This multidisciplinary program will utilize concepts and techniques of cell and molecular biology to investigate lung development, lung structure, alterations in lung structure due to inflammation, mechanisms of alveolar repair, and alveolar surface proteins. Our overall hypothesis is that extracellular matrix has a fundamental role in lung development and the preservation of normal lung architecture and function, and that disturbances in extracellular matrix are pivotal in emphysema, the acute respiratory disease syndrome, pulmonary fibrosis, chronic pulmonary hypertension, and other disorders in which lung structure is altered. In this program we will study: (1) alveolar basement membranes in lung development and disease; (2) alveolar surface proteins as factors in host defense; (3) matrix metalloproteinase expression by alveolar epithelium; (4) macrophage elastase in emphysema; and (5) pulmonary vascular development and remodeling. A number of molecules will receive emphasis, including laminin alpha chains, surfactant proteins A and D (SP-A and SP- D), cytokines (TNF-alpha, IL-1, IL-6), LPS binding protein, matrilysin, macrophage elastase, tropoelastin, fibrillin-2, microfibril-associated glycoprotein (MAGP), and latent TGF-beta/1-binding protein-2 (LTBP-2). The proposed studies will encompass lung cells in culture, embryonic lungs in culture, transgenic mice, rodent models of alveolar injury induced by hyperoxia, bleomycin, N-nitroso-N-methylurethane, and tobacco smoke, and interactions between SP-D, microorganisms, and macrophages. Human lung tissue and lung cells will be analyzed in some studies. A Morphology Core organized into Histology, Immunology, and Molecular Biology components will assist with tissue processing and diverse morphologic procedures, including 'in situ' hybridization and immunostaining, and will assist in the development of immunologic reagents. The Morphology Core will provide a center for correlative interactions among the investigators in their independent, yet complementary, studies of lung biology.
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