Title: When Cells Fight Back: Acute Inflammation and Repair Mechanisms

Authors: Jina Kum (Author)
Licence: CC BY-NC-SA 4.0

Acute Inflammation & Repair Mechanisms

When Cells Fight Back:

ACUTE INFLAMMATION & REPAIR MECHANISMS

Image from the University of Leeds, https://www.virtualpathology.leeds.ac.uk/.

Funded by the Government of Ontario.
The views expressed in this publication are the views of the author(s) and do not necessarily reflect those of the Government of Ontario or the Ontario Online Learning Consortium.

Overview

Click the audio button for narration.

OVERVIEW

Case Study #1: Acute Inflammation

- Vascular & Cellular Events
- Inflammatory Cells
- Chemical Mediators
- Outcomes of Acute Inflammation

Case Study #2: Tissue Repair

- Regeneration
- First vs Second Intention Healing
- Rate of Wound Healing

Scenario

You are a fourth-year kinesiology student eager to learn about athletic injuries.

You will be supervised by Dr. Rodriguez, an experienced sports medicine physician, who will help walk you through cases of various patients visiting the clinic.

Case Study #1

Your first patient is Emily, a 21-year-old college athlete. She comes to the clinic after sustaining a knee injury during a soccer match last night.

Acute Inflammation - Vascular Events

Acute Inflammation

1. VASCULAR EVENTS

Dr. Rodriguez examines Emily’s knee and observes signs of redness and swelling. She explains how these signs reflect the processes of vasodilation (the widening of blood vessels to increase blood flow) and increased vascular permeability (making blood vessels more porous to small molecules and whole cells), respectively.

These vascular events are crucial for bringing immune cells and nutrients to the injured knee. She explains how inflammation is the body’s response to injury and proceeds the same way regardless of the source of injury (e.g., infection, trauma, and metabolic injury).

Figure 1: The swelling of the right knee. This swelling of Emily's knee is indicative of an ongoing inflammatory response.
Figure from Hahn YS, Kim JG. Pathogenesis and clinical manifestations of juvenile rheumatoid arthritis. Korean J Pediatr. 2010 Nov;53(11):921-30. doi: 10.3345/kjp.2010.53.11.921. PMID: 21218013.

Acute Inflammation - Cellular Events

Acute Inflammation

You learn that an essential feature of inflammation is the accumulation of leukocytes (white blood cells) at the site of injury. This process involves multiple cellular events.

2. CELLULAR EVENTS

i. Margination and Rolling: Vascular permeability causes blood to become viscous, which pushes white blood cells (WBCs) to the periphery of the vasculature. WBCs roll and transiently stick to the endothelium via selectin molecules.

Acute Inflammation - Cellular Events (continued)

Acute Inflammation

2. CELLULAR EVENTS (continued)

ii. Adhesion: WBCs adhere firmly to the endothelium via integrins expressed on their cell surface.

iii. Transmigration: WBCs squeeze between endothelial cells and pass through the basement membrane to enter tissue.

Acute Inflammation - Cellular Events (continued)

Acute Inflammation

2. CELLULAR EVENTS (continued)

iv. Chemotaxis: WBCs migrate towards the site of injury, attracted by a chemical (chemokine) gradient.

v. Activation and Phagocytosis: Receptors on WBCs recognize offending agents (e.g., necrotic tissue), which induce intracellular signalling pathways leading to their activation and production of chemical mediators of inflammation (e.g., TNF, IL-1, leukotrienes, and chemokines). WBCs then engulf and degrade offending agents.

Inflammatory Cells

Dr. Rodriguez shows you a peripheral blood smear to help you identify key immune cells involved in inflammation. Click on the buttons to learn more about each cell type.

Identifying Blood Cells MCQ

Q: Which cell type is indicated by the orange question mark icon?
- A. Neutrophil (correct)
- B. Lymphocyte
- C. Monocyte
- D. Red blood cell

Monocyte: The largest white blood cell in the blood. Monocytes differentiate into macrophages, which are effector cells in chronic inflammation, working alongside lymphocytes.

