Infection and the inflammatory response

Question 1

What are the key signs of inflammation?

Answer 1

1. Redness
2. Swelling
3. Heat
4. Pain
5. Loss of function

Question 2

Describe the key steps and cells involved in initiating inflammation.

Answer 2

1. Breach of barrier and infiltration by microbes.
2. Small blood vessels adjacent to the injury dilate (vasodilatation) and blood flow to the area increases.
3. The endothelial cells initially swell, then contract to increase the space between them, thereby increasing the permeability of the vascular barrier (regulated by chemical mediators).
4. Exudation of fluid leads to a net loss of fluid from the vascular space into the interstitial space, resulting in oedema. This allows inflammatory proteins to migrate through. It may also help to remove pathogens and cell debris in the area through lymphatic drainage.
5. Neutrophils are attracted to the site of injury by the presence of chemotaxins, the mediators released into the blood immediately after the insult.

Question 2

Describe the key steps and cells involved in initiating inflammation.

Answer 2

1. Release of inflammatory mediators:
   -Recognition of DAMPs and PAMPs by tissue resident innate immune cells (Macrophages & Dendritic Cells).
   - Release of inflammatory mediators (cytokines, chemokine, prostaglandins and leukotrienes)
2. Vasodilation:
   - Small blood vessels adjacent to the injury dilate (vasodilatation) and blood flow to the area increases.
3. Permeability:
   - The endothelial cells initially swell, then contract to increase the space between them, thereby increasing the permeability of the vascular barrier (regulated by chemical mediators).
4. Exudation of fluid:
   - Leads to a net loss of fluid from the vascular space into the interstitial space, resulting in oedema. This allows inflammatory proteins to migrate through.
   -It may also help to remove pathogens and cell debris in the area through lymphatic drainage.
5. Cell adhesion:
   - Endothelial cells activated and increase in cell adhesion molecules promotes binding of circulating immune cells (‘rolling’)
6. Extravasation:
   - Upon microbe detection, macrophages release cytokines (IL-1, TNF) and chemokine (IL-8)
   - Neutrophils are attracted to the site of injury by the presence of chemotaxins, the mediators released into the blood immediately after the insult.
   - Monocytes follow (slower).
7. Activation of neutrophils.
8. Activation and differentiation of monocytes.
9. Activation of mast cells (histamine release).

Question 3

What is extravasation?

Answer 3

1. Upon microbe detection, macrophages release cytokines (IL-1, TNF) and chemokine (IL-8)
2. IL-1 and TNF causes endothelial cells express Selectin (binds to carbohydrate on leukocyte cell surface (rolling adhesion))
3. IL-8 displayed on luminal surface of endothelial cells helps the adhesion of circulating leukocytes
4. This stimulates Integrin on the leukocytes which leads to a firm binding/arrest of the rolling leukocytes (stable/tight adhesion)
5. Leukocytes migrate through the vessel wall and follow the concentration gradient of IL-8 to the site of infection

Question 4

What is the role of cytokines (IL-1 & TNF)?

Answer 4

1. Danger Signal – induces cells to move from blood to site of infection.
2. Activate themselves and other cells to produce more IL-1/TNF thereby ^ adhesion molecules.
3. Change the morphology, permeability and adhesive properties of endothelial cells.
4. Hypothalamus to induce fever & arachidonic pathway
5. Liver to produce acute phase proteins to fight infection (e.g CRP)

Question 5

What is the role of cytokines IL-6?

Answer 5

1. Bacteria induce macrophages to produce IL-6, which acts on hepatocytes to induce acute phase proteins.
2. CRP binds phosphocholine on bacterial surfaces acting as opsonin and also activating compliment.
3. Lectin binds mannose residues on bacterial surfaces, acting as opsonin and also activating compliment.

Question 6

What is the role of chemokines?

Answer 6

1. Chemokines are released by damaged cells and immune cells.
2. IL-8 is a chemokine and it brings more cells (particularly neutrophils) to infected region - ‘Chemoattractants’ and increase expression of adhesion molecules.

Question 7

What is the role of lipids?

Answer 7

1. Prostaglandin: powerful vasodilators and vasoconstrictors
2. Leukotrienes: powerful vasodilators and vasoconstrictors (works with histamine and prostaglandins).
3. Platelet-activating Factor (PAF): - increases permeability

Question 8

What is the role of NADPH oxidase in killing bacteria?

Answer 8

1. NADPH oxidase is a critical regulator of both antimicrobial host defence and inflammation.
2. Activated by microbes and microbial-derived products, the phagocyte NADPH oxidase is rapidly assembled, and generates reactive oxidant intermediates (ROIs) in response to infectious threat.
3. Leads to respiratory burst.
4. Defect in this system results in chronic granulomatous disease.

Question 9

Describe the steps in resolution of acute inflammation.

Answer 9

1. Short half life of neutrophils and inflammatory mediators.
2. Macrophages will change character and promote repair, releasing inhibitory cytokines (IL-10 and TGF-b) to limit inflammation.
3. Macrophages also release growth factors (FGF) to which acts on fibroblasts to promote repair.
4. Lipid mediators – switch to production of anti-inflammatory lipoxins, resolvins, and protectins.

Question 10

What are the consequences of chronic inflammation?

Answer 10

1. Constant release of inflammatory mediators results in tissue injury
2. Macrophages constantly trying to repair this injury
3. End up with fibrosis of tissue, instead of functional tissue get scarring and loss of function