The cytokine, TNF-alpha, is strongly implicated in the pathogenesis of fibrotic lung diseases yet the mechanisms that sustain TNF-mediated inflammation and promote fibrosis are complex and poorly understood. Fibrosis caused by inhalation of crystalline silica, still a significant worldwide health problem, is a highly relevant model of lung disease mediated by chronic TNF-alpha activity. TNF-alpha is induced, rapidly and persistently, by even a single silica exposure. The pathogenic importance of TNF-alpha in the disease is supported by the absence of fibrotic silicosis in TNF receptor Rl/ll double null mice. Accumulating evidence supports the theory that epithelial cell death, subsequent hyperplasia and production of pro-fibrotic factors direct the process of lung fibrosis. Since silica-induced fibrosis does not occur in the absence of TNF receptors, we propose and present evidence that direct TNF receptor mediated epithelial cell injury is necessary for the development of silicosis. This proposal will determine the role of TNFRI/II expression in cells of parenchymal versus hematopoietic origin in the lung response to crystalline silica, chosen as a model of chronic TNF-induced fibrosis. Utilizing an intra-tracheal instillation model and chimeric mice generated by bone marrow reconstitution (BMT) of irradiated WT or TNF receptor null mice with WT or TNFR null marrow, we will test the hypothesis that 1) silica-induced parenchymal cell apoptosis and production of inflammatory mediators does not occur in the absence of TNF receptors on parenchymal cells and 2) in the absence of parenchymal cell TNF receptor-mediated responses, silica-induced fibrosis is reduced or prevented. In addition, based on novel observations made in our laboratory, TNF receptor associated factor 1 null (TRAF1 -/-) mice will be used to further support the hypothesis that enhanced sensitization to parenchymal cell TNF response modulates silica-induced fibrosis. In order to identify mechanisms involved, we will analyze parenchymal cell TNF receptor-dependent differences in silica-induced gene expression of isolated, primary a) leukocytes, b) epithelial and c) parenchymal, non-epithelial cells. Direct analysis of proteins currently identified as modulators of pulmonary fibrosis, including TGFbeta and MIP2, will be performed in these novel, chimeric models of silica-sensitive and -resistant lung. Lung disease caused by inhaled dust is a significant world wide health problem. This proposal will identify new targets for therapy of these chronic and often deadly diseases with reduced side effects. ? ? ?
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