REGULATION OF PGH SYNTHASE IN ALVEOLAR MACROPHAGES--NORMAL AND CIGARETTE SMOKERS

脂多糖刺激的正常人肺泡巨噬细胞 (LPS)选择性地产生大量的介体， 前列腺素E2（PGE 2）。 这种增强转化的机制 花生四烯酸通过人肺泡巨噬细胞对PGE 2维斯PGH合酶的作用， PGH-PGE异构酶未知。 吸烟会抑制这种转化 花生四烯酸转化为前列腺素E2。 的机制 这种抑制作用也是未知的。 本研究的目的是确定 正常人肺泡巨噬细胞产生PGE 2的调节， 确定吸烟如何改变这些机制。 的 这些研究的总体假设是，PGE 2的形成是在 正常肺泡巨噬细胞通过调节PGH合成酶的量， 催化PGE 2形成的第一个关键步骤， 花生四烯酸 另一个假设是， 花生四烯酸对吸烟者巨噬细胞中PGE 2的影响与总体 香烟烟雾成分对这些细胞造成的氧化应激。 这些假设的总体方法将是系统地评估 正常人花生四烯酸转化为PGE_2的调节 然后确定体内或体外暴露于 香烟烟雾改变了花生四烯酸转化为 前列腺素E2。 调查人员将试图将这些缺陷与 香烟烟雾对这些细胞造成的总氧化应激。 未来 研究，单独的，但直接联系到这一建议将评估 花生四烯酸利用率和5-脂氧合酶产物的影响 对正常和烟雾暴露肺泡巨噬细胞PGE 2形成的影响。

Normal human alveolar macrophages (HAMs) stimulated with lipopolysaccharide (LPS) selectively produce large amounts of the antiinflammatory mediator, prostaglandin E2 (PGE2). The mechanisms for this enhanced conversion of arachidonic acid by human alveolar macrophages to PGE2 vis PGH synthase and PGH-PGE isomerase are unknown. Cigarette smoking inhibits this conversion of arachidonic acid to PGE2 by alveolar macrophages. The mechanisms for this inhibition are also unknown. The goal of this research proposal is to determine the mechanism for regulation of PGE2 production by normal human alveolar macrophages and to determine how these mechanisms are altered by cigarette smoking. The overall hypothesis of these studies is that PGE2 formation is regulated in normal alveolar macrophages by regulating amounts of PGH synthase, which catalyzes the first committed step in the formation of PGE2 from arachidonic acid. A further hypothesis is that the reduced conversion of arachidonic acid to PGE2 in smokers macrophages is related to the overall oxidant stress imposed on these cells by components of cigarette smoke. The overall approach to these hypotheses will be to systematically evaluate the regulation of the conversion of arachidonic acid to PGE2 in normal macrophages and then to determine how in vivo or in vitro exposure to cigarette smoke alters each step in the conversion of arachidonic acid to PGE2. The investigators will then try to relate these defects to the overall oxidant stress placed on these cells by cigarette smoke. Future studies, separate, but directly linked to this proposal will evaluate the effects of arachidonic acid availability and 5 lipoxygenase product formation on normal and smoke exposed alveolar macrophage PGE2 formation.