ROLE OF 5-LIPOXYGENASE PRODUCTS IN ARDS

5-脂氧合酶（LO）花生四烯酸代谢产物的释放是重要的 成人呼吸窘迫综合征（ARDS）的发病机制， 肺外多器官功能障碍综合征（MODS）是一种 是ARDS患者死亡的主要原因。 具体目标1： 5-LO途径在细胞中如何调节的基本机制， 介导ARDS患者肺部炎症和MODS。 我们将 检验脂多糖（LPS）增加肺动脉压的假设， 吞噬细胞通过增加5-LO途径的mRNA释放白三烯 组件[例如，5-LO，5-LO激活蛋白（FLAP）]在人肺泡上皮细胞中的表达 巨噬细胞 我们假设LPS结合蛋白（LBP）将在 在介导LPS诱导的类花生酸释放的引发中重要。 的 干扰素（IFN）-γ对白三烯释放作用也将 考察 我们预测5-LO途径蛋白的上调发生在 与正常肺泡巨噬细胞相比， 磷脂酶A2、呼吸爆发氧化酶组分的活化，以及 细胞因子如白细胞介素-1 β和肿瘤坏死因子α。 具体目标2是检查5-LO产品在调解中的作用 继发于a）单侧肺动脉 闭塞/再灌注，和B）败血症， 或腹膜感染源。 我们预测抑制LTB4 在缺血或E.杆菌 感染将抑制嗜中性粒细胞进入肺部， 减少有害的中性粒细胞产物，如髓过氧化物酶（MPO）， 改善肺损伤。 具体目标3是审查 选择性5-LO抑制剂对ARDS患者的治疗作用 将入选继发于脓毒症或创伤的ARDS患者 进入一项随机、双盲、安慰剂对照的初步研究， 他们将接受5-LO抑制剂药物A-79175或安慰剂， 14天 将在给药前进行支气管肺泡灌洗（BAL）。 A-79175或安慰剂组和ARDS发作后3、7和14天。 我们假设5-LO抑制剂治疗将导致： 在气道嗜中性粒细胞中和嗜中性粒细胞衍生产物的释放（例如， MPO弹性蛋白酶）继发于LTB 4释放的抑制，B）BAL中的减少 继发于硫肽白三烯抑制的蛋白质水平，c） 急性肺损伤和/或MODS严重程度评分降低。 的目标 这些研究是为了确定5-LO通路激活在 ARDS中肺部炎症的调节。

Release of 5-lipoxygenase (LO) arachidonic acid metabolites is important in the pathogenesis of the adult respiratory distress syndrome (ARDS) and the extrapulmonary multiple organ dysfunction syndrome (MODS) that is a major cause of mortality of ARDS patients. Specific aim 1 is to examine basic mechanisms of how the 5-LO pathway is regulated in cells which mediate pulmonary inflammation and MODS in ARDS patients. We will examine the hypothesis that lipopolysaccharide (LPS) augments pulmonary phagocyte leukotriene release by increasing mRNA of 5-LO pathway components [e.g., 5-LO, 5-LO activating protein (FLAP)] in human alveolar macrophages. We hypothesize that LPS binding protein (LBP) will be important in mediating LPS-induced priming of eicosanoid release. The effect of interferon(IFN)-gamma on leukotriene release will also be examined. We predict that upregulation of 5-LO pathway proteins occurs in ARDS compared to normal alveolar macrophages and correlates with activation of phospholipase A2, respiratory burst oxidase components, and cytokines such as interleukin-1beta and tumor necrosis factor alpha. Specific aim 2 is to examine the role of 5-LO products in the mediation of lung injury secondary to a) unilateral pulmonary artery occlusion/reperfusion, and b) sepsis resulting from either a pulmonary or peritoneal source of infection. We predict that inhibition of LTB4 release in rabbits undergoing lung injury from ischemia or E. coli infection will inhibit the movement of neutrophils into the lungs, decrease injurious neutrophil products such as myeloperoxidase (MPO) and ameliorate pulmonary injury. Specific aim 3 is to examine the antiinflammatory effects of a selective 5-LO inhibitor in ARDS patients. Patients with ARDS secondary to either sepsis or trauma will be entered into a randomized, double-blind, placebo-controlled pilot study in which they will receive either the 5-LO inhibitor drug A-79175 or placebo for 14 days. Bronchoalveolar lavage (BAL) will be performed prior to receiving A-79175 or placebo and 3, 7 and 14 days after onset of ARDS. We hypothesize that 5-LO inhibitor treatment will lead to: a) reduction in airway neutrophils and release of neutrophil-derived products (e.g., MPO elastase) secondary to inhibition of LTB4 release, b) decrease in BAL protein levels secondary to sulfidopeptide leukotriene inhibition, c) reduction in acute lung injury and/or MODS severity scores. The goal of these studies is to define the role of 5-LO pathway activation in the mediation of lung inflammation in ARDS.