Research: Alveolar macrophage (AM)-derived metabolites of arachidonic acid (AA), eicosanoids, are important in the pathogenesis of inflammation and injury of the lung. In view of the uniquely high oxidant burden sustained by the lung, the applicant has investigated the influence of oxidant stress on AA metabolism in the rat AM. The biologically important oxygen metabolite, hydrogen peroxide (H2O2), and the profiles of eicosanoids produced by the AM in distinct ways. The goal of the present proposal is to elucidate the mechanisms by which oxidant stress influences eicosanoid formation in the AM, based on the hypothesis that the expression and regulation of oxidant-induced AA metabolism are determined by specific biochemical interactions of oxidants with enzymes, enzyme co-factors, and other molecules which regulate the arachidonate turnover cycle and metabolic cascade. AMs obtained from the rat and studied in vitro will enzymatic mechanisms of accumulation of free AA in AMs exposed to H2O2 and hyperoxia; 2) Explore the regulation of oxidant-induced AA metabolism by glucocorticoids; 3) Investigate interactions between oxidants and protein kinase C activation in the regulation of AA metabolism; and 4) Evaluate the ability of hyperoxia to augment AA metabolism when AMs are cultured on biological substrates which mimic aspects of the alveolar milieu of the hyperoxic lung, including alveolar epithelial cell monolayers and extracellular matrix proteins, as opposed to being cultured on plastic. These studies should enhance our basic understanding of how macrophage AA metabolism is regulated in the lung, especially in the setting of oxidant injury. Ultimately such knowledge may lead to new approaches for pharmacologic modulation of inflammatory and immunologic pulmonary diseases.
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