Regulation of fibroblast functions by products of schistosomal egg granulomas: potential role in the pathogenesis of hepatic fibrosis.

Recent observations suggest a molecular link between granuloma formation and hepatic fibrosis in schistosomiasis. Egg granulomas isolated from Schistosoma mansoni-infected mice, when cultured in serum-free medium, produce a variety of biologically active molecules that affect fibroblast function. One group of molecules--proteins with an estimated relative molecular mass (Mr) of 30 000--stimulate fibroblast proliferation in vitro. These molecules have interleukin (IL)-1-like activity when assayed in thymocyte cultures but are biochemically distinct from previously characterized murine IL-1. Fibroblast mitogenic activity is also produced by macrophages isolated from granulomas and by extracts of S. mansoni eggs. The egg-derived activity is distinct from the granuloma cell-derived material on the basis of Mr and isoelectric point determinations. Egg extracts also contain concanavalin A-binding substances which are not directly mitogenic for fibroblasts but can stimulate spleen cells from infected mice to produce fibroblast mitogenic activity in vitro. A large chemoattractant molecule (greater than 200 000 Mr) for fibroblasts has also been identified in supernatants from granuloma cultures and in supernatants from macrophages isolated from granulomas. This activity is abolished by treatment with anti-fibronectin antibody, suggesting that it is fibronectin or a cleavage product thereof. Molecules similar to or identical with the fibroblast mitogenic factors from the granulomas have been identified, and they inhibit the contraction of fibroblast-populated collagen lattices. These activities may be important in the pathogenesis of hepatic fibrosis in schistosomiasis, and pharmacological modification of their production or of their effects on target fibroblasts might theoretically prevent hepatic fibrosis in this disease.