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 在成人呼吸窘迫综合征(ARDS)和 肺外多器官功能障碍综合征(MODS) ARDS患者死亡的主要原因。具体目标1是检查 细胞内5-LO途径调控的基本机制 介导ARDS患者的肺部炎症和MODS。我们会 验证脂多糖(LPS)增加肺功能的假说 吞噬细胞通过增加5-LO途径的mRNA释放白三烯 人肺泡内组分[如5-LO，5-LO激活蛋白(FLIP)] 巨噬细胞。我们假设内毒素结合蛋白(LBP)将是 在介导脂多糖诱导的二十烷类化合物释放的启动中起重要作用。这个 干扰素-γ对白三烯释放的影响也将是 检查过了。我们预测5-LO途径蛋白表达上调 急性呼吸窘迫综合征与正常肺泡巨噬细胞的比较 磷脂酶A2、呼吸爆发氧化酶成分的激活，以及 白介素1β和肿瘤坏死因子α等细胞因子。 具体目标2是检查5-LO产品在调解中的作用 继发于a)单侧肺动脉的肺损伤 闭塞/再灌注，以及b)由以下两种原因之一引起的脓毒症 或腹膜感染源。我们预测LTB4的抑制作用 兔肺缺血或大肠杆菌损伤后的释放 感染会抑制中性粒细胞进入肺部， 减少髓过氧化物酶(MPO)和中性粒细胞损伤产物 改善肺损伤。具体目标3是检查 选择性5-LO抑制剂对ARDS患者的抗炎作用。 继发于脓毒症或创伤的ARDS患者将进入 一项随机、双盲、安慰剂对照的先导研究 他们将接受5-LO抑制剂药物A-79175或安慰剂治疗 14天。支气管肺泡灌洗(BAL)将在 在急性呼吸窘迫综合征发病后3、7和14天接受A-79175或安慰剂治疗。 我们假设5-LO抑制剂治疗将导致：a)减少 在气道中性粒细胞和中性粒细胞衍生产物的释放(例如， MPO弹性酶)继发于LTB4释放的抑制，b)BAL减少 继发于硫多肽白三烯抑制的蛋白质水平，c) 减少急性肺损伤和/或MODS严重程度评分。的目标是 这些研究旨在明确5-LO通路激活在血管紧张素转换酶激活中的作用 急性呼吸窘迫综合征时肺部炎症的调节作用。

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.