Acute Inflammation

Question 1

[15-minute video]: Inflammation Part 1: General concepts, types and vascular changes in Acute Inflammation

Answer 1

🔥

Question 2

[12-minute video]: Inflammation Part 2: Cellular Events - Leukocyte Recruitment

Answer 2

🔥

Question 3

[14-minute video]: Inflammation Part 3: Leukocyte Activation - PHAGOCYTOSIS

Answer 3

🔥

Question 4

[10-minute video]: Inflammation Part 7: Morphology & Outcomes of Acute Inflammation

Answer 4

🔥

Question 5

[1-minute video]: Neutrophil Chemotaxis

[4-minute video]: Human neutrophil versus Coccidioides (cause of Valley fever): Chemotaxis, adhesion, and phagocytosis

Answer 5

🔥

Question 6

Define inflammation.

Answer 6

Inflammation is the body’s natural response to injury or infection, characterized by redness, heat, swelling, pain, and loss of function.

Question 7

What are two tissue level types of changes that occur in acute inflammation?

Answer 7

(a) Vascular changes: vasodilation, vascular leakage and activation of endothelial cells
(b) Cellular changes: leukocyte emigration

Question 8

What are the five cardinal signs of inflammation?

Answer 8

(1) Rubor (Redness): This occurs due to increased blood flow to the affected area.
(2) Tumor (Swelling): Swelling, or edema, results from the exudation of fluid from blood vessels into the surrounding tissues.
(3) Calor (Heat): The heat associated with inflammation is also due to increased blood flow to the affected area. Additionally, the release of inflammatory mediators, such as cytokines and prostaglandins, can raise the local temperature.
(4) Dolor (Pain): Pain during inflammation is caused by the stretching of pain receptors and nerves due to the inflammatory exudates.
(5) Functio laesa (Loss of Function): The loss of function in inflamed tissues can result from several factors, including pain, which limits movement, and the disruption of tissue structure.
[Diagram]

Question 9

Discuss three vascular changes associated with inflammation.

Answer 9

(1) Transient vasoconstriction: This initial response lasts only a few seconds and involves the narrowing of blood vessels. It is a brief phase that precedes the more prolonged vasodilation.
(2) Vasodilation of arterioles: Histamine and other vasodilators like nitric oxide cause the arterioles to widen, resulting in increased blood flow to the affected area [= redness + heat]. The increased hydrostatic pressure within the blood vessels causes protein-poor fluid (exudate) to seep into the interstitial space, contributing to swelling.
(3) Reduced blood flow: As fluid moves out of the blood vessels into the interstitial tissue, the hydrostatic pressure within the vessels decreases. This fluid loss increases the concentration of red blood cells (RBCs) in the blood, making it more viscous.

Question 10

Discuss the mechanisms of vascular leakage during inflammation.

Answer 10

(1) Endothelial cell contraction
🔥 Binding of histamine, kinins, and leukotrienes to specific receptors on endothelial cells causes them to contract, creating intercellular gaps in postcapillary venules [lasts for about 15 - 30 minutes].
🔥 Cell retraction then follows. This involves the reorganization of the cytoskeleton within endothelial cells, leading to a more prolonged separation of the cells. It is mediated by cytokines such as TNF and IL-1.
🔥 This response is slower, taking several hours (up to 4-6 hours) to develop and can last for 24 hours or more. It facilitates sustained leakage of fluid and proteins, supporting the prolonged phase of inflammation.

(2) Severe endothelial injury
🔥 This results from leukocyte-mediated damage or thermal injury, leading to endothelial cell necrosis and detachment, which causes vascular leakage.

(3) Increased transcytosis of proteins
🔥 This is mediated by VEGF (vascular endothelial growth factor). It involves the uptake of proteins from the luminal side of the endothelial cell into vesicles, which then travel across the cell and release their contents on the basement membrane side.
🔥 In this way, VEGF increases the permeability of blood vessels, allowing more proteins and other molecules to pass through the endothelial barrier.

(4) Leakage from new blood vessels
🔥 Newly formed vessels during inflammation lack tight junctions, making them more permeable and prone to leakage.

Question 11

Briefly discuss the role of lymphatics in inflammation.

Answer 11

🔥 Increased lymph flow helps drain edematous fluid, leukocytes, and cell debris from the extravascular space.
🔥 The lymphatic system can transport pathogens, toxins, or other offending agents away from the site of inflammation. However, this can sometimes lead to secondary inflammation of the lymphatic vessels (lymphangitis) or the draining lymph nodes (lymphadenitis).

