The adult respiratory distress syndrome is a form of acute respiratory failure often associated with gram-negative sepsis and a mortality rate exceeding 50%. Recent investigations suggest that mobilization of endogenous arachidonic acid metabolites and activation of formed blood elements, especially neutrophils, are intimately involved in the pathogenesis. In the present proposal, we will examine the role of lipoxygenase products of arachidonate metabolism in mediating endotoxin-induced acute respiratory failure in the pig. The specific objectives are: 1) to determine the effect of blocking the lipoxygenase pathway on cardiopulmonary function during infusion of E.Coli endotoxin; 2) to determine if the lipoxygenase products, leukotriene C4,eukotriene B4, and 12-HETE, are increased in bronchoalveolar lavage fluid obtained from endotoxemic pigs; 3) to determine the effect of granulocytopenia on cardiopulmonary function and production of lipoxygenase products in normal and endotoxemic pigs. Cardiopulmonary function will be evaluated for 4.5 hrs in anesthetized endotoxemic pigs. Parameters to be measured or calculated include: mean arterial, pulmonary artery, pulmonary artery wedge and airway opening pressures; crdiac output, pulmonary vascular resistance, dynamic lung compliance, lung water, arterial gas tensions and pH; hematocrit, plasma proteins, total white blood cell, polymorphonuclear, lymphocyte and platelet counts; bronchoalveolar lavage albumin and neutrophil content and postmortem ravimetric lung water. Assay for lipoxygenase metabolites will be by radioimmunoassay and high-pressure liquid chromatography. If in the proposed model, increased lipoxygenase products occur and can be correlated with abnormal cardiopulmonary function then future studies will focus on identifying specific mechanisms by which lipoxygenase products contribute to acute respiratory failure.
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