Two rat models of hepatic fibrosis. A morphologic and molecular comparison

We present a morphologic and molecular comparison of two models of hepatic fibrosis. Immune complexes are the source of insult in one model. In the other model, CCl4 induces fibrosis. For the immune complex model, rats were immunized intraperitoneally over the course of 4 weeks with human albumin, then injected through a tail vein three times a week for at least 5 more weeks with the same albumin. Seventy-five percent of all treated animals developed fibrosis characterized by fine collagen bands. There was a mild degree of hepatocyte trapping and necrosis as well as some bile duct hyperplasia and tissue eosinophilia. However, there was no significant Kupffer cell hyperplasia or inflammatory reaction. Quantification of specific mRNA species was determined by Northern blot hybridization analysis of total RNA. In comparison with CCl4-induced fibrosis in rats, a hepatotoxin-mediated model with a much greater inflammatory response, this immune complex model showed a less pronounced increase in type I procollagen mRNA, but a relatively greater increase in types III and IV procollagen mRNA. Whereas transforming growth factor-beta 1 mRNA levels were markedly increased in CCl4-induced fibrosis, there was only a slight increase in this cytokine, known to stimulate type I collagen synthesis, in the immune complex model. A comparison of the two model systems indicates that a variety of mechanisms may be involved in the process of hepatic fibrogenesis. It appears that an inflammatory response and elevated transforming growth factor-beta 1 levels are associated with a marked increased synthesis of type I collagen in a hepatotoxin model while other, as yet undefined, mediators may be responsible for the increase in types III and IV procollagen mRNA species found in the immune complex model.