Question 12

What is inflammatory lymphadenitis?

Answer 12

This condition is characterized by swollen and tender lymph nodes. It occurs due to hyperplasia of lymphoid follicles and the accumulation of lymphocytes and phagocytic cells lining the sinuses of the lymph nodes.

Question 13

List the steps in leukocyte recruitment.

Answer 13

(1) Margination and rolling along the vessel wall
(2) Firm adhesion to the endothelium
(3) Transmigration between endothelial cells
(4) Migration to interstitial tissues toward a chemotactic stimulus

[Short video 1]: Leukocyte recruitment timelapse
[Short video 2]: Leukocyte recruitment timelapse
[2-minute video]: Leukocyte rolling

Question 14

Discuss margination and rolling in leukocyte recruitment.

Answer 14

🔥 With increased vascular permeability, fluid leaves the vessel causing leukocytes to settle-out of the central flow column and “marginate” along the endothelial surface. This happens as RBCs form rouleaux.
🔥 Activated endothelial cells and leukocytes have complementary surface adhesion molecules which briefly stick and release causing the leukocyte to roll along the endothelium like a tumbleweed until it eventually comes to a stop as mutual adhesion reaches a peak.
🔥 After margination, activated endothelial cells express P selectins which hook onto leukocyte’s sialylated oligosaccharides (e.g., sialyl-Lewis X).
🔥 E-selectin and the ligand for L-selectin, which are not expressed on normal endothelium, are induced after stimulation by the cytokines IL-1 and TNF.

Question 15

Discuss firm adhesion in leukocyte recruitment.

Answer 15

🔥 Rolling comes to a stop and then adhesion results.
🔥 Other sets of adhesion molecules participate:
◾ Endothelial: ICAM [Intercellular Adhesion Molecule], VCAM-1 [Vascular Cell Adhesion Molecule 1] (activation mediated by IL-1 and TNF)
◾ Leukocytes: LFA-1 [Lymphocyte Function-Associated Antigen 1], Mac-1 [Macrophage-1 Antigen], VLA-4 [Very Late Antigen-4]
◾ (ICAM-1 binds LFA-1/Mac-1, VCAM-1 binds VLA-4)
🔥 Under normal conditions, integrins on leukocytes are in a low-affinity, inactive conformation.
🔥 During inflammation, chemokines and other signaling molecules activate integrins, causing a conformational change that increases their affinity for their ligands. This activation allows for strong binding and firm adhesion to the endothelium.

Further notes:
LFA-1, Mac-1 and VLA-4 are collectively called integrins.

Question 16

Discuss transmigration in leukocyte recruitment.

Answer 16

🔥 Transmigration/diapedesis occurs after firm adhesion.
🔥 Neutrophils, a type of leukocyte, migrate through the vessel wall by squeezing between endothelial cells at intercellular junctions.
🔥 Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1), also known as CD31, is a key molecule involved in transmigration. It is expressed on both endothelial cells and leukocytes and facilitates the passage of leukocytes through the endothelial layer.
🔥 After passing through the endothelial layer, leukocytes secrete enzymes called collagenases. These enzymes break down the collagen in the vascular basement membrane, allowing leukocytes to penetrate deeper into the tissue.
🔥 Early on during inflammation, transmigration involves neutrophils but later monocytes and lymphocytes join.

Question 17

Discuss chemotaxis and activation in leukocyte recruitment.

Answer 17

🔥 Chemotaxis is the directed movement of leukocytes towards the site of infection or injury in response to chemical signals (chemoattractants).
🔥 Leukocytes extend pseudopods, which are temporary, arm-like projections of the cell membrane. These pseudopods contain surface adhesion molecules called integrins that bind to the extracellular matrix and guide the leukocyte towards the source of the chemoattractants.
🔥 Upon reaching the site of inflammation, leukocytes undergo activation, which prepares them to effectively combat pathogens and facilitate tissue repair. Activation involves:
(a) preparation of arachidonic acid (AA) metabolites: Leukocytes convert phospholipids in their cell membranes into arachidonic acid metabolites, such as leukotrienes and prostaglandins. These metabolites play crucial roles in mediating inflammation and immune responses.
(b) preparation for degranulation and release of lysosomal enzymes
(c) regulation of adhesion molecule affinity: for stable adhesion and effective migration to the site of inflammation.

Question 18

After leukocyte recruitment, phagocytosis of invading pathogens occurs. Discuss the mechanism of phagocytosis.

Answer 18

It occurs in several steps:

(1) Opsonization: pathogens are marked for destruction by phagocytes. This marking is done by opsonins, which are molecules like antibodies or complement proteins that bind to the surface of the pathogen.

