LUNG REPAIR--ROLE OF TGF-ALPHA, TGF-BETA & PDGF

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The proposed research will examine the hypothesis that Transforming Growth Factor-alpha (TGF-alpha), a mitogen for epithelial and mesenchymal cells, Transforming Growth Factor - beta (TGF-beta), an inhibitor of epithelial cell proliferation and an inducer of collagen synthesis, and Platelet- derived Growth Factor (PDGF) a mitogen for mesenchymal cells, regulate the cellular proliferation and fibrosis that occurs following lung injury. These studies will evaluate growth factor expression in patients with Adult Respiratory Distress Syndrome and in rabbits with bleomycin-induced lung injury. The first Specific Aim is to evaluate transcription and secretion of TGF-alpha, TGF-beta and PDGF following lung injury. Studies are planned to determine steady-state mRNA levels in alveolar macrophages for TGF- alpha, TGF-beta and the A- and B- chains of PDGF; to determine TGF-alpha, TGF-beta and PDGF activity levels in lavage fluid and macrophage conditioned medium; and to determine steady-state mRNA levels for TGF- alpha, TGf-beta and PDGF in injured lung. These studies are expected to delineate the release of these cytokines in the alveolar compartment, to determine if alveolar macrophages are a cellular source of these factors in vivo, nad to examine the possibility that other lung parenchymal cells may express these cytokines following lung injury. The second Specific Aim focuses upon macrophage-derived TGF-alpha which may play a crucial role in alveolar reepithelialization during lung repair. These studies are designed to determine the molecular size(s) and cellular processing of macrophage-derived TGF-a; to determine the time course of TGF-a gene transcription and protein secretion; to evaluate TGF-a message stability and the regulation of TGF-a gene transcription; and to determine the effects of specific agonists and antagonists on TGF-a gene expression by human peripheral blood monocytes and alveolar macrophages.