This project will determine whether CD40, a member of the TNF receptor superfamily, is a critical element in mediating pulmonary inflammation, dysplasia and fibrosis. The lung is susceptible to damage by treatments for respiratory distress in infants and adults (i.e., oxygen), by therapies for cancer (e.g. chemotherapy) and by exposure to environmental agents (e.g. ozone). Lung damage may induce chronic inflammation, which stimulates fibroblast proliferation and fibrosis. Pulmonary derangement, including bronchopulmonary dysplasia (BPD) in premature infants, is a potentially fetal consequence of severe lung damage. Treatments for pulmonary fibrotic conditions are essentially nonexistent. The fibroblast is the key effector cell responsible for lung fibrosis. T lymphocytes and mast cells are closely associated with lung inflammation and fibrosis and may directly stimulate the fibroblast. The mechanism of interaction between these cells is largely unknown. This laboratory discovered that pulmonary fibroblasts display CD40, a receptor previously thought to be associated with bone marrow derived cells (e.g. B cells). The importance of CD40 is that its ligand (L) is found on T lymphocytes and mast cells and the CD40-CD40L interaction is critical for the stimulation of the CD40 displaying cell. The hypothesis to be tested in this proposal is that CD40 is also a critical regulatory molecule for fibroblasts, important for their proliferation and synthesis of proinflammatory cytokines and collagen. Disruption of the fibroblast CD40 signaling mechanism may inhibit lung inflammation and fibrosis. The significance of fibroblast CD40 for lung inflammation and fibrosis will be determined by answering the following questions as our specific aims. (1) Does CD40 act as a cytokine/growth factor receptor and induce protein tyrosine phosphorylation and fibroblast proliferation? (2) Does crosslinkage of CD40 induce lung fibroblasts to synthesize proinflamatory/profibrotic cytokines and is their production of collagen increased? (3) Does disruption of the CD40-DC40L system in vivo prevent the onset of a BPD-like syndrome in an animal model? Results of this project may lead to the development of new therapeutic strategies to arrest the progression of lung dysplasia in premature infants, and to prevent lung fibrosis in patients' lungs damaged by cancer treatments or environmental agents.
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