This proposal describes studies which are part of a project with the long-term objectives of understanding the cellular and molecular network involved in regulating fibrosis complicating chronic inflammation. Such knowledge might suggest pharmacological strategies for preventing pathologic fibrosis in general diseases. We will exploit as a model Schistosoma mansoni infection in mice. In an effort to assess how hepatic egg granuloma macrophages become activated in vivo to secrete molecules which stimulate fibroblasts (to migrate, proliferate and secrete matrix proteins) we will determine whether murine T cell hybridoma-derived macrophage activating factor(s) [MAF] can stimulate quiescent macrophages in vitro to secrete fibrogenic substances. We will test for the presence of such MAF activity in 1) granuloma culture supernatants 2) supernatants from dissociated granuloma cell suspensions enriched for T lymphocytes, and 3) supernatants of sensitized spleen cells triggered in vitro with egg antigens. We will also test for the ability of granuloma T cells to secrete lymphokines with direct fibroblast-stimulating activity. Biochemical characterization of the biologically-active substances will be performed. Specific attention will also be given to the ability of the cytokines to stimulate fibronectin secretion by fibroblasts. Some of the biological consequences of the secreted fibronectin (macrophage activation and fibroblast and monocyte/macrophages chemotaxis) will be studied.
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