Mediators of Inflammation

Question 1

What are the cell-derived mediators of inflammation?

Answer 1

1. Vasoactive amines
2. Arachidonic acid metabolites (prostaglandins and leukotrienes)
3. Platelet-activating factor
4. Cytokines
5. ROSs
6. Nitric Oxide
7. Lysosomal enzymes
8. Neuropeptides

“Lame, noisy republican politicians are certainly voted NO”

Question 2

What are the plasma protein-derived mediators of inflammation

Answer 2

1. Complement

2. Coagulation and Kinin

Question 3

Vasoactive amines

Answer 3

histamine, serotonin

stored until release.

Histamine: arterial dilation, endothelial contraction (increased exudate)
>in mast cells, basophils, platelets, among others

Serotonin: vasoconstriction (to aid in clotting)
>in platelets

Question 4

Arachidonic Acid metabolites

Answer 4

AA —–> prostaglandins and thromboxanes (via COX-1, -2)
AA —–> leukotrienes (via lipoxygenase)

Prostaglandins: pain, fever, vasodilation, (inhibition of) platelet aggregation
>presence of specific enzymes determine which compounds are made

Leukotrienes: chemotaxis, increase vascular permeability

Lipoxins: antagonize leukotrienes, are anti-inflammatory

Question 5

Platelet-activating factor

Answer 5

platelet aggregation, vasodilation, vascular permeability, bronchoconstriction, platelet and cell stimulation

Question 6

Cytokines

Answer 6

(Acute Inflammation) TNF-alpha, IL-1: endothelial activation, induce fever and protein synthesis
> produced esp. by macrophages, mast cells, endothelial cells

(Chronic Inflammation) FN-γ: stimulates macrophage activation; IL-12: stimulates T cells

(Subgroup) chemokines: mediate chemotaxis, activate leukocytes
>CXC: chemotactic for neutrophils
>CC: chemotactic for variety of cells

Question 7

ROSs

Answer 7

highly toxic oxidizers: damage microbes and host tissues

Question 8

Nitric oxide

Answer 8

Free radical: kills microbes

Mediates vasodilation, antagonizes platelet activation, reduces leukocyte recruitment

Made by nitric oxide synthase (NOS)
Inflammation–>Inducible NOS: induced in macrophages and endothelial cells by IL-1, TNF, IFN-γ and bacterial endotoxins

(Endothelial NOS: constitutively expressed in endothelial cells)

Question 9

Lysosomal enzymes

Answer 9

kill microbes and digest ingested materials (can also damage host tissues)

Acid proteases, active within phagolysosomes (@ low pH); neutral proteases, active outside the cell (@ neutral pH)

Alpha-1-antitrypsin: neutrophil elastase inhibitor

Alpha-2-Macroglobulin: inhibits a large variety of proteinases (e.g. collagenase)

Question 10

Neuropeptides

Answer 10

can initiate inflammation, influence vascular tone and permeability
> esp. present in lung and GI

Substance P: secreted by nerves and inflammatory cells, binds to neurokinin-1 receptor –> proinflammatory effect

Question 11

Complement

Answer 11

C1-9
opsonize pathogens, induce inflammatory response, increase vascular permeability & leukocyte chemotaxis

Activated: classical, alternative, lectin

Question 12

Specific functions of Complement molecules

Answer 12

C3a and C5a: increase vascular permeability

C5a: activates AA metabolism

C3a, C4a, C5a: activate leukocytes

C3b: opsonin for enhanced phagocytosis (C3b + Fc of Ab recognized by macrophages)

C5b-C9: MAC

C1 inhibitor: blocks C1 activation

Question 13

Coagulation/Kinin Systems

Answer 13

Stimulates the clotting cascade, many of these factors are active inflammatory mediators resulting in vascular permeability, dilation and C3a formation

Factor XII (clotting factor)—> bradykinin —>increased vascular permeability, vascular dilation, pain.

Question 14

Anti-inflammatory mediators

Answer 14

Lipoxins: antagonize leukotrienes

C1 inhibitor

IL-10: (secreted by macrophages) downregulates activated macrophages

TGF-beta (promotes fibrosis): anti-inflammatory