The pathogenic mechanisms involved in the development of pulmonary fibrosis are obscure and complex. The fibrotic lesion in classically characterized by an influx of inflammatory cells, type II epithelial cell proliferation, and the presence of abnormal and increased deposits of collagen. The pathologic features of the lesion include the inflammatory process and collagen deposition. In the healing process there must be an optimal balance between scar formation and regeneration of normal architecture. Unfortunately, in many pulmonary and nonpulmonary disease states this is not the case; abnormal and pathologic amounts of collagen are commonly deposited. The mechanism for this increased collagen synthesis is not understood. The fibroblast is the primary cell responsible for the deposition of collagen in the fibrotic lesion. There is growing evidence that fibroblasts and fibroblast cultures are not homogeneous but consist of subpopulations of cells, each possibly metabolically distinguishable. The purpose of this proposal is to characterize fibroblast populations in the lung at various stages of bleomycin-induced pulmonary fibrosis in the rat and to examine whether immune or inflammatory mediators can lead to preferential growth of certain fibroblast subpopulations (clonal selection). The metabolic activity of whole fibroblast populations and cloned subpopulations will be characterized in terms of proliferation, prostaglandin E2, collagen and collagenase synthesis, and mRNA levels for alpha 1(I), alpha 2(I) and alpha 1(III) collagen in the baseline state and in response to various mediators such as IL-1, gamma-interferon and complement components. Monoclonal antibodies will be made to lung fibroblast clones and immunohistochemical studies will be done on lung tissue at various stages of the disease process to determine the prevalence of various clones in vivo.
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