APOPTOSIS EXPRESSION IN CONGENITAL HEPATIC FIBROSIS

5 Introduction. Congenital hepatic fibrosis is a rare disease characterized by portal fibrosis and biliary ductular ectasia. We previously demonstrated increased expression of TGF β1 and Thrombospondin 1 in congenital hepatic fibrosis tissue as well as in stellate cell conditioned media. TGF β1 exerts in biological effects through types I and II serine threonine kinase receptors, we sought to determine if this signaling pathway was altered in congenital hepatic fibrosis. Methods. Liver tissue homogenates and formalin-fixed tissue samples from patients with congenital hepatic fibrosis and normal controls were analyzed using anti-TGF β1 type I and II receptor antibodies. Semi quantitative evaluation of receptor expression using optical densitometry of Western blot isolates of both receptors was used for tissue homogenates. Immunohistochemical studies localized the extent and site of receptor expression on hepatocytes and cholangiocytes. Results. Congenital