The long-term objective of this SCOR is to further our understanding of the pathogenesis of idiopathic pulmonary fibrosis (IPF), and ultimately to develop new treatment strategies for this disease. The general hypothesis is that the initiation and resolution of inflammatory and immune processes in the lung involve bidirectional regulatory interactions between leukocytes and cells of the alveolar-capillary wall. We contend that these interactions are major factors in determining the persistence of inflammation and progression to pulmonary fibrosis. The specific hypotheses are: 1. Cytokine networks regulating inflammation and repair are disrupted in IPF. These abnormalities are most evident when directly examining lung tissue, rather than bronchoalveolar cells or alveolar fluid. 2. Pulmonary immune responses are compartmentalized in the lung. Dendritic cells initiate antigen processing in the interstitium, but become immunostimulatory in lymphoid tissue. Alveolar epithelial cells actively participate in immune responses by elaborating a lymphocyte suppressive factor. 3. Alveolar epithelial cells actively participate in regulating the appropriate clearance of parenchymal fibrin deposits in the inflamed alveolus. This is likely achieved by expression of a plasminogen activator (PA), a PA inhibitor, and a cell surface PA receptor. 4. Cytokines induce alterations in pulmonary endothelial cells which augment lymphocyte recruitment in inflammatory lung diseases. The basis for altered lymphocyte recruitment can be elucidated by characterization of a lung-specific lymphocyte homing receptor. 5. Interactions between alveolar macrophages and alveolar epithelial cells regulate phospholipase and cyclooxygenase enzymes of both cell types, thereby controlling the production of eicosanoids that modulate inflammation, immune function, and fibrogenesis. This SCOR will take a multidisciplinary approach to testing these hypotheses, bringing to bear the expertise of investigators trained in internal medicine, pathology, cell and molecular biology, biochemistry, and biostatistics. The strengths of this proposal are the investigators' long- standing interests in IPF and pulmonary immunobiology, the proven commitment to collaborative research by both clinicians and basic scientists, access to a large population of IPF patients, and extraordinary institutional resources for biomedical research.
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