OXIDANT-INDUCED MACROPHAGE ARACHIDONIC ACID METABOLISM

研究：肺泡巨噬细胞（AM）衍生的花生四烯酸代谢产物 (AA)类二十烷酸在炎症的发病机制中很重要， 肺损伤。 鉴于持续的独特的高氧化剂负荷， 通过肺，申请人研究了氧化应激的影响 对大鼠AM中AA代谢的影响。 生物学上重要的氧气 代谢产物，过氧化氢（H2 O2）和类二十烷酸的特征 由AM以不同的方式产生。 本提案的目标是 阐明氧化应激影响类花生酸的机制 在AM中形成，基于表达和 氧化剂诱导的AA代谢的调节是由特定的 氧化剂与酶、酶辅因子的生物化学相互作用， 调节花生四烯酸周转周期的其他分子， 代谢级联 从大鼠获得并在体外研究的AM将 暴露于H2 O2的AM中游离AA积累的酶机制， 2）探讨氧化诱导的AA代谢的调节， 糖皮质激素; 3）研究氧化剂和蛋白质之间的相互作用 激酶C活化在AA代谢调节中的作用;以及4）评估 高氧增加AA代谢的能力，当AM培养在 生物基质，其模拟人的肺泡环境的方面， 高氧肺，包括肺泡上皮细胞单层， 细胞外基质蛋白，而不是在塑料上培养。 这些研究应该加强我们对巨噬细胞AA 代谢在肺中受到调节，特别是在氧化剂的环境中。 损伤 最终，这些知识可能会导致新的方法， 炎症和免疫肺的药理学调节 疾病

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.