10-14 - Acute Inflammation 2 (Levitt).txt

• Hageman factor = Factor 12
• activated by kinin, complement, clotting, and fibrinolytic systems
• interact continuously in course of inflammation to localize area of destruction

• kallikreins (proteases) generate kininogens (vasoactive peptides)
• HMWK (high-molecular weight kininogen) + 12 --> 12a + Prekallikrein --> Kallikrein (activates F12 in loop feedback) + HMWK --> Bradykinin
• most important product: bradykinin
• • causes arteriolar dilation
  • pain & contraction of smooth muscle
• kallikrein is a potent activator of Hageman factor (F12)
• • converts C5--> C5a
  • chemotactic

• protective mechanism with survival value (link to consciousness)
• sensory nerves stimulated by
• • low pH
  • high extracellular [K+]
  • 5-HT
  • bradykinin
  • Net result: pain!
• painless infectious are more dangerous (go undetected)
• • silent chlamydial salpingitis is more important cause of infertility and ectopic pregnancy (bc of tubul damage)

• Classical & Alt. Pathways
• • C3 is critical control point (interacts with both pathways)
  • C3a & C5a = anaphylotoxins
  • • release histamine from mast cells
    • C5a = chemotaxis
  • C3b & C5a = stimulate neutrophil degranulation
  • C3b, C2a, C4b = opsonins
  • MAC complex
  • • C5-C9
    • cell lysis
  • C5-C7 = chemotactic for neutrophils

• release of enzymes from dying cells (tissue necrosis)
• Ag-Ab complexes --> classical pathway
• endotoxins of Gram(-) --> alternative pathway
• products of kinin, coagulation, and fibrinolytic pathways

• Intrinsic pathway
• • Hageman Factor (F12) is activated by surface contact
• Extrinsic pathway
• • Tissue Factor released at sites of injury activates F7
• Results in clotting & fibrinolysis balanced by 12a --> kallikrein --> plasmin

Commonalities

• inducted by 12a (Hageman factor)
• complement & counterbalance each other
• important molecules: fibrinogen, fibrin, thrombin, plasminogen, plasmin

• Thrombin splits fibrinogen to fibrinopeptides
• • induces vascular permeability
  • chemotactic
• Thrombin increases leukocyte adhesion & fibroblast proliferation
• Factor 10a increases vascular permeability & leukocyte exudation
• Plasmin cleaves C3 & fibrin resulting in vascular permeability
• Plasmin actives Hageman factor

Eicosanoids = Arachidonic acid metabolites

• Synthesized from cell membrane phospholipids through phospholipase action (inhibited by corticosteroids)
• Form leukotrienes via lipoxygena pathway (LOX)
• Form prostaglandins & thromboxana (COX-1 & COX-2)
• • COX-1 inhibited by aspirin & indomethacin

• vasodilation
• increased vascular permeability
• pain
• pyrogenesis (fever)
• neutrophil activation

Mediated by COX1 & COX 2 - leads to formation of prostaglandins. Results in a variety of mediators:

• Prostaglandins - PGD2 causes vasodilation, PGE2 causes pain & fever
• Prostacyclin (PG12) - formed in vascular endothelium to cause vasodilation & inhibit platelet aggregation
• Thromboxane (TXA2) - formed in platelets to cause vasoconstriction & promote platelet aggregation

Blocked by:

• NSAIDS
• Steroids - blocks at cell membrane level; regulation of lipocortin-1 inhibits release of arachidonic acids from membrane phospholipid

COX-3 recently discovered; plenty in brain; ? site of action for tylenol ?

• leads to formation of leukotrienes, which cause
• • chemotaxis (eosinophils, PMNs)
  • vasoconstriction
  • bronchospasm
  • increased vascular permeability
• act late in inflammation
• Inhibitors of leukotriens are used in asthmatics

• Formed by platelets with LTA4 from leukocytes
• Inhibits neutrophil chemotaxis & adhesion
• Stimulates monocyte adhesion
• Stimulates vasodilation
• Inhibits action of LTC4 (vasoconstriction)
• May be negative regulator of leukotrienes
• Collaborative productoin: PMNs / platelets
• Inhibit PMN activities

• Histamine - abundant in mast cell granules which are abundant arond blood vessels
• Serotonin - action similar to histamine; found in platelets & released after platelet aggregation or PAF influence
• PAF - numerous effects which are 100-100,000x more effective than histamine including vasodilation & increased vascular permeability

• Produced by lymphocytes or macrophages after stimulation by toxins, injury, or inflammatory mediators
• • Biggest influences: LPS (Gram-) & IFNg (viruses, etc.)
• Include: lymphokines, monokines, chemokines, colony stimulating factors, interleukins, & growth factors
• Categorized by actions
• • Autocrine
  • Paracrine - activation of neighboring cells including neutrophiles & fibroblasts
  • Endocrine - acts systemically (acute phase rxns) including: fever, fatigue, lower appetite, increased WBC

• Regulate lymphocytes - IL2, 4, 10 & TGF-b
• Natural immunity - TNF-a, IL1b, IL6, IFNg, & IFNb
• Activate macrophages - IFNg, TNFa&b, IL5, 10, 12
• Chemokines - IL8 (leukocytes), lymphotaxin, eotaxin
• Stimulate hematopoiesis - IL3, 7, c-kit, CSF, & stem cell factor

IL-1: endothelial cell activation

IL-2: T-cell growth factor

TNF-a: a.k.a. cachectin

IL-1 & TNFa are the most important

• endothelial cell activation
• acute phase response
• fibroblast stimulation
• stimulate leukocytes to secrete cytokines

• Formed by NO synthase (NOS)
• • constitutively expressed
  • expression increased with Ca influx
  • NOS induced in macrophages by TNF-a or IFN-g
• Potent vasodilator
• Involved in pathogenesis of septic shock
• Actions: short-lived; depend on [NO]
• • small amounts in endothelial cells cause smooth muscle relaxation & vasodilation; anti-thrombogenic to platelets
  • small amouns in neurons --> neurotransmitter
  • large amounts in macrophages --> cytotoxic free radical; kill bacteria / tumors
  • inappropriate release --> shock