ROLE OF 5-LIPOXYGENASE PRODUCTS IN ARDS

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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.