Despite current therapies, the mortality rates from septic shock and one of its sequelae, the adult respiratory distress syndrome (ARDS) exceed 50%. Eicosanoids (prostaglandins (PGs), thromboxanes (Txs) and leukotrienes (LTs) are potent inflammatory mediators. Our previous studies in endotoxic shock and experimental and clinical septic shock have implicated a potential pathophysiologic role for eicosanoids. The proposed experiments will investigate two related hypotheses: (1) LT synthesis is altered and contributes to certain pathophysiologic sequelae of endotoxic and septic shock; and (2) endotoxemia and endotoxin tolerance alter cellular lipoxygenase and cyclo- oxygenase metabolism.
The specific aims proposed to test the first hypothesis will quantitate the levels of and establish temporal relationships among LTs, PGs and TxA2 formation in experimental endotoxic and septic shock. The effects of selective 5-lipoxygenase inhibitors, LT antagonists, and an inhibitor of LTB4 synthesis (5,8,11 eicosatrienoic acid) on certain sequelae of sepsis and endotoxemia will be examined. Pulmonary sequestration of 111 In-oxine labeled neutrophils and microvascular permeability to 99m TC labeled human serum albumin will be assessed in rats during endotoxemia and sepsis, and in patients with ARDS. Rats also will be exchange transfused with an artificial blood substitute to evaluate the contribution of circulating blood components as sources of LTs during endotoxic shock.
The specific aims proposed to test the second hypothesis will investigate changes in arachidonic acid content; its uptake into and release from phospholipids and phospholipase activity of peritoneal macrophages from rates following endotoxemia and the induction of endotoxin tolerance. These studies will begin to address cellular regulatory mechanisms mediating changes in cyclo-oxygenase and lipoxygenase metabolism induced by endotoxin. The proposed investigations have the potential to yield new insights into the role of eicosanoids as inflammatory mediators and the cellular mechanisms controlling altered eicosanoid production during endotoxemia. The goal of these studies is to achieve improved therapy for the still significant clinical problems of sepsis and ARDS.
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