This multidisciplinary program, comprised of five projects and three cores, will apply the concepts and techniques of cell and molecular biology to study lung structure and cellular function in response to injury due to inflammation. The focal points of the studies proposed are airway and alveolar epithelial cells, extracellular matrix, neutrophil-derived proteinases, matrix metalloproteinases (MMPs), and surfactant associatedprotein D (SP-D). The following hypotheses will be tested: (1) laminin-5 has in important role in lung development and the response to alveolar injury via its effects on alveolar epithelial cell migration; (2) neutrophil-derived proteinases degrade SP-D and contribute to enhanced clearance of SP-D in alveolar injury; (3) matrilysin cleaves the ectodomain of syndecan-1 and that cleavage is required for airway epithelial cell migration and repair; (4) collagen turnover in COPD is complex with divergent changes in airway and alveolar collagen and with divergent effects of MMPs on airway and alveolar collagen, and (5) remodeling of airway epithelial structure after experimental viral bronchiolitis involves prolonged epithelial cell survival. The proposed studies encompass murine lung cells and embryonic lungs in culture, transgenic and gene targeted mice, and murine models of airway and alveolar injury induced by paramyxovirus, lipopolysaccharide (LPS), Pseudomonas aeruginosa, bleomycin and cigarette smoke. A Morphology Core for assistance with diverse morphologic procedures, and a Mouse Core for production of transgenic and gene targeted mice and for implementing the model of cigarette smoke-induced emphysema, will provide specialized centers for correlative interactions among the investigators in their complementary, yet independent, studies.
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