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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Unknown (R22)
Project #
2R22AI017615-07
Application #
3444538
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Project Start
1987-09-30
Project End
1992-08-31
Budget Start
1987-09-30
Budget End
1988-08-31
Support Year
7
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02111
Prakash, S; Robbins, P W; Wyler, D J (1995) Cloning and analysis of murine cDNA that encodes a fibrogenic lymphokine, fibrosin. Proc Natl Acad Sci U S A 92:2154-8
Greenwel, P; Wyler, D J; Rojkind, M et al. (1993) Fibroblast-stimulating factor 1, a novel lymphokine produced in schistosomal egg granulomas, stimulates liver fat-storing cells in vitro. Infect Immun 61:3985-7
Wyler, D J (1992) Molecular and cellular basis of hepatic fibrogenesis in experimental schistosomiasis mansoni infection. Mem Inst Oswaldo Cruz 87 Suppl 4:117-25
Prakash, S; Wyler, D J (1992) Fibroblast stimulation in schistosomiasis. XII. Identification of CD4+ lymphocytes within schistosomal egg granulomas as a source of an apparently novel fibroblast growth factor (FsF-1). J Immunol 148:3583-7
Prakash, S; Postlethwaite, A E; Wyler, D J (1991) Alterations in influence of granuloma-derived cytokines on fibrogenesis in the course of murine Schistosoma mansoni infection. Hepatology 13:970-6
Prakash, S; Wyler, D J (1991) Fibroblast stimulation in schistosomiasis. XI. Purification to apparent homogeneity of fibroblast-stimulating factor-1, an acidic heparin-binding growth factor produced by schistosomal egg granulomas. J Immunol 146:1679-84
Wyler, D J (1991) Schistosomes, fibroblasts, and growth factors: how a worm causes liver scarring. New Biol 3:734-40
Prakash, S; Postlethwaite, A E; Stricklin, G P et al. (1990) Fibroblast stimulation in schistosomiasis. IX. Schistosomal egg granulomas from congenitally athymic mice are deficient in production of fibrogenic factors. J Immunol 144:317-22
Prakash, S; Dinarello, C A; Danko, K et al. (1989) Schistosomal egg granuloma-derived fibroblast-stimulating factor is apparently distinct from interleukin-1. Infect Immun 57:679-84
Wyler, D J; Lammie, P J; Michael, A I et al. (1987) In vitro and in vivo evidence that autoimmune reactivity to collagen develops spontaneously in Schistosoma mansoni-infected mice. Clin Immunol Immunopathol 44:140-8

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