The basic theme of the program is the notion that the pathogenesis of lung injury involves oxidant stress, the generation of cytokines and the generation of eicosanoids, all interrelated events. In humans, we will determine effects of administration of a polyclonal anti-tumor necrosis factor antibody or enhanced resistance to oxidant stress produced by administration of gluthanione analogs on pathophysiology and generation cytokines and eicosanoids by alveolar macrophages and other cells. In the sheep and mice endotoxin model we will conduct parallel studies with similar interventions to those in humans, but will extent observations to include additional biochemical and molecular mechanisms. In several macrophage preparations, including alveolar macrophages form sheep and humans, we will study mechanisms of alterations in expression of the macrophage mannose receptor during lung inflammation. We believe that xanthine dehydrogenase/oxidase (XD/O) contributes to oxidant stress in lung injury and we will elucidate molecular mechanism of XD/O gene expression in sheep and humans. Finally, we will develop methods for gene transfer in intact animals which target delivery and expression of transgenes to cell populations in lung and liver which are critical to the pathogenesis of lung injury (Project V) and determine effects of in vivo expression of sense and antisense cDNA for XD/O (liver) and prostaglandin G/H synthase (lungs) on responses of animals to endotoxemia. The five-projects will be supported by five core areas. This highly integrated group of projects will provide new insights into the pathophysiology, biochemistry, cell biology and molecular mechanisms of acute lung injury, provide rationales for innovative new therapies, and test interventions in humans which have therapeutic promise.
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