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

脂多糖刺激正常人肺泡巨噬细胞(HAMs) (脂多糖)选择性地产生大量的抗炎介质， 前列腺素E2(PGE2)。这一增强转换的机制 花生四烯酸对人肺泡巨噬细胞前列腺素E_2-前列腺素H合成酶的影响 前列腺素H-前列腺素E异构酶是未知的。吸烟抑制了这种转化 肺泡巨噬细胞将花生四烯酸转化为前列腺素E_2。实现以下目标的机制 这种抑制作用也是未知的。 这项研究提案的目标是确定 正常人肺泡巨噬细胞产生前列腺素E_2的调节 确定吸烟是如何改变这些机制的。这个 这些研究的总体假设是PGE2的形成在 正常肺泡巨噬细胞通过调节PGH合成酶的量， 催化PGE2形成的第一个步骤 花生四烯酸。另一种假设是，减少的转化率 花生四烯酸对吸烟者巨噬细胞中PGE2的影响 香烟烟雾的成分对这些细胞造成的氧化压力。 对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前列腺素E_2的调节 然后确定如何在体内或体外暴露于巨噬细胞 香烟烟雾改变花生四烯酸转化为花生四烯酸的每一步 PGE2。然后，调查人员将试图将这些缺陷与 总体而言，香烟烟雾对这些细胞造成了氧化压力。未来 独立但直接与该提案相关的研究将评估 花生四烯酸利用率和5-脂氧合酶产物的影响 正常和烟雾暴露的肺泡巨噬细胞PGE2的形成。

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.