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物 (AA)，类二十烷酸，在炎症和炎症的发病机制中很重要 肺部损伤。 鉴于持续的独特高氧化剂负荷 通过肺，申请人研究了氧化应激的影响 大鼠 AM 中 AA 代谢的影响。 具有重要生物学意义的氧气 代谢物、过氧化氢 (H2O2) 和类二十烷酸的概况 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二十烷酸的机制 AM 中的形成，基于表达和 氧化剂诱导的 AA 代谢的调节由特定的因素决定 氧化剂与酶、酶辅因子和酶的生化相互作用 调节花生四烯酸周转周期的其他分子和 代谢级联。 从大鼠身上获得并进行体外研究的 AM 暴露于 H2O2 的 AM 中游离 AA 积累的酶促机制 高氧; 2）探索氧化剂诱导的AA代谢的调控 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 激活调节 AA 代谢； 4) 评估 当 AM 培养时，高氧增强 AA 代谢的能力 模拟肺泡环境各方面的生物基质 高氧肺，包括肺泡上皮细胞单层和 细胞外基质蛋白，而不是在塑料上培养。 这些研究应该增强我们对巨噬细胞 AA 如何 新陈代谢在肺中受到调节，特别是在氧化剂的情况下 受伤。 最终，这些知识可能会带来新的方法 肺部炎症和免疫的药理调节 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.