Chronic lung allograft rejection, Bronchiolitis Obliterans Syndrome (BOS) is a chronic process that demonstrates features of dysregulated and aberrant repair of airways. This process of fibroproliferation and deposition of extracellular matrix that ultimately leads to fibro-obliteration of airways, and impaired lung function. In this proposal, the investigators hypothesize that the persistent expression of monocyte chemoattractant protein-1 (MCP-1) during an allogeneic response and recruitment and activation of mononuclear phagocytes expression CC chemokine receptor 2 (CCR2) is a pivotal event that promotes the continuum of acute to chronic lung allograft rejection. Specifically, MCP-1 production, and the recruitment and activation of CCR2 expressing mononuclear phagocytes occurs during acute rejection. Moreover, the persistent presence of MCP-1 in the allograft maintains recruitment and activation of specific populations of mononuclear phagocytes expressing CCR2. These cells have a unique pro- fibrogenic phenotype that promotes fibrogenesis of chronic allograft rejection, BOS. Understanding the interaction between MCP-1 and CCR2 during the continuum of acute to chronic lung allograft rejection, will lead to novel therapies in the treatment and prevention of BOS. This proposal ,will test this hypothesis by performing the following experiments: I) determine the time-course, magnitude of expression, and cellular sources of MCP-1, as correlated to the recruitment of monocular cells expression CCR2 in an orthotopic rat model of acute lung allograft rejection. II) determine the specific contribution of MCP-1 to the pathogenesis of acute lung allograft rejection by a strategy of depletion of MCP-1. III) determine the time-course of MCP-1 expression, as correlated to the recruitment of mononuclear cells expression CCR2 in a murine model of BOS. B) determine the specific contribution of MCP-1/CCR2 biology to the pathogenesis of BOS by using genetic approaches for deletion of the bioactivity of MCP-1 and/or CCR2. IV) determine if CCR2 expression mononuclear phagocytes are phenotypically profibrogenic (i.e., produce higher levels of TGF-beta and PDGF) and promote fibrogenesis during the pathogenesis of BOS. By successfully completing these objectives, the applicants hope to have gained significant insight into the persistence of MCP-1/CCR2 biology that impacts on the continuum and transition of acute lung allograft rejection to BOS. The understanding of this pathobiology will lead to novel therapies in the treatment and prevention of chronic lung allograft rejection, BOS.
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