The overall purpose of this SCOR proposal is to investigate the immunologic regulation of pulmonary fibrosis. We have developed a research program to focus on those factors which will minimize or attenuate the fibrotic response to lung injury. The central concept behind this SCOR application has emerged from the observation that diffuse interstitial pulmonary diseases with the pathologic diagnosis of Usual Interstitial Pneumonitis (UIP) have extensive and progressive fibrosis while granulomatous lung disease has in general much less fibrosis and a markedly improved prognosis. Therefore, we hypothesize that there is less fibrosis in granulomatous lung disease because of factors within the granuloma that suppress the fibrotic response, specifically interferon- gamma (IFNgamma) and keratinocyte growth factor (KGF). A major emphasis in this proposal will be on investigating the mechanisms by which IFNgamma and KGF limit or, more desirably, prevent, the development of fibrosis. This general hypothesis will be addressed by five projects. Project 1 (Dr. Augustin) will investigate the role of the immune system in the pathogenesis of pulmonary fibrosis with particular emphasis on the role of gamma/delta T-lymphocytes, which express high levels of both IFNgamma and KGF, and alpha/beta T-lymphocytes which produce IFNgamma with different kinetics to gamma/delta T-cells but which do not produce KGF. Project 2 (Dr. Mason) will address the mechanisms underlying the protection of the lung against the development of fibrosis by KGF and will investigate (i) gene therapy approaches to establish sustained expression of KGF in the alveoli and lower airways, (ii) the expression of type II cell growth factors in the lung and the ability of type II cells to induce apoptosis in fibroblasts, and (iii) the possible stem cell origin of hyperplastic alveolar type II epithelial cells in injury and repair. Project 3 (Dr. Riches) will investigate the mechanisms underlying the observed repression of fibrogenic growth factor expression in macrophages by IFNgamma with the goal of defining novel IFNgamma-responsive elements in the promoter region of the insulin-like growth factor-I gene and their cognate """"""""repressor"""""""" proteins. Project 4 (Dr. Newman) will investigate (i) the mechanism by which beryllium salts stimulate IFNgamma production by human T-lymphocytes and (ii) how this cytokine inhibits basic fibroblast growth factor expression in mast cells. Lastly, project 5 (Dr. King) is the major clinical project. This project will interact extensively with the other projects to investigate (i) the types of T-lymphocytes present in UIP and granulomatous lung disease with emphasis on understanding the cells responsible for IFNgamma and KGF expression, (ii) the control of growth factor and cytokine expression in macrophages and mast cells and (iii) the efficacy of aerosolized IFNgamma in retarding the progressive fibrosis and loss of gas exchange function in patients with UIP. By investigating mechanisms to enhance or stimulate processes that minimize fibrosis and promote restoration of gas exchange units, we should be able to develop new treatment programs that will complement or replace existing treatments which focus largely on inhibiting the inflammatory response.
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