VII. Inflammation overview
a. TLRs and NODs→ phosphorylation cascade leads to phosphorylation of I-kappa-B which degrades releasing Nf-kappa-B
i. Transcription and translation of inflammatory cytokines
b. NF-kappa-B→ release causing promotion of transcription of cytokine proteins
c. Expression of inflammatory cytokines → promotion of transcription by Nf-kappa-B leads to translation and protein production
i. Recruite WBCs to infection site
ii. Can be stored in some granules in mas cells and macrophages → immediate release
d. Rubor, calor, tumor, dolor- redness, heat, swelling, pain → caused by release of cytokines → vascular permeability and cell catabolism
VIII. Mediators of Inflammation
a. Cytokines: short proteins
i. Inflammatory cytokines: fever=human proteins working more efficiently than bacterial proteins (figure 3.3 p 56)
1. *IL-1ß→ attracts neutrophils, makes endothelial cells stickier
2. *TNF-alpha → increase cell catabolism to get energy → endothelial cells stickier
3. IL-6 → acts on hypothalamus to increase internal body temperature (fever) and release of acute phase proteins from liver (inflammatory mediators)
4. IL-8 → recruits neutrophils
5. IL-12 → fever, recruits natural killer cells ← kill cells with intracellular infection
ii. Anti-inflammatory cytokines- released later than inflammatory cytokines; released in response to steroid hormones
1. IL-10 → stops TNF/IL-12 transcription and translation
2. TGF-beta; counter effects of IL-1 & TNF to reduce vascular permeability and cell stickiness
a. Stops neutrophils from localizing at sight of inflammation
b. Complement components
i. C3a- increase vascular permeability and vasodilation
ii. C5a- increase vascular permeability and vasodilation (but better) and attracts neutrophils
c. Lipid mediators
i. Prostaglandins- increase vascular permeability and vasodilation
1. Negative feedback at high levels
ii. Leukotrienes- activate blood clotting LOCALLY
1. Prevents systemic movement of bacteria
2. Clotting to prevent blood loss
iii. Arachidonic acid pathway: from phospholipids → prostaglandins or leukotrienes
1. NSAIDs→ reduce inflammation (non-steroidal anti-inflammatory drugs)
a. Ex: Aspirin, ibuprofen
b. Prevent prostaglandin and leukotriene synthesis
IX. Endothelial cell signaling (figure p 314)
a. Gradient of inflammatory cytokines= increased concentration on tissue side moving towards blood vessel
b. Selectins ~ adhesive molecules on endothelial cells (on lumen side) catch neutrophiols make slowly roll on endothelial surface
i. P-selectin (pre-made) moves to lumen side surface in response to IL-1 and TNF
ii. E-selectin expressed with activation from IL-1 & TNF, moves to lumen side
c. Leukocyte adhesion
i. ICAM and VCAM → expressed in response to IL-1 and TNF, tightly hold neutrophil allowing neutrophil to move through endothelial layer
d. Diapedesis and extravasation- movement of neutrophil through endothelial cells following IL-8, C5a & C3a gradient
X. Regulation of inflammation
a. Positive feedback → IL-1 leads to MORE Il-1 expression and release
b. Negative feedback → TNF makes macrophages less sensitive to TNF
i. Acetylcholine- released in response to pain, increase adrenaline levels
1. Leads to secretion of IL-10 and TGF-ß
2. Stops action of TNF, stops action of IL-1
XI. Inflammation gone wild
a. Septic shock and LPS- IL-1 positive feedback at recognition of LPS in blood; 50% death rate of sepsis, no negative feedback to stop inflammatory response due to systemic spread of bacterial
b. Necrotizing fasciitis- “Flesh eating bacteria”
i. Inflammatory response causes local tissue damage, but damage is out of control due to self amplification
a. noe negative feedback
ii. Debridement- removal of marginal tissue surrounding area of affected tissue to prevent destructive inflammatory signaling
c. Red hot chili peppers → capsasin causes release of IL-1, tears are a form of releasing edima, → dissolves in alcohol not water

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