The mechanism of the association between inflammation and pulmonary fibrosis is poorly understood. Previous studies have demonstrated an important role for the T-lymphocyte in modulating bleomycin-induced pulmonary fibrosis in mice. The T-cell is a known source of regulatory factors capable of stimulating and inhibiting fibroblast proliferation, collagen synthesis, as well as a fibroblast chemotactic factor. Thus, the central hypothesis of this proposal is that bleomycin-induced injury causes an inflammatory state which eventually causes an alteration in lung T-cells which favors the production of regulatory factors with fibrogenic potential. To examine this hypothesis, the mechanism of bleomycin induced tissue injury and subsequent activation of the inflammatory and immune systems, will be analysed from the stand point of recent data implicating key roles for oxidants and arachidonate metabolites in mediating tissue injury and modulation of the inflammatory/immune system and collagen metabolism. To assess the role of oxidative mechanisms, the following approaches will be used: 1) direct measurements of oxidant production and lipid peroxidation byproducts in bleomycin-injured lungs, 2) examine the effect of antioxidants and free radical scavengers on bleomycin-induced injury, inflammation and fibrosis, and 3) examine the effects of a) increasing by direct supplementation, and b) decreasing by the use of selective inhibitors, the tissue and cellular antioxidant activities, on bleomycin-induced injury, inflammation and fibrosis. The role of arachidonate metabolites will be assessed also by direct quantitation of their production by lung tissue and cells using high pressure liquid chromatography (HPLC) and radioimmunoassay methodology. The effect of selective inhibitors of arachidonate metabolism should complement and confirm these findings. These effects will be correlated with a) activation of lung T-cells, and b) any changes in lung T-cell trafficking and T-cell subset ratios as assessed by the use of monoclonal antibodies and flow cytometry. This is turn will be analysed with respect to any association with fibrogenesis - in terms of alterations in fibroblast regulatory factor production. These correlational analyses should provide new insight into the pathogenesis of pulmonary fibrosis in general. This should in turn have positive implications on the development of more effective therapeutic approaches.
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