwhelming the cancer in a similar way as they do for viruses. Cancer vaccines have been developed for malignant melanoma, a highly fatal skin cancer, and renal (kidney) cell carcinoma. These vaccines are still in the development stages, but some positive and encouraging results have been obtained clinically.

It is tempting to focus on the complexity of the immune system and the problems it causes as a negative. The upside to immunity, however, is so much greater: The benefit of staying alive far outweighs the negatives caused when the system does sometimes go awry. Working on “autopilot,” the immune system helps to maintain your health and kill pathogens. The only time you really miss the immune response is when it is not being effective and illness results, or, as in the extreme case of HIV disease, the immune system is gone completely.

Everyday Connection

How Stress Affects the Immune Response: The Connections between the Immune, Nervous, and Endocrine Systems of the Body

The immune system cannot exist in isolation. After all, it must protect the entire body from infection. Therefore, the immune system is required to interact with other organ systems, sometimes in complex ways. Thirty years of research focusing on the connections between the immune system, the central nervous system, and the endocrine system have led to a new science with the unwieldy name of called psychoneuroimmunology. The physical connections between these systems have been known for centuries: All primary and secondary organs are connected to sympathetic nerves. What is more complex, though, is the interaction of neurotransmitters, hormones, cytokines, and other soluble signalling molecules, and the mechanism of “crosstalk” between the systems, for example white blood cells, including lymphocytes and phagocytes, have receptors for various neurotransmitters released by associated neurons. Additionally, hormones such as cortisol (naturally produced by the adrenal cortex) and prednisone (synthetic) are well known for their abilities to suppress T cell immune mechanisms, hence, their prominent use in medicine as long-term, anti-inflammatory drugs.

One well-established interaction of the immune, nervous, and endocrine systems is the effect of stress on immune health. In the human vertebrate evolutionary past, stress was associated with the fight-or-flight response, largely mediated by the central nervous system and the adrenal medulla. This stress was necessary for survival. The physical action of fighting or running, whichever the animal decides, usually resolves the problem in one way or another. On the other hand, there are no physical actions to resolve most modern-day stresses, including short-term stressors like taking examinations and long-term stressors such as being unemployed or losing a spouse. The effect of stress can be felt by nearly every organ system, and the immune system is no exception (Table 7.7.3).

Table 7.7.3. Effects of stress on body systems

At one time, it was assumed that all types of stress reduced all aspects of the immune response, but the last few decades of research have painted a different picture. First, most short-term stress does not impair the immune system in healthy individuals enough to lead to a greater incidence of diseases. However, older individuals and those with suppressed immune responses due to disease or immunosuppressive drugs may respond even to short-term stressors by getting sicker more often. It has been found that short-term stress diverts the body’s resources towards enhancing innate immune responses, which have the ability to act fast and would seem to help the body prepare better for possible infections associated with the trauma that may result from a fight-or-flight exchange. The diverting of resources away from the adaptive immune response, however, causes its own share of problems in fighting disease.

Chronic stress, unlike short-term stress, may inhibit immune responses even in otherwise healthy adults. The suppression of both innate and adaptive immune responses is clearly associated with increases in some diseases, as seen when individuals lose a spouse or have other long-term stresses, such as taking care of a spouse with a fatal disease or dementia. The new science of psychoneuroimmunology, while still in its relative infancy, has great potential to make exciting advances in our understanding of how the nervous, endocrine, and immune systems have evolved together and communicate with each other.

Click the drop down below to review the terms learned from this chapter.

The major organs of the respiratory system function primarily to provide oxygen to body tissues for cellular respiration, remove the waste product carbon dioxide, and help to maintain acid-base balance. Portions of the respiratory system are also used for non-vital functions, such as sensing odours, speech production, and for straining, such as during childbirth or coughing (Figure 8.1.1).

Functionally, the respiratory system can be divided into a conducting zone and a respiratory zone. The conducting zone of the respiratory system includes the organs and structures not directly involved in gas exchange. The gas exchange occurs in the respiratory zone.

Conducting Zone

The major functions of the conducting zone are to provide a route for incoming and outgoing air, remove debris and pathogens from the incoming air, and warm and humidify the incoming air. Several structures within the conducting zone perform other functions as well. The epithelium of the nasal passages, for example, is essential to sensing odours, and the bronchial epithelium that lines the lungs can metabolise some airborne carcinogens.

The Nose and its Adjacent Structures

The major entrance and exit for the respiratory system is through the nose. When discussing the nose, it is helpful to divide it into two major sections: the external nose, and the nasal cavity or internal nose.

