Abstract: . . .  Exotoxins (staph aureus) / Gram-positive cell wall products / Yeast, viral and fungal antigens Septic Shock mechanism : endotoxin binds monocytes and macrophages cytokines turn on acute inflammatory response at high level with local or systemic effects (systemic effects in the case of DIC). Amplified signal causes systemic response: fever, DIC, cardiovascular depression. Can lead to death very quickly. Basic steps : (1) bacterial lysis (2) formation of LPS-LPB (LPS binding protein complex) in blood) (3) monocyte/macrophage binding of complex at CD 14 receptor (4) trigger cytokine secretion . . .
. . .  coronary/cerebral/iliac/femoral (e.g. leg pain after relatively little exertion, a syndrome called intermittent claudication, may be due to thrombus in fem or iliac ) Mural (the wall of): generally refers to heart ventricle, forms when a portion of wall is less kinetic (i.e. from scarring due to previous infarct.) Venous: 90% in leg veins (deep calf/femoral/popliteal/iliac) may be source of pulmonary embolism slide w/ coronary thrombus : Occlusion. Intima and media hard to distinguish and replaced by grey lipid material with cleft-like formations of cholesterol. Cholesterol looks like lens-like empty spaces with surrounding grew material from . . .
. . .  (e.g. thromboembolus from a mitral valve , or local thrombosis due to sickle cell disease ). Yellow portion typical of necrotic tissue. slide w/ pulmonary embolus: in pulmonary artery, total infarction of upper lobe evident compared to other lobes. DISSEMINATED INTRAVASCULAR COAGULATION (DIC): Widespread thrombosis in the microcirculation with platelets and fibrin (few RBC) in capillaries. Activation of intrinsic pathway of coagulation. (Think sepsis or cancer) DIC mechanism : activation of intrinsic pathway Clinical findings: shock , respiratory distress, CNS depression, heart/renal failure Pathophysiology . . .
. . .  - Toll-like receptors (TLR) are the actual signaling receptors -> activate Nf kappaB to initiate massive cytokine synthesis (positive feedback loop) *potential therapeutic target* - TLR4 gram negative shock, TLR2 gram positive sepsis highly specific. (TLR4 KO mice do not develop shock even when injected with high levels of endotoxins) slide w/ nutmeg liver : massive amount of congestion Main culprit for low bp: NITRIC OXIDE 1. produced by endothelium and macrophages 2. NO Synthetase is induced in macrophages by numberous cytokines (iNOS) 3. deletion of cNOS (constitutive) from mice leads to systemic hypertension . . .
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