COMPLEMENT-DEPENDENT PROSTAGLANDIN SYNTHESIS IN SEPSIS

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Although low systemic vascular resistance is a consistent hemodynamic feature of sepsis in humans, relatively little is known about the mechanisms involved. The problem is important, however, because defective regulation of peripheral vasomotor tone is a contributing factor leading to the development of systemic arterial hypotension (i.e., septic shock) in patients with overwhelming infections. Shock remains the single most important predictor of mortality in septic patients. The purpose of this study is to test the hypothesis that decreased vasomotor tone in sepsis is mediated (at least in part) by vasodilating prostaglandins (PGE2 and/or PGI2) and that release of these substances is initiated by activation of the complement system. The studies will employ a rabbit model of endotoxemia that is characterized by low systemic vascular resistance and high cardiac output; i.e., the model satisfactorily replicates the systemic hemodynamic profile of human sepsis. Cardiac output will be measured by thermodilution; regional blood flow will be assessed using radioactive microspheres; plasma levels of metabolites of PGE2 and PGI2 will be determined by radioimmunoassay. Three series of experiments will be conducted. The first will examine the effect of pharmacologically limiting the formation of prostaglandins or complement-derived peptides on systemic and regional hemodynamics and plasma prostaglandin levels in endotoxic rabbits. Prostaglandin synthesis will be inhibited by administering meclofenamate or ibuprofen; formation of complement-derived peptides will be inhibited by prior decomplementation with cobra venom factor or treatment with inhibitors of complement activation. The second series of experiments will investigate systemic and regional hemodynamics and plasma prostaglandin levels in rabbits infused with graded doses of either zymosan- activated plasma (a source of complement-derived peptides) or cobra venom factor (to initiate the formation of these peptides in vivo). The studies will be performed in the presence and absence of PG synthesis inhibitors. The third series of experiments will ascertain whether the hemodynamic effects of vasodilating doses of endotoxin or activated complement depend upon interaction with polymorphonuclear leukocytes. These studies should provide important new insights into the mechanisms underlying the derangements in vasomotor tone in sepsis and possibly lead to improved therapeutic strategies.