OXIDANT-INDUCED MACROPHAGE ARACHIDONIC ACID METABOLISM

研究：花生四烯酸的肺泡巨噬细胞(AM)代谢物 (AA)，二十烷类化合物，在炎症和炎症的发病机制中起重要作用 肺部损伤。鉴于持续的独特的高氧化剂负担 通过肺部，申请人已经调查了氧化应激的影响 大鼠AM中AA代谢的研究具有重要生物意义的氧气 代谢物过氧化氢(H_2O_2)和二十烷类化合物的分布 由AM以不同的方式制作。本提案的目标是 阐明氧化应激影响二十烷类化合物的机制 在AM中形成，基于表达和 氧化诱导的AA代谢的调节是由特定的 氧化剂与酶的生化相互作用、酶辅助因子和 其他调节花生四烯酸周转周期的分子和 代谢级联反应。从大鼠体内获得并在体外进行研究的AM将 H_2O_2和H_2O_2对肺泡巨噬细胞内游离AA积累的影响 2)探讨高氧对氧化诱导的AA代谢的调节 糖皮质激素；3)研究氧化剂与蛋白质的相互作用 激活在调节AA代谢中的作用；以及4)评估 培养AM时高氧促进AA代谢的能力 模拟牙槽周围环境的生物底物 高氧性肺，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。 这些研究应该会增强我们对巨噬细胞AA是如何 新陈代谢在肺中受到调节，尤其是在氧化剂的作用下。 受伤。最终，这些知识可能会导致新的方法 炎性和免疫性肺的药理调节 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.