The external nose consists of the surface and skeletal structures that result in the outward appearance of the nose and contribute to its numerous functions (Figure 8.1.2). The root is the region of the nose located between the eyebrows. The bridge is the part of the nose that connects the root to the rest of the nose. The dorsum nasi is the length of the nose. The apex is the tip of the nose. On either side of the apex, the nostrils are formed by the alae (singular = ala). An ala is a cartilaginous structure that forms the lateral side of each naris (plural = nares), or nostril opening. The philtrum is the concave surface that connects the apex of the nose to the upper lip.

Underneath the thin skin of the nose are its skeletal features (see Figure 8.1.2, lower illustration). While the root and bridge of the nose consist of bone, the protruding portion of the nose is composed of cartilage. As a result, when looking at a skull, the nose is missing. The nasal bone is one of a pair of bones that lies under the root and bridge of the nose. The nasal bone articulates superiorly with the frontal bone and laterally with the maxillary bones. Septal cartilage is flexible hyaline cartilage connected to the nasal bone, forming the dorsum nasi. The alar cartilage consists of the apex of the nose; it surrounds the naris.

The nares open into the nasal cavity, which is separated into left and right sections by the nasal septum (Figure 8.1.3). The nasal septum is formed anteriorly by a portion of the septal cartilage (the flexible portion you can touch with your fingers) and posteriorly by the perpendicular plate of the ethmoid bone (a cranial bone located just posterior to the nasal bones) and the thin vomer bones (whose name refers to its plough shape). Each lateral wall of the nasal cavity has three bony projections, called the superior, middle, and inferior nasal conchae. The inferior conchae are separate bones, whereas the superior and middle conchae are portions of the ethmoid bone. Conchae serve to increase the surface area of the nasal cavity and to disrupt the flow of air as it enters the nose, causing air to bounce along the epithelium, where it is cleaned and warmed. The conchae and meatuses also conserve water and prevent dehydration of the nasal epithelium by trapping water during exhalation. The floor of the nasal cavity is composed of the palate. The hard palate at the anterior region of the nasal cavity is composed of bone. The soft palate at the posterior portion of the nasal cavity consists of muscle tissue. Air exits the nasal cavities via the internal nares and moves into the pharynx.

Several bones that help form the walls of the nasal cavity have air-containing spaces called the paranasal sinuses, which serve to warm and humidify incoming air. Sinuses are lined with a mucosa. Each paranasal sinus is named for its associated bone: frontal sinus, maxillary sinus, sphenoidal sinus, and ethmoidal sinus. The sinuses produce mucus and lighten the weight of the skull.

The nares and anterior portion of the nasal cavities are lined with mucous membranes, containing sebaceous glands and hair follicles that serve to prevent the passage of large debris, such as dirt, through the nasal cavity. An olfactory epithelium used to detect odours is found deeper in the nasal cavity.

The conchae, meatuses, and paranasal sinuses are lined by respiratory epithelium composed of pseudostratified ciliated columnar epithelium (Figure 8.1.4). The epithelium contains goblet cells, one of the specialised, columnar epithelial cells that produce mucus to trap debris. The cilia of the respiratory epithelium help remove the mucus and debris from the nasal cavity with a constant beating motion, sweeping materials towards the throat to be swallowed. Interestingly, cold air slows the movement of the cilia, resulting in accumulation of mucus that may in turn lead to a runny nose during cold weather. This moist epithelium functions to warm and humidify incoming air. Capillaries located just beneath the nasal epithelium warm the air by convection. Serous and mucus-producing cells also secrete the lysozyme enzyme and proteins called defensins, which have antibacterial properties. Immune cells that patrol the connective tissue deep to the respiratory epithelium provide additional protection.

Pharynx

The pharynx is a tube formed by skeletal muscle and lined by mucous membrane that is continuous with that of the nasal cavities (see Figure 8.1.3). The pharynx is divided into three major regions: the nasopharynx, the oropharynx and the laryngopharynx (Figure 8.1.5).

The nasopharynx is flanked by the conchae of the nasal cavity, and it serves only as an airway. At the top of the nasopharynx are the pharyngeal tonsils. A pharyngeal tonsil, also called an adenoid, is an aggregate of lymphoid reticular tissue similar to a lymph node that lies at the superior portion of the nasopharynx. The function of the pharyngeal tonsil is not well understood, but it contains a rich supply of lymphocytes and is covered with ciliated epithelium that traps and destroys invading pathogens that enter during inhalation. The pharyngeal tonsils are large in children, but interestingly, tend to regress with age and may even disappear. The uvula is a small bulbous, teardrop-shaped structure located at the apex of the soft palate. Both the uvula and soft palate move like a pendulum during swallowing, swinging upward to close off the nasopharynx to prevent ingested materials from entering the nasal cavity. In addition, auditory (Eustachian or pharyngotympanic) tubes that connect to each middle ear cavity open into the nasopharynx. This connection is why colds often lead to ear infections.