(2) Recognition and attachment: The opsonized pathogen is recognized and attached to the phagocyte through receptors on the phagocyte’s surface that bind to the opsonins.

(3) Ingestion: Once attached, the phagocyte extends its membrane around the pathogen, engulfing it and forming a phagosome. The phagosome then fuses with a lysosome, and this fusion creates a phagolysosome.

(4) Killing and degradation: Inside the phagolysosome, the pathogen is exposed to a hostile environment, including ROS and hydrolytic enzymes which kill and degrade the pathogen.

[Diagram]

Question 19

Discuss the oxygen dependent myeloperoxidase (MPO) system as a mechanism in bacterial killing.

Answer 19

🔥 The MPO system is primarily found in neutrophils and monocytes. [It is one of the most potent microbicidal mechanisms in the immune response.]
🔥 NADPH oxidase, a key component of MPO, reduces molecular oxygen to superoxide (O₂⁻), a reactive oxygen species. This reaction releases energy in the form of an oxidative burst, which is essential for the destruction of pathogens.
🔥 Superoxide is then converted to hydrogen peroxide (H₂O₂) by superoxide dismutase. Some peroxide is converted to hydroxyl free radicals by iron.
🔥 MPO then combines hydrogen peroxide (H₂O₂) with chloride ions to produce hypochlorous acid (HOCl). HOCl is a powerful antimicrobial agent. It is often referred to as “bleach”.
🔥 [Diagram]

Question 20

With regards to bacterial killing, briefly discuss the oxygen independent system.

Answer 20

The oxygen-independent system relies on various antimicrobial substances stored in the granules of leukocytes. Here are some key components of the system:

(1) Lactoferrin: this protein binds iron, thus inhibiting bacterial growth and reproduction.

(2) Bactericidal Permeability Increasing protein (BPI): this is a protein that binds to the outer membrane of Gram-negative bacteria. It increases the permeability of the bacterial membrane, leading to the leakage of cellular contents and ultimately bacterial death.

(3) Lysozyme: this is an enzyme that breaks down the peptidoglycan layer of bacterial cell walls, particularly in Gram-positive bacteria. This enzymatic activity weakens the cell wall, causing the bacteria to lyse and die.

(4) Defensins: these are small peptides that can insert themselves into bacterial membranes, creating pores or holes, leading to the leakage of cellular contents and bacterial death. [Diagram]

Question 21

List three types of defects in leukocyte function.

Answer 21

(a) Defects of adhesion
(b) Defects of chemotaxis/phagocytosis
(c) Defects of microbicidal activity

Question 22

Discuss defects of leukocyte adhesion. [Hint: LAD-1, LAD-2]

Answer 22

(1) Leukocyte Adhesion Deficiency Type 1 (LAD-1):
Cause: Defects in the subunits of integrins LFA-1 (Lymphocyte Function-Associated Antigen 1) and Mac-1 (Macrophage-1 Antigen).
Effect: Impaired adhesion of leukocytes to the endothelium, leading to reduced migration to sites of infection or injury.

(2) Leukocyte Adhesion Deficiency Type 2 (LAD-2):
Cause: Absence of sialyl-Lewis X, a carbohydrate structure on leukocytes, and defects in E- and P-selectin sugar epitopes.
Effect: Impaired rolling and adhesion of leukocytes, leading to similar issues as LAD-1.

Question 23

How long do chemical mediators typically last?

Answer 23

Chemical mediators typically have short half-lives, lasting from seconds to minutes. This means they act quickly and are rapidly degraded or inactivated.

Question 24

What are some of the diverse functions of chemical mediators?

Answer 24

(a) Inflammation: Mediators like histamine and prostaglandins play a key role in the inflammatory response.

(b) Vasodilation and Vasoconstriction: Some mediators cause blood vessels to dilate (widen) or constrict (narrow), affecting blood flow and pressure.

(c) Pain and Fever: Prostaglandins are involved in the sensation of pain and the development of fever.

(d) Immune Response: Cytokines and chemokines are mediators that regulate the immune response, including the activation and recruitment of immune cells.

(e) Tissue Repair: Growth factors are mediators that promote tissue repair and regeneration.

Question 25

List 5 types of acute inflammation.

Answer 25

(1) Suppurative (purulent) inflammation
(2) Fibrinous inflammation
(3) Serous inflammation
(4) Hemorrhagic inflammation
(5) Catarrhal inflammation

Question 26

Briefly discuss suppurative (purulent) inflammation.

