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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Harabin, Andrea L
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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Herrero, Raquel; Matute-Bello, Gustavo (2015) How to measure alterations in alveolar barrier function as a marker of lung injury. Curr Protoc Toxicol 63:24.3.1-15
Grazioli, Serge; Gil, Sucheol; An, Dowon et al. (2015) CYR61 (CCN1) overexpression induces lung injury in mice. Am J Physiol Lung Cell Mol Physiol 308:L759-65
Herrero, Raquel; Tanino, Mishie; Smith, Lincoln S et al. (2013) The Fas/FasL pathway impairs the alveolar fluid clearance in mouse lungs. Am J Physiol Lung Cell Mol Physiol 305:L377-88
Tanino, Yoshinori; Chang, Mary Y; Wang, Xintao et al. (2012) Syndecan-4 regulates early neutrophil migration and pulmonary inflammation in response to lipopolysaccharide. Am J Respir Cell Mol Biol 47:196-202
Gil, Sucheol; Farnand, Alex W; Altemeier, William A et al. (2012) Fas-deficient mice have impaired alveolar neutrophil recruitment and decreased expression of anti-KC autoantibody:KC complexes in a model of acute lung injury. Respir Res 13:91
Herrero, Raquel; Kajikawa, Osamu; Matute-Bello, Gustavo et al. (2011) The biological activity of FasL in human and mouse lungs is determined by the structure of its stalk region. J Clin Invest 121:1174-90
Lipke, Anne B; Matute-Bello, Gustavo; Herrero, Raquel et al. (2011) Death receptors mediate the adverse effects of febrile-range hyperthermia on the outcome of lipopolysaccharide-induced lung injury. Am J Physiol Lung Cell Mol Physiol 301:L60-70
Martin, Thomas R; Matute-Bello, Gustavo (2011) Experimental models and emerging hypotheses for acute lung injury. Crit Care Clin 27:735-52
Smith, Lincoln S; Gharib, Sina A; Frevert, Charles W et al. (2010) Effects of age on the synergistic interactions between lipopolysaccharide and mechanical ventilation in mice. Am J Respir Cell Mol Biol 43:475-86
Lipke, Anne B; Matute-Bello, Gustavo; Herrero, Raquel et al. (2010) Febrile-range hyperthermia augments lipopolysaccharide-induced lung injury by a mechanism of enhanced alveolar epithelial apoptosis. J Immunol 184:3801-13

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