The oropharynx is a passageway for both air and food. The oropharynx is bordered superiorly by the nasopharynx and anteriorly by the oral cavity. The fauces is the opening at the connection between the oral cavity and the oropharynx. As the nasopharynx becomes the oropharynx, the epithelium changes from pseudostratified ciliated columnar epithelium to stratified squamous epithelium. The oropharynx contains two distinct sets of tonsils, the palatine and lingual tonsils. A palatine tonsil is one of a pair of structures located laterally in the oropharynx in the area of the fauces. The lingual tonsil is located at the base of the tongue. Similar to the pharyngeal tonsil, the palatine and lingual tonsils are composed of lymphoid tissue, and trap and destroy pathogens entering the body through the oral or nasal cavities.

The laryngopharynx is inferior to the oropharynx and posterior to the larynx. It continues the route for ingested material and air until its inferior end, where the digestive and respiratory systems diverge. The stratified squamous epithelium of the oropharynx is continuous with the laryngopharynx. Anteriorly, the laryngopharynx opens into the larynx, whereas posteriorly, it enters the oesophagus.

Larynx

The larynx is a cartilaginous structure inferior to the laryngopharynx that connects the pharynx to the trachea and helps regulate the volume of air that enters and leaves the lungs (Figure 8.1.6). The structure of the larynx is formed by several pieces of cartilage. Three large cartilage pieces—the thyroid cartilage (anterior), epiglottis (superior), and cricoid cartilage (inferior)—form the major structure of the larynx. The thyroid cartilage is the largest piece of cartilage that makes up the larynx. The thyroid cartilage consists of the laryngeal prominence, or “Adam’s apple,” which tends to be more prominent in males. The thick cricoid cartilage forms a ring, with a wide posterior region and a thinner anterior region. Three smaller, paired cartilages—the arytenoids, corniculates, and cuneiforms—attach to the epiglottis and the vocal cords and muscle that help move the vocal cords to produce speech.

The epiglottis, attached to the thyroid cartilage, is a very flexible piece of elastic cartilage that covers the opening of the trachea (see Figure 8.1.3). When in the “closed” position, the unattached end of the epiglottis rests on the glottis. The glottis is composed of the vestibular folds, the true vocal cords, and the space between these folds (Figure 8.1.7). A vestibular fold, or false vocal cord, is one of a pair of folded sections of mucous membrane. A true vocal cord is one of the white, membranous folds attached by muscle to the thyroid and arytenoid cartilages of the larynx on their outer edges. The inner edges of the true vocal cords are free, allowing oscillation to produce sound. The size of the membranous folds of the true vocal cords differs between individuals, producing voices with different pitch ranges. Folds in males tend to be larger than those in females, which create a deeper voice. The act of swallowing causes the pharynx and larynx to lift upward, allowing the pharynx to expand and the epiglottis of the larynx to swing downward, closing the opening to the trachea. These movements produce a larger area for food to pass through, while preventing food and beverages from entering the trachea.

Continuous with the laryngopharynx, the superior portion of the larynx is lined with stratified squamous epithelium, transitioning into pseudostratified ciliated columnar epithelium that contains goblet cells. Similar to the nasal cavity and nasopharynx, this specialised epithelium produces mucus to trap debris and pathogens as they enter the trachea. The cilia beat the mucus upward towards the laryngopharynx, where it can be swallowed down the oesophagus.

Trachea

The trachea (windpipe) extends from the larynx toward the lungs (Figure 8.1.8a). The trachea is formed by 16 to 20 stacked, C-shaped pieces of hyaline cartilage that are connected by dense connective tissue. The trachealis muscle and elastic connective tissue together form the fibroelastic membrane, a flexible membrane that closes the posterior surface of the trachea, connecting the C-shaped cartilages. The fibroelastic membrane allows the trachea to stretch and expand slightly during inhalation and exhalation, whereas the rings of cartilage provide structural support and prevent the trachea from collapsing. In addition, the trachealis muscle can be contracted to force air through the trachea during exhalation. The trachea is lined with pseudostratified ciliated columnar epithelium, which is continuous with the larynx. The oesophagus borders the trachea posteriorly.

Bronchial Tree

The trachea branches into the right and left primary bronchi at the carina. These bronchi are also lined by pseudostratified ciliated columnar epithelium containing mucus-producing goblet cells (Figure 8.1.8b). The carina is a raised structure that contains specialised nervous tissue that induces violent coughing if a foreign body, such as food, is present. Rings of cartilage, similar to those of the trachea, support the structure of the bronchi and prevent their collapse. The primary bronchi enter the lungs at the hilum, a concave region where blood vessels, lymphatic vessels, and nerves also enter the lungs. The bronchi continue to branch into bronchial a tree. A bronchial tree (or respiratory tree) is the collective term used for these multiple-branched bronchi. The main function of the bronchi, like other conducting zone structures, is to provide a passageway for air to move into and out of each lung. In addition, the mucous membrane traps debris and pathogens.