?

Neutrophil: The predominant effector cell involved in acute inflammation. Acute inflammation is characterized by a short duration (minutes to days post-injury) and tissue infiltration by neutrophils. You can identify neutrophils by their multilobular nuclei.

Lymphocyte (e.g., T or B cell): One of the predominant effector cells involved in chronic inflammation. Chronic inflammation is characterized by longer duration and tissue infiltration by lymphocytes and macrophages. Note the small, round, and condensed appearance of lymphocytes and their nuclei compared to those of other WBCs.

Figure 2: Peripheral blood smear showing the various cells present in the blood.
Image from the University of Leeds, https://www.virtualpathology.leeds.ac.uk/.

Chemical Mediators

A blood test reveals elevated levels of inflammatory markers. Dr. Rodriguez discusses the role of chemical mediators, such as histamines and prostaglandins, in amplifying the inflammatory response.

They are responsible for inducing hallmarks of inflammation, such as vasodilation, vascular permeability, fever, and pain.

Outcomes of Acute Inflammation

Dr. Rodriguez explains that there are three possible outcomes following acute inflammation:

- Complete resolution
- Healing by connective tissue replacement
- Progression to chronic inflammation

Luckily for Emily, her knee is not severely injured and will likely undergo complete resolution. Dr. Rodriguez advises Emily to keep her knee on ice to bring down the swelling, rest well, and take ibuprofen (an anti-inflammatory drug, which blocks the production of prostaglandins that mediates pain) if she experiences excessive pain.

Knowledge Check

Acute Inflammation MCQ

Q: Why is vasodilation important in acute inflammation?
- A. To decrease blood flow to the affected area
- B. To increase blood flow to the affected area (correct) (The answer is B: to increase blood flow to the affected area. Vasodilation increases blood flow, ensuring a swift delivery of immune cells and nutrients to the inflamed area, promoting healing. Note: Vascular permeability allows immune cells to leave the bloodstream and migrate to the affected tissue.) (if not chosen: The answer is B: to increase blood flow to the affected area. Vasodilation increases blood flow, ensuring a swift delivery of immune cells and nutrients to the inflamed area, promoting healing. Note: Vascular permeability allows immune cells to leave the bloodstream and migrate to the affected tissue.)
- C. To inhibit the release of chemical mediators
- D. To prevent immune cell migration
- E. To allow immune cells to leave the bloodstream

Check Your Understanding

Consider the following question. Once you have an answer, click the "Turn" button below to check your understanding.

Reducing Swelling in Inflammation

Q: How does keeping Emily’s knee on ice limit the swelling induced by inflammation?
A: Ice will reduce swelling in Emily's injured knee by constricting the blood vessels and decreasing blood flow to the affected area. As a result, less fluid will leak out from the intravascular compartment into the interstitial space to cause swelling. Recall that a hallmark of inflammation is fever or heat at the affected area. This prolongs the dilation (widening) of blood vessels and perpetuates the inflammatory response. Applying cold to the affected area induces the opposite, providing relief.

Case Study #2

Your second patient is Christopher, a 20-year-old hockey player, who sustained a painful scrape on his cheek during a recent game.

Christopher is worried about how long the wound will take to heal because it is noticeable to others. He is also concerned about whether a large scar will remain.

Dr. Rodriguez explains that several factors influence the rate of cutaneous wound healing and how tissue repair might occur.

Photo by cottonbro studio (Pexels, a Canva Germany GmbH).

Tissue Repair

Dr. Rodriguez explains that tissue repair can occur by two types of reactions:

- Regeneration: The cells replacing the injured tissue are identical to those lost. Uninjured remaining cells proliferate, or tissue stem cells differentiate to allow regeneration to occur.
- Connective tissue deposition with scar formation: The cells replacing the injured tissue are different from those lost. This occurs by laying down connective tissue, and results in scarring.

Note: Oftentimes, both regeneration and connective tissue deposition (scar formation) work together to repair tissue.

