Pulmonary fibrosis is a patchy, focal process that begins in the alveolus. Repair following insults which induce fibrosis is critically dependent on alveolar epithelial cell (AEC) reconstitution in the injured alveolus. Chronic inflammatory cells provide crucial signals to both AEC and fibroblasts during the processes that repair the alveolar wall. We believe that chemokine receptor-2 (CCR2) is crucial to the maintenance of a homeostatic balance between regenerative and fibrotic alveolar responses. Hypothesis: CCR2 activation promotes a pathologic fibrotic response by turning off local expression of molecules that otherwise would support normal repair. In the absence of CCR2 activation, AEC and alveolar macrophages (AMO) at the site of injury display a phenotype that supports repair, with local expression of GM-CSF, PGE2 and IFN to limit fibrosis. In the presence of CCR2 activation, local expression of these protective factors is reduced, resulting in decreased NEC proliferation, increased AEC apoptosis and increased matrix deposition. This hypothesis will be addressed using a model in which a single intratracheal challenge with fluorescein isothiocyanate (FITC) leads to chronic inflammation and patchy, focal pulmonary fibrosis in areas initially involved in injury. The pulmonary fibroproliferative response is persistent and does not spontaneously regress. CCR2 expressing mice (CCR2 +/+) and mice which lack CCR2 (CCR2 -/-) will be utilized. We will determine the kinetics and sites of expression of CCR2, IFNy, GM-CSF and the enzymes responsible for PGE2 synthesis. We will determine the effects of CCR2 and GM-CSF on AEC proliferation and apoptosis in FITC-induced pulmonary fibrosis. The roles of IFN and PGE2 as mediators of enhanced repair in CCR2 -/- mice will be determined. Regulation of CCR2 expression on AMO and murine AEC will be explored. Finally, the effects of GM-CSF and MCP-1 on Al,.C synthesis of PGE2 will be determined.
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