A bronchiole branches from the tertiary bronchi. Bronchioles, which are about 1 mm in diameter, further branch until they become the tiny terminal bronchioles, which lead to the structures of gas exchange. There are more than 1000 terminal bronchioles in each lung. The muscular walls of the bronchioles do not contain cartilage like those of the bronchi. This muscular wall can change the size of the tubing to increase or decrease airflow through the tube.

Respiratory Zone

In contrast to the conducting zone, the respiratory zone includes structures that are directly involved in gas exchange. The respiratory zone begins where the terminal bronchioles join a respiratory bronchiole, the smallest type of bronchiole (Figure 8.1.9), which then leads to an alveolar duct, opening into a cluster of alveoli.

Alveoli

An alveolar duct is a tube composed of smooth muscle and connective tissue, which opens into a cluster of alveoli. An alveolus is one of the many small, grape-like sacs that are attached to the alveolar ducts.

An alveolar sac is a cluster of many individual alveoli that are responsible for gas exchange. An alveolus is approximately 200 μm in diameter with elastic walls that allow the alveolus to stretch during air intake, which greatly increases the surface area available for gas exchange. Alveoli are connected to their neighbours by alveolar pores, which help maintain equal air pressure throughout the alveoli and lung (Figure 8.1.10).

The alveolar wall consists of three major cell types: type I alveolar cells, type II alveolar cells, and alveolar macrophages. A type I alveolar cell is a squamous epithelial cell of the alveoli, which constitute up to 97 percent of the alveolar surface area. These cells are about 25 nm thick and are highly permeable to gases. A type II alveolar cell is interspersed among the type I cells and secretes pulmonary surfactant, a substance composed of phospholipids and proteins that reduces the surface tension of the alveoli. Roaming around the alveolar wall is the alveolar macrophage, a phagocytic cell of the immune system that removes debris and pathogens that have reached the alveoli.

The simple squamous epithelium formed by type I alveolar cells is attached to a thin, elastic basement membrane. This epithelium is extremely thin and borders the endothelial membrane of capillaries. Taken together, the alveoli and capillary membranes form a respiratory membrane that is approximately 0.5 mm thick. The respiratory membrane allows gases to cross by simple diffusion, allowing oxygen to be picked up by the blood for transport and CO2 to be released into the air of the alveoli.

Diseases of the Respiratory System: Asthma

Asthma is common condition that affects the lungs in both adults and children. Almost 3 million Australians suffer from asthma (over 10% of the population). In United States 18.7 million adults (8.2%) and 7 million children (9.4%) suffer from asthma. In addition, asthma is the most frequent cause of hospitalisation in children.

Asthma is a chronic disease characterised by inflammation and oedema of the airway, and bronchospasms (that is, constriction of the bronchioles), which can inhibit air from entering the lungs. In addition, excessive mucus secretion can occur, which further contributes to airway occlusion (Figure 8.1.11). Cells of the immune system, such as eosinophils and mononuclear cells, may also be involved in infiltrating the walls of the bronchi and bronchioles. In 2016, a high pollen count mixed with meteorological conditions resulted in a thunderstorm-asthma event that resulted with over 3,500 people to be hospitalised in Melbourne, Australia.

Bronchospasms occur periodically and lead to an “asthma attack.” An attack may be triggered by environmental factors such as dust, pollen, pet hair, or dander, changes in the weather, mould, tobacco smoke, wood smoke, and respiratory infections, or by exercise and stress.

Symptoms of an asthma attack involve coughing, shortness of breath, wheezing, and tightness of the chest. Symptoms of a severe asthma attack that requires immediate medical attention would include difficulty breathing that results in blue (cyanotic) lips or face, confusion, drowsiness, a rapid pulse, sweating, and severe anxiety. The severity of the condition, frequency of attacks, and identified triggers influence the type of medication that an individual may require. Longer-term treatments are used for those with more severe asthma. Short-term, fast-acting drugs that are used to treat an asthma attack are typically administered via an inhaler. For young children or individuals who have difficulty using an inhaler, asthma medications can be administered via a nebuliser.

In many cases, the underlying cause of the condition is unknown. However, recent research has demonstrated that certain viruses, such as human rhinovirus C (HRVC), and the bacteria Mycoplasma pneumoniae and Chlamydia pneumoniae that are contracted in infancy or early childhood, may contribute to the development of many cases of asthma.

Click the drop down below to review the terms learned from this chapter.

A major organ of the respiratory system, each lung houses structures of both the conducting and respiratory zones. The main function of the lungs is to perform the exchange of oxygen and carbon dioxide with air from the atmosphere. To this end, the lungs exchange respiratory gases across a very large epithelial surface area—about 70 square metres—that is highly permeable to gases.

