Temporal and cellular distribution of transcripts for transforming growth factor (TGF)-beta1, procollagen I, III and IV, as well as for type IV collagenase (72 kDa gelatinase) were studied in order to elucidate (1) the pathogenesis of liver fibrosis (or cirrhosis) and (2) the possible role of TGF-beta1. Our study on liver fibrosis suggests that TGF-beta1 derived from inflammatory cells may have enhanced the expression of type I collagen as well as that of the TGF-beta1 gene itself in desmin-positive perisinusoidal cells by the paracrine mechanism. The simultaneous expression of TGF-beta1 and type I, III and IV collagen genes in mesenchymal cells during the fibrotic process also suggests the possibility that TGF-beta1 may have an important role in the production of liver fibrosis. We studied the regulatory mechanisms of synthesis and degradation of type IV collagen which is one of the main components of basement membrane and of accumulated fibrous tissue in liver fibrosis. The data suggest that the imbalance observed in 72 kDa gelatinase and type IV collagen expression in early stages of liver fibrosis may lead to the accumulation of type IV collagen. Furthermore, the data indicate that desmin-positive perisinusoidal cells play a central role in regulating type IV collagen deposition in CCl-4-induced rat liver fibrosis. In Solt-Farber's chemical hepato-carcinogenesis process, non-parenchymal cells of the liver, mainly desmin-positive perisinusoidal cells, are the principal source of TGF-beta1 production. Our data suggest that the close interaction between non-parenchymal cells and carcinoma cells may be necessary for the activation of latent TGF-beta1. It is hypothesized that regulatory effects of TGF-beta1 on growth of preneoplastic or carcinoma cells in the liver are exerted via paracrine mechanism.
