Abstract: . . .  monocytes - CD 14 on cells and in the plasma binds LPS - Other cell surface receptors, such as CCR chemokine receptors and integrins may also bind LPS - 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 Mechanism : NO made by endothelial cells/macrophages diffuses through basement membrane due to gaseous properties relaxes vascular smooth muscle hypotension  . . .
. . .  acute myocardial infarct coagulative necrosis . Color looks like tiger skin pale and yellow (necrotic) areas juxtaposed to normal beefy red areas. Under high power: myocytes with absent nuclei and deep red color, surrounded by neutrophils. slide w/ splenic infarct : result of arterial thrombotic occlusion (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 : rapid consumption of fibrinogen, platelets, prothombin, factors V, VIII, X, and at same time generation of fibrin split products D-DIMERS (important diagnostic entity produced by plasmin. slide w/ DIC : capillary with platelets and fibrin Enter Dr. Marcantonio: PART II SEPTIC SHOCK (often see DIC in this . . .
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