Role of the spleen in liver fibrosis in rats may be mediated by transforming growth factor β-1

Background: The effect of the spleen on the cirrhotic liver is unknown. Transforming growth factor-beta1 (TGF-beta1), which plays a crucial role in the matrix production during liver fibrosis, is an inhibitory factor regarding the regeneration of hepatocytes. In this study, we investigated the TGF-beta1 production in the spleen of cirrhotic rats and the effects of a splenectomy on the healing process from liver fibrosis. Methods: Thirty-six Wister male rats were used. Thioacetamide (TAA) was administered intraperitoneally for 24 weeks. The rats underwent either a sham operation (TAA+Sham) or a splenectomy (TAA+SPL). The improvements in liver fibrosis and liver regeneration were investigated 10, 30 and 60 days after the operations in each group. The effect of a splenectomy on the plasma concentration of TGF-beta1 in the portal vein was investigated by ELISA. The TGF-beta1 expressions in the spleen were measured using immunohistochemical staining and the degree of such expression was measured using RT-PCR. The activity of TGF-beta1 in the portal vein of TAA + Sham and TAA + SPL was assessed by the inhibiting effect of rat parenchymal hepatocyte proliferation in primary culture. Results: Liver regeneration (PCNA-labeling index) in the TAA+SPL rats was stimulated more at 10 and 30 days after the operation (P<0.05) than in the TAA+Sham rats, and the improvement of liver fibrosis (fibrosis rate) in the TAA+SPL rats was higher at 60 days (P< 0.05) than in the TAA+Sham rats. The plasma concentration of TGF-beta1 of the portal vein in TAA+ SPL rats was significantly lower than in the TAA+Sham rats for each period. Immunohistochemically, TGF-beta1-positive stained cells were recognized in the spleen macrophages in the red pulp of cirrhotic rats. The plasma of the TAA+Sham rats at 10 and 30 days after the operation was significantly stronger than that of the TAA+SPL rats in inhibiting the proliferation of rat hepatocytes of primary culture. Inhibitory effects were then dose-dependently neutralized by monoclonal TGF-beta1 antibody. Conclusion: Spleen-derived TGF-beta1 may thus play an inhibitory role in the healing of liver cirrhosis by inhibiting the regeneration of the damaged liver. (C) 2002 Blackwell Science Asia Pty Ltd.