EPITHELIAL GROWTH FACTORS IN ENVIRONMENTAL LUNG DISEASE

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DESCRIPTION: This proposal focuses on the molecular mechanisms for inhaled inorganic particle-induced fibroproliferative lung disease (FLD). The central hypothesis being examined is that interstitial fibrogenic lung disease is mediated by the mesenchymal cell growth factors, PDGF, TGF-alpha, TGF-beta and TNF-alpha, that are synthesized and secreted by the bronchiolar-alveolar epithelium as a result of lung injury. Four specific aims are given to test this hypothesis. In aim 1, two strains of mice resistant to the fibrogenic effects of inhaled asbestos are used to determine if the temporal and anatomic expression of the genes and growth factors by the alveolar epithelium correlates with resistance. In aim 2 alveolar epithelial cells are isolated from these same mice strains to determine if the asbestos-resistance phenotype is maintained in vitro. In aim 3 the principal investigator proposes to focus on PCNA expression in cells capable of forming fibrogenic lesions versus those from resistant mouse strains. In aim 4 transgenic mice overexpressing human PDGF-B within the bronchiolar-alveolar epithelium and spontaneously developing fibroproliferative abnormalities in the lung will be crossed with asbestos-resistant strains to determine if the offspring have increased susceptibility to asbestos. This would implicate PDGF-B in fibrogenic lung disease and target this growth factor for antibody or gene therapy.