Gross Anatomy of the Lungs

The lungs are pyramid-shaped, paired organs that are connected to the trachea by the right and left bronchi; on the inferior surface, the lungs are bordered by the diaphragm. The diaphragm is the flat, dome-shaped muscle located at the base of the lungs and thoracic cavity. The lungs are enclosed by the pleurae, which are attached to the mediastinum. The right lung is shorter and wider than the left lung, and the left lung occupies a smaller volume than the right. The cardiac notch is an indentation on the surface of the left lung, and it allows space for the heart (Figure 8.2.1). The apex of the lung is the superior region, whereas the base is the opposite region near the diaphragm. The costal surface of the lung borders the ribs. The mediastinal surface faces the midline.

Each lung is composed of smaller units called lobes. Fissures separate these lobes from each other. The right lung consists of three lobes: the superior, middle, and inferior lobes. The left lung consists of two lobes: the superior and inferior lobes. A bronchopulmonary segment is a division of a lobe, and each lobe houses multiple bronchopulmonary segments. Each segment receives air from its own tertiary bronchus and is supplied with blood by its own artery. Some diseases of the lungs typically affect one or more bronchopulmonary segments, and in some cases, the diseased segments can be surgically removed with little influence on neighbouring segments. A pulmonary lobule is a subdivision formed as the bronchi branch into bronchioles. Each lobule receives its own large bronchiole that has multiple branches. An interlobular septum is a wall, composed of connective tissue, which separates lobules from one another.

Blood Supply and Nervous Innervation of the Lungs

The blood supply of the lungs plays an important role in gas exchange and serves as a transport system for gases throughout the body. In addition, innervation by the both the parasympathetic and sympathetic nervous systems provides an important level of control through dilation and constriction of the airway.

Blood Supply

The major function of the lungs is to perform gas exchange, which requires blood from the pulmonary circulation. This blood supply contains deoxygenated blood and travels to the lungs where erythrocytes, also known as red blood cells, pick up oxygen to be transported to tissues throughout the body. The pulmonary artery is an artery that arises from the pulmonary trunk and carries deoxygenated, arterial blood to the alveoli. The pulmonary artery branches multiple times as it follows the bronchi, and each branch becomes progressively smaller in diameter. One arteriole and an accompanying venule supply and drain one pulmonary lobule. As they near the alveoli, the pulmonary arteries become the pulmonary capillary network. The pulmonary capillary network consists of tiny vessels with very thin walls that lack smooth muscle fibres. The capillaries branch and follow the bronchioles and structure of the alveoli. It is at this point that the capillary wall meets the alveolar wall, creating the respiratory membrane. Once the blood is oxygenated, it drains from the alveoli by way of multiple pulmonary veins, which exit the lungs through the hilum.

Nervous Innervation

Dilation and constriction of the airway are achieved through nervous control by the parasympathetic and sympathetic nervous systems. The parasympathetic system causes bronchoconstriction, whereas the sympathetic nervous system stimulates bronchodilation. Reflexes such as coughing, and the ability of the lungs to regulate oxygen and carbon dioxide levels, also result from this autonomic nervous system control. Sensory nerve fibres arise from the vagus nerve, and from the second to fifth thoracic ganglia. The pulmonary plexus is a region on the lung root formed by the entrance of the nerves at the hilum. The nerves then follow the bronchi in the lungs and branch to innervate muscle fibres, glands, and blood vessels.

Pleurae of the Lungs

Each lung is enclosed within a cavity that is surrounded by the pleura. The pleura (plural = pleurae) is a serous membrane that surrounds the lung. The right and left pleurae, which enclose the right and left lungs, respectively, are separated by the mediastinum. The pleurae consist of two layers. The visceral pleura is the layer that is superficial to the lungs, and extends into and lines the lung fissures (Figure 8.2.2). In contrast, the parietal pleura is the outer layer that connects to the thoracic wall, the mediastinum, and the diaphragm. The visceral and parietal pleurae connect to each other at the hilum. The pleural cavity is the space between the visceral and parietal layers.

The pleurae perform two major functions: They produce pleural fluid and create cavities that separate the major organs. Pleural fluid is secreted by mesothelial cells from both pleural layers and acts to lubricate their surfaces. This lubrication reduces friction between the two layers to prevent trauma during breathing and creates surface tension that helps maintain the position of the lungs against the thoracic wall. This adhesive characteristic of the pleural fluid causes the lungs to enlarge when the thoracic wall expands during ventilation, allowing the lungs to fill with air. The pleurae also create a division between major organs that prevents interference due to the movement of the organs, while preventing the spread of infection.

