Recent evidence suggests potentially novel biological activities for the C-C chemokine, monocyte chemotactic protein-1 (MCP-1) beyond its chemotactic properties. Its ability to up-regulate collagen gene expression in lung fibroblasts mediated by endogenous TGFbeta1, suggests a potentially important role in the accumulation of extracellular matrix characteristic of pulmonary fibrosis. Thus this C-C chemokine has the potential ability to drive the deposition by fibroblasts. Hence the central hypothesis of this project continues to be focussed on the role of this chemokine in mediating important signals for pulmonary fibrosis. Specifically, MCP-1 initially secreted by eosinophils and other cells, is hypothesized to be important in up-regulating TGFbeta1 expression in fibroblasts and perhaps other lung cells, resulting in the differentiation of fibroblasts to myofibroblasts and stimulation of collagen synthesis. Subsequent MCP-1 expression by myofibroblasts has the potential of propagating these effects in autocrine fashion. The experimental plan will investigate the effects of anti-MCP-1 antibodies on bleomycin-induced pulmonary inflammation, cytokine expression and fibrosis, to see what cytokines are upstream to the regulation of lung myofibroblast cytokine and collagen gene expression. The networking between MCP-1 TGFbeta1 will be examined by studying the effects of neutralizing one cytokine in vivo using specific antibodies and monitoring the effects on lung expression of the other cytokine. The regulation of eosinophil MCP-1 expression will be examined to evaluate the mediators responsible as a means of providing insight into the MCP-1 mediate mechanism. The C-C chemokine receptor(s) (CC-CKR) involved in mediating the MCP-1 effects on fibroblasts will be identified, and their expression evaluated in bleomycin-injured lungs and cells isolated from those lungs. The identity and functional significance of these receptors will be confirmed using cells isolated from selective CC-CKR knockout mice and their role in fibrosis examined by applying the bleomycin model on these mice. Given the unique importance of the myofibroblast, special attention will be focussed on the possible differential expression of the identified receptor(s) by this cell vis-a- vis the undifferentiated fibroblast. Attainment of these aims should clarify the multifaceted roles of MCP-1 in pulmonary fibrosis, and provide further insight into key mechanisms, which relate chronic inflammation to fibrogenesis.
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