Regeneration

Whether healing can occur by regeneration depends on two factors:

1. The proliferative potential of the injured cell type
  - Labile cells: Proliferate throughout life (e.g., epidermis and blood cells)
  - Stable cells: Low physiological levels of replication, but could be stimulated to divide (e.g., epithelia of most parenchymal organs, such as the liver and kidney)
  - Permanent cells: Cannot divide after birth (e.g., cardiac muscle)
    - Thus, regeneration is NOT possible, and healing must occur by scarring
2. Whether the extracellular matrix (ECM) has been damaged
  - If the ECM has been damaged, a new scaffold must be formed by scarring (regardless of the proliferative potential of the injured cell type). The newly formed ECM will never acquire 100% of its original strength.

1st vs 2nd Intention Healing

VS

1ST INTENTION HEALING

2ND INTENTION HEALING

- Occurs in cutaneous wounds with significant tissue loss (large gap to fill)
- Granulation tissue forms (a meshwork of capillaries, fibroblasts and inflammatory cells) by day 3-5 post-injury

- Occurs when the edges of a cutaneous wound are in close proximity (minimizing the gap to be filled)
- Healing occurs rapidly with minimal scarring

- Healing occurs slowly with scarring

Conclusions

Fortunately for Christopher, several factors apply to his case which increase the rate of cutaneous wound healing:

- Younger people's wounds tend to heal faster than older people.
- Our faces are well-vascularized (increased blood flow at site of injury to optimize healing).
- Skin epithelial cells proliferate throughout life (i.e., they are labile).
- The wound edges are well-approximated (enables 1st intention rapid healing).

To promote healing further, Dr. Rodriguez advises Christopher to:

- Irrigate (wash) and protect his wound from infection.
- Avoid tight dressings, which might reduce blood supply to the wound.
- Immobilize his site of injury as much as possible.

Photo by cottonbro studio (Pexels, a Canva Germany GmbH).

Knowledge Check

Regeneration MCQ

Q: Which of the following injuries would NOT be able to heal by regeneration?
- A. Nerve cells in the spinal cord after a motor vehicle collision
- B. Myocardial tissue after a myocardial infarction
- C. A skinned knee after falling off a bicycle
- D. Hepatocytes after a Hepatitis A infection
- E. A and B (correct) (The answer is A and B because nerve cells and and myocardial cells are both permanent cells, which means they can no longer divide (i.e., regenerate). Thus, healing can only occur by scar formation. Epithelial cells in the epidermis of the knee are labile cells, and hepatocytes (liver cells) are stable cells, which both have a capacity to regenerate.) (if not chosen: The answer is A and B because nerve cells and and myocardial cells are both permanent cells, which means they can no longer divide (i.e., regenerate). Thus, healing can only occur by scar formation. Epithelial cells in the epidermis of the knee are labile cells, and hepatocytes (liver cells) are stable cells, which both have a capacity to regenerate.)

Knowledge Check

Rate of Wound Healing MCQ

Q: Which of the following factors would delay the healing of Christopher’s wound?
- A. Excessive yawning (correct) (The answer is A, excessive yawning, because since Christopher's wound lies on his cheek, yawning could impose mechanical stress and stretch the wound, thus delaying healing time. Covering the wound lightly (not too tightly) with a bandage would protect against infection and preserve blood supply to optimize healing. Irrigating the wound with water in the shower could also optimize healing and protect against infection. Applying cold/hot as appropriate could also alleviate pain, swelling, and facilitate healing.) (if not chosen: The answer is A, excessive yawning, because since Christopher's wound lies on his cheek, yawning could impose mechanical stress and stretch the wound, thus delaying healing time. Covering the wound lightly (not too tightly) with a bandage would protect against infection and preserve blood supply to optimize healing. Irrigating the wound with water in the shower could also optimize healing and protect against infection. Applying cold/hot as appropriate could also alleviate pain, swelling, and facilitate healing.)
- B. Lightly covering the wound with a bandage
- C. Rinsing the wound daily in the shower
- D. Applying thermal modification (ice/warm compress)
- E. None of the above