Everyday Connection

The Effects of Second-Hand Tobacco Smoke

The burning of a tobacco cigarette creates multiple chemical compounds that are released through mainstream smoke, which is inhaled by the smoker, and through side stream smoke, which is the smoke that is given off by the burning cigarette. Second-hand smoke, which is a combination of side stream smoke and the mainstream smoke that is exhaled by the smoker, has been demonstrated by numerous scientific studies to cause disease. At least 40 chemicals in side stream smoke have been identified that negatively impact human health, leading to the development of cancer or other conditions, such as immune system dysfunction, liver toxicity, cardiac arrhythmias, pulmonary oedema, and neurological dysfunction. Furthermore, second-hand smoke has been found to harbor at least 250 compounds that are known to be toxic, carcinogenic, or both. Some major classes of carcinogens in second-hand smoke are polyaromatic hydrocarbons (PAHs), N-nitrosamines, aromatic amines, formaldehyde, and acetaldehyde.

Tobacco and second-hand smoke are considered to be carcinogenic. Exposure to second-hand smoke can cause lung cancer in individuals who are not tobacco users themselves. It is estimated that the risk of developing lung cancer is increased by up to 30 percent in non-smokers who live with an individual who smokes in the house, as compared to non-smokers who are not regularly exposed to second-hand smoke. Children are especially affected by second-hand smoke. Children who live with an individual who smokes inside the home have a larger number of lower respiratory infections, which are associated with hospitalisations, and higher risk of sudden infant death syndrome (SIDS). Second-hand smoke in the home has also been linked to a greater number of ear infections in children, as well as worsening symptoms of asthma.

Click the drop down below to review the terms learned from this chapter.

Pulmonary ventilation is the act of breathing, which can be described as the movement of air into and out of the lungs. The major mechanisms that drive pulmonary ventilation are atmospheric pressure (Patm); the air pressure within the alveoli, called alveolar pressure (Palv); and the pressure within the pleural cavity, called intrapleural pressure (Pip).

Mechanisms of Breathing

The alveolar and intrapleural pressures are dependent on certain physical features of the lung. However, the ability to breathe—to have air enter the lungs during inspiration and air leave the lungs during expiration—is dependent on the air pressure of the atmosphere and the air pressure within the lungs.

Pressure Relationships

Inspiration (or inhalation) and expiration (or exhalation) are dependent on the differences in pressure between the atmosphere and the lungs. In a gas, pressure is a force created by the movement of gas molecules that are confined. For example, a certain number of gas molecules in a two-litre container has more room than the same number of gas molecules in a one-litre container (Figure 8.3.1). In this case, the force exerted by the movement of the gas molecules against the walls of the two-litre container is lower than the force exerted by the gas molecules in the one-litre container. Therefore, the pressure is lower in the two-litre container and higher in the one-litre container. At a constant temperature, changing the volume occupied by the gas changes the pressure, as does changing the number of gas molecules. Boyle’s law describes the relationship between volume and pressure in a gas at a constant temperature. Boyle discovered that the pressure of a gas is inversely proportional to its volume: If volume increases, pressure decreases. Likewise, if volume decreases, pressure increases. Pressure and volume are inversely related (P = k/V). Therefore, the pressure in the one-litre container (one-half the volume of the two-litre container) would be twice the pressure in the two-litre container. Boyle’s law is expressed by the following formula:

P₁V₁ = P₂V₂

In this formula, P1 represents the initial pressure and V1 represents the initial volume, whereas the final pressure and volume are represented by P2 and V2, respectively. If the two- and one-litre containers were connected by a tube and the volume of one of the containers were changed, then the gases would move from higher pressure (lower volume) to lower pressure (higher volume).

Pulmonary ventilation is dependent on three types of pressure: atmospheric, intra-alveolar, and interpleural. Atmospheric pressure is the amount of force that is exerted by gases in the air surrounding any given surface, such as the body. Atmospheric pressure can be expressed in terms of the unit atmosphere, abbreviated atm, or in millimetres of mercury (mm Hg). One atm is equal to 760 mm Hg, which is the atmospheric pressure at sea level. Typically, for respiration, other pressure values are discussed in relation to atmospheric pressure. Therefore, negative pressure is pressure lower than the atmospheric pressure, whereas positive pressure is pressure that it is greater than the atmospheric pressure. A pressure that is equal to the atmospheric pressure is expressed as zero.

Intra-alveolar pressure is the pressure of the air within the alveoli, which changes during the different phases of breathing (Figure 8.3.2). Because the alveoli are connected to the atmosphere via the tubing of the airways (similar to the two- and one-litre containers in the example above), the interpulmonary pressure of the alveoli always equalises with the atmospheric pressure.

Intrapleural pressure is the pressure of the air within the pleural cavity, between the visceral and parietal pleurae. Similar to intra-alveolar pressure, intrapleural pressure also changes during the different phases of breathing. However, due to certain characteristics of the lungs, the intrapleural pressure is always lower than, or negative to, the intra-alveolar pressure (and therefore also to atmospheric pressure). Although it fluctuates during inspiration and expiration, intrapleural pressure remains approximately –4 mm Hg throughout the breathing cycle.

Competing forces within the thorax cause the formation of the negative intrapleural pressure. One of these forces relates to the elasticity of the lungs themselves—elastic tissue pulls the lungs inward, away from the thoracic wall. Surface tension of alveolar fluid, which is mostly water, also creates an inward pull of the lung tissue. This inward tension from the lungs is countered by opposing forces from the pleural fluid and thoracic wall. Surface tension within the pleural cavity pulls the lungs outward. Too much or too little pleural fluid would hinder the creation of the negative intrapleural pressure; therefore, the level must be closely monitored by the mesothelial cells and drained by the lymphatic system. Since the parietal pleura is attached to the thoracic wall, the natural elasticity of the chest wall opposes the inward pull of the lungs. Ultimately, the outward pull is slightly greater than the inward pull, creating the –4 mm Hg intrapleural pressure relative to the intra-alveolar pressure. Transpulmonary pressure is the difference between the intrapleural and intra-alveolar pressures, and it determines the size of the lungs. A higher transpulmonary pressure corresponds to a larger lung.

Physical Factors Affecting Ventilation

In addition to the differences in pressures, breathing is also dependent upon the contraction and relaxation of muscle fibres of both the diaphragm and thorax. The lungs themselves are passive during breathing, meaning they are not involved in creating the movement that helps inspiration and expiration. This is because of the adhesive nature of the pleural fluid, which allows the lungs to be pulled outward when the thoracic wall moves during inspiration. The recoil of the thoracic wall during expiration causes compression of the lungs. Contraction and relaxation of the diaphragm and intercostals muscles (found between the ribs) cause most of the pressure changes that result in inspiration and expiration. These muscle movements and subsequent pressure changes cause air to either rush in or be forced out of the lungs.

Other characteristics of the lungs influence the effort that must be expended to ventilate. Resistance is a force that slows motion, in this case, the flow of gases. The size of the airway is the primary factor affecting resistance. A small tubular diameter forces air through a smaller space, causing more collisions of air molecules with the walls of the airways. The following formula helps to describe the relationship between airway resistance and pressure changes:

F = ∆P / R

As noted earlier, there is surface tension within the alveoli caused by water present in the lining of the alveoli. This surface tension tends to inhibit expansion of the alveoli. However, pulmonary surfactant secreted by type II alveolar cells mixes with that water and helps reduce this surface tension. Without pulmonary surfactant, the alveoli would collapse during expiration.

Thoracic wall compliance is the ability of the thoracic wall to stretch while under pressure. This can also affect the effort expended in the process of breathing. In order for inspiration to occur, the thoracic cavity must expand. The expansion of the thoracic cavity directly influences the capacity of the lungs to expand. If the tissues of the thoracic wall are not very compliant, it will be difficult to expand the thorax to increase the size of the lungs.

Pulmonary Ventilation

The difference in pressures drives pulmonary ventilation because air flows down a pressure gradient, that is, air flows from an area of higher pressure to an area of lower pressure. Air flows into the lungs largely due to a difference in pressure; atmospheric pressure is greater than intra-alveolar pressure, and intra-alveolar pressure is greater than intrapleural pressure. Air flows out of the lungs during expiration based on the same principle; pressure within the lungs becomes greater than the atmospheric pressure.

Pulmonary ventilation comprises two major steps: inspiration and expiration. Inspiration is the process that causes air to enter the lungs, and expiration is the process that causes air to leave the lungs (Figure 8.3.3). A respiratory cycle is one sequence of inspiration and expiration. In general, two muscle groups are used during normal inspiration: the diaphragm and the external intercostal muscles. Additional muscles can be used if a bigger breath is required. When the diaphragm contracts, it moves inferiorly toward the abdominal cavity, creating a larger thoracic cavity and more space for the lungs. Contraction of the external intercostal muscles moves the ribs upward and outward, causing the rib cage to expand, which increases the volume of the thoracic cavity. Due to the adhesive force of the pleural fluid, the expansion of the thoracic cavity forces the lungs to stretch and expand as well. This increase in volume leads to a decrease in intra-alveolar pressure, creating a pressure lower than atmospheric pressure. As a result, a pressure gradient is created that drives air into the lungs.

The process of normal expiration is passive, meaning that energy is not required to push air out of the lungs. Instead, the elasticity of the lung tissue causes the lung to recoil, as the diaphragm and intercostal muscles relax following inspiration. In turn, the thoracic cavity and lungs decrease in volume, causing an increase in interpulmonary pressure. The interpulmonary pressure rises above atmospheric pressure, creating a pressure gradient that causes air to leave the lungs.

There are different types, or modes, of breathing that require a slightly different process to allow inspiration and expiration. Quiet breathing, also known as eupnoea, is a mode of breathing that occurs at rest and does not require the cognitive thought of the individual. During quiet breathing, the diaphragm and external intercostals must contract.

A deep breath, called diaphragmatic breathing, requires the diaphragm to contract. As the diaphragm relaxes, air passively leaves the lungs. A shallow breath, called costal breathing, requires contraction of the intercostal muscles. As the intercostal muscles relax, air passively leaves the lungs.

In contrast, forced breathing, also known as hyperpnea, is a mode of breathing that can occur during exercise or actions that require the active manipulation of breathing, such as singing. During forced breathing, inspiration and expiration both occur due to muscle contractions. In addition to the contraction of the diaphragm and intercostal muscles, other accessory muscles must also contract. During forced inspiration, muscles of the neck, including the scalenes, contract and lift the thoracic wall, increasing lung volume. During forced expiration, accessory muscles of the abdomen, including the obliques, contract, forcing abdominal organs upward against the diaphragm. This helps to push the diaphragm further into the thorax, pushing more air out. In addition, accessory muscles (primarily the internal intercostals) help to compress the rib cage, which also reduces the volume of the thoracic cavity.

Respiratory Volumes and Capacities

Respiratory volume is the term used for various volumes of air moved by or associated with the lungs at a given point in the respiratory cycle. There are four major types of respiratory volumes: tidal, residual, inspiratory reserve, and expiratory reserve (Figure 8.3.4). Tidal volume (TV) is the amount of air that normally enters the lungs during quiet breathing, which is about 500 millilitres. Expiratory reserve volume (ERV) is the amount of air you can forcefully exhale past a normal tidal expiration, up to 1,200 millilitres for men. Inspiratory reserve volume (IRV) is produced by a deep inhalation, past a tidal inspiration. This is the extra volume that can be brought into the lungs during a forced inspiration. Residual volume (RV) is the air left in the lungs if you exhale as much air as possible. The residual volume makes breathing easier by preventing the alveoli from collapsing. Respiratory volume is dependent on a variety of factors, and measuring the different types of respiratory volumes can provide important clues about a person’s respiratory health (Figure 8.3.5).

Respiratory capacity is the combination of two or more selected volumes, which further describes the amount of air in the lungs during a given time. For example, total lung capacity (TLC) is the sum of all of the lung volumes (TV, ERV, IRV, and RV), which represents the total amount of air a person can hold in the lungs after a forceful inhalation. TLC is about 6,000 mL air for men, and about 4,200 mL for women. Vital capacity (VC) is the amount of air a person can move into or out of his or her lungs and is the sum of all of the volumes except residual volume (TV, ERV, and IRV), which is between 4,000 and 5,000 millilitres. Inspiratory capacity (IC) is the maximum amount of air that can be inhaled past a normal tidal expiration, is the sum of the tidal volume and inspiratory reserve volume. On the other hand, the functional residual capacity (FRC) is the amount of air that remains in the lung after a normal tidal expiration; it is the sum of expiratory reserve volume and residual volume (see Figure 8.3.4).

In addition to the air that creates respiratory volumes, the respiratory system also contains anatomical dead space, which is air that is present in the airway that never reaches the alveoli and therefore never participates in gas exchange. Alveolar dead space involves air found within alveoli that are unable to function, such as those affected by disease or abnormal blood flow. Total dead space is the anatomical dead space and alveolar dead space together and represents all of the air in the respiratory system that is not being used in the gas exchange process.

Respiratory Rate and Control of Ventilation

Breathing usually occurs without thought, although at times you can consciously control it, such as when you swim under water, sing a song, or blow bubbles. The respiratory rate is the total number of breaths, or respiratory cycles, that occur each minute. Respiratory rate can be an important indicator of disease, as the rate may increase or decrease during an illness or in a disease condition. The respiratory rate is controlled by the respiratory centre located within the medulla oblongata in the brain, which responds primarily to changes in carbon dioxide, oxygen, and pH levels in the blood.

The normal respiratory rate of a child decreases from birth to adolescence. A child under 1 year of age has a normal respiratory rate between 30 and 60 breaths per minute, but by the time a child is about 10 years old, the normal rate is closer to 18 to 30. By adolescence, the normal respiratory rate is similar to that of adults, 12 to 18 breaths per minute.

Ventilation Control Centres

The control of ventilation is a complex interplay of multiple regions in the brain that signal the muscles used in pulmonary ventilation to contract (Table 8.3.1). The result is typically a rhythmic, consistent ventilation rate that provides the body with sufficient amounts of oxygen, while adequately removing carbon dioxide.

Table 8.3.1. Summary of ventilation regulation