Acute lung injury (ALl) affects more than 200,000 patients in the U.S. each year and is an important cause of morbidity and mortality in hospitalized patients. Changes in ventilator management have improved outcome, but further progress will depend on a better understanding of the factors that control the pathogenesis and resolution of ALI Our work has shown that Fas-dependent pathways are activated in the lungs of patients with ALI, and that stimulation of Fas-dependent pathways causes epithelial apoptosis and inflammation in the lungs of rabbits and mice. Our work in progress using a model of repeated Fas activation in the lungs of mice shows that Fas stimulation produces a proteolytic phenotype in the lungs with significant fibrosis and that matrix metalloproteinases play an important role. Major Goals: The major goals of this proposal are to determine the mechanisms that link Fas-dependent apoptosis and fibrosis in experimental lung injury, and to test important new therapies to reduce the fibrotic response in ALI. We hypothesize that activation of Fas-dependent pathways is an important cause of lung injury and fibrosis in ALI, and that the mechanisms involve aggregation of sFasL in the lungs by neutrophil-derived oxidants, which cause Fas activation on macrophages and epithelial cells. This leads to epithelial apoptosis and the production of macrophage-specific MMP-12, which degrades matrix and leads to late fibrosis. A second hypothesis is that this process is amplified by triggers of innate immunity, including endogenous matrix fragments, and exogenous bacterial products in the airspaces. Experimental Approach: We will trigger Fas-dependent pathways in the lungs of experimental mice using a Fas-activating antibody (JO-2) and evaluate the fibrotic response using light microscopy, biochemical methods, and gene expression arrays. We will test the effects of neutrophil-derived oxidants in activating sFasL (Aim 1). We will study the roles of MMP-12 and related MMPs (Aim 2). We will determine whether co-existing activation of innate immunity pathways amplify the effect of Fas activation (Aim 3). Lastly, we will compare the effects of Fas-pathway inhibitors and MMP inhibitors in protecting mice from fibrosis following Fas-activation (Aim 4). Importance of the Results: The results of these studies will fill important gaps in our understanding of the links between epithelial apoptosis and fibrosis in the lungs, and could lead to novel new treatments to reduce pulmonary dysfunction and improve outcome for critically ill patients with acute lung injury.
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