Acute Inflammation

Question 1

what are the main mediators of acute inflammation?

Answer 1

TLRs, arachidonic acid metabolites, mast cells, complement and hageman factor (Factor XII)

Question 2

Describe the role of TLRs

Answer 2

present on cells of innate and adaptive immune system so are important for both acute and chronic inflammation

activated by PAMPs that are commonly shared by microbes. activation results in upregulation of NF-kB, a nuclear TF that activates immune response genes leading to production of multiple immune mediators

Question 3

describe role of arachidonic acid metabolites

Answer 3

AA is released from phospholipid cell membrane by phospholipase A2.

cyclooxygenase acts on phospholipase A2 to produce prostaglandins: PG12, PGD2 and PGE2 mediate vasodilation (arterioles) and increased vascular permeability (post capillary venules); PGE2 also mediates pain and fever

5-lipoxygenase produces leukotrienes: LTB4 attracts and activates neutrophils; LTC4, LTD4, and LTE4 (slow reacting substances of anaphylaxis) mediate vasoconstriction, bronchospasm and increased vascular permeability

Question 4

describe the role of mast cells

Answer 4

activated by: tissue trauma, C3a, C5a or cross-linking of cell surface IgE by antigen

immediately release performed histamine granules, which mediate vasodilation of arterioles and increased vascular permeability

delayed response involves production of arachidonic acid metabolites (esp LTs)…helps prolong acute inflammatory response

Question 5

describe the role of complement

Answer 5

C3a and C5a: trigger mast cell degranulation (anaphylatoxins)

C5a: chemotactic for neutrophils

C3b: opsonin for phagocytosis

MAC: lyses microbes by creating holes in cell membrane

Question 6

Describe the role of Hageman factor

Answer 6

inactive proinflammatory protein produced in liver

activated upon exposure to subendothelial or tissue collagen

activates coagulation and fibrinolytic systems, complement and Kinin system (kinin cleaves high molecular weight kininogen to bradykinin, which mediates vasodilation and increased vascular permeability and pain)

plays an important role in DIC and sepsis

Question 7

describe how the cardinal signs of inflammation occurs

Answer 7

redness and warmth: vasodilation which results in increased blood flow; occurs via relaxation of arteriolar smooth muscle; mediated by histamine, PGs and bradykinin

swelling: due to leakage of fluid from postcapillary venules into interstitial space; mediators are histamine and tissue damage (disrupts wall of blood vessels)
pain: bradykinin and PGE2 sensitize sensory nerve endings
fever: pyrogens cause macrophages to release IL-1 and TNF; these increase COX activity in perivascular cells of hypothalamus; increased PGE2 (by COX) which raises temperature set point

Question 8

how do neutrophils leave blood vessels

Answer 8

1. margination: vasodilation slows blood flow in postcapillary venules and cells go to the periphery of vessel
2. rolling: selectin “speed bumps” are upregulated on endothelial cells - P-selecting release from Weibel-Palade bodies mediated by histamine and E-selectin induced by TNF and IL-1; selectins bind sialyl Lewis X on leukocytes
3. Adhesion: ICAM and VCAM are upregulated on endothelium by TNF and IL-1; integrins upregulated on leukocytes by C5a and LTB4
4. transmigration and chemotaxis: leukocytes transmigrate and move toward chemical attractants: bacterial products, IL-8, C5a and LTB4

Question 9

what do neutrophils do at site of infection?

Answer 9

1. phagocytosis: enhanced by opsonins (IgG and C3b); pseudopods extend from leukocytes to form phagosomes, then internalized and merge with lysosomes
2. Destruction of phagocytosed material: O2 dependent killing; HOCl generated by oxidative burst; NADPH oxidase takes O2 -> O2-, superoxide dismutase takes O2- to H2O2 and myeloperoxidase converts H2O2 to HOCl (bleach); can also be O2 independent killing but is less effective; occurs via enzymes in secondary granules
3. resolution: neutrophils undergo apoptosis and disappear within 24 hours after resolution of inflammatory stimulus

Question 10

describe role of macrophages

Answer 10

arrive in tissue via margination, rolling, adhesion and transmigration

ingest organisms via phagocytosis (augmented by opsonins) and destroy material using enzymes in secondary granules - O2 independent

manage next phase of inflammatory process: resolution and healing (produce IL-10 and TGF-B); continued acute inflammation (produce IL-8 to recruit additional neutrophils; more pus formation); abscess (fibrosis via fibrogenic GF and cytokines); chronic inflammation (present antigen to activate CD4+ cells which secrete cytokines that promote chronic inflamamtion)