Answer 26

Suppurative inflammation is characterized by the production of pus, which consists of neutrophils, necrotic cells, and edema fluid. It often leads to abscess formation.

Question 27

What is an abscess and what causes it?

Answer 27

An abscess is a focal collection of pus that can be caused by the seeding of pyogenic (pus-forming) organisms into a tissue or by secondary infections of necrotic foci (areas of dead tissue).

Further notes:
[8-minute video]: Abscesses - causes, symptoms, diagnosis, treatment, pathology

Question 28

What is the typical structure of an abscess?

Answer 28

An abscess typically has a central region that is largely necrotic, surrounded by a layer of preserved neutrophils, and encircled by a zone of dilated blood vessels and fibroblast proliferation, indicating an attempt at repair.
[Diagram 1] [Diagram 2]

Question 29

What is the usual outcome of abscess formation?

Answer 29

The usual outcome of abscess formation is scarring, as the body heals the affected area.

Question 30

Briefly discuss fibrinous inflammation.

Answer 30

Fibrinous inflammation occurs due to more severe injuries that result in increased vascular permeability, allowing large molecules such as fibrinogen to pass through the endothelial barrier into the extravascular space. Once fibrinogen escapes into the extravascular space, it is converted to fibrin, which forms a meshwork.
[Image 1] [Image 2] [Image 3] [Image 4]

Question 31

What is the histological appearance of fibrinous inflammation and where does it commonly occur?

Answer 31

Histologically, the accumulated extravascular fibrin appears as as eosinophilic meshwork of threads or sometimes as an amorphous coagulum. Fibrinous inflammation commonly occurs on teh serosal linings of the pericardium, peritoneoum, or pleura.
[Image 1] [Image 2] [Image 3] [Image 4]

Question 32

Briefly discuss serous inflammation.

Answer 32

This is a type of inflammation characterized by the production of a serum-like exudate. This exudate is typically clear and watery, resembling serum, and is derived from either increased capillary permeability or active secretion by cells lining body cavities.

Serous inflammation often occurs in response to mild injuries or irritants. It can be seen in conditions such as viral infections, burns, and allergic reactions.

[Image]

Question 33

What is the histological appearance of serous inflammation?

Answer 33

Histologically, the accumulated extravascular fluid appears as an eosinophilic (pink-staining) meshwork of threads or sometimes as an amorphous coagulum. This fluid is rich in proteins but contains few cells.
[Image]

Question 34

Where does serous inflammation commonly occur?

Answer 34

Serous inflammation commonly occurs on the serosal linings of body cavities, such as the pericardium (heart lining), pleura (lung lining), and peritoneum (abdominal lining). It can also be seen in the skin, where it manifests as blisters in response to burns or viral infections.

Further notes:
If inflammation persists, it can progress to more severe forms of inflammation, such as fibrinous or purulent inflammation.

Question 35

Give a brief description of each of the following types of inflammation.
(a) Hemorrhagic inflammation
(b) Catarrhal inflammation

Answer 35

(a) Hemorrhagic inflammation: This type of inflammation is characterized by the presence of significant amount of red blood cells in the inflammatory exudate. It often occurs in severe infections or conditions where there is extensive tissue damage, leading to the rupture of blood vessels and bleeding into the affected area.

(b) Catarrhal inflammation: This type of inflammation is marked by the production of a large amount of mucus. It typically affects mucous membranes, such as those in the respiratory or gastrointestinal tracts. Common causes include viral infections, allergies, and irritants.

Question 36

List factors involved in the termination of inflammation.

Answer 36

(1) Short half-life of inflammatory mediators
(2) Lipoxins
(3) Resolvins
(4) Clearance of neutrophils by apoptosis

Question 37

What are lipoxins and resolvins and what is their role in the termination of inflammation.

Answer 37

Lipoxins are anti-inflammatory mediators derived from arachidonic acid metabolites.
Resolvins are synthesized from omega-3 fatty acids.

These two pro-resolving mediators act by:
(1) inhibition of inflammatory cell activity
(2) promotion of clearance and resolution

Question 38

Briefly discuss consequences of acute inflammation.

Answer 38

(1) Complete resolution: occurs when injury is mild and the affected cells can regenerate.

(2) Tissue destruction and scar formation: when the injury is extensive or affects permanent cells (such as neurons or cardiac muscle cells), the tissue cannot regenerate, leading to tissue destruction and scar formation.

(3) Formation of abscesses

(4) Progression to chronic inflammation: occurs if the acute inflammatory response fails to eliminate the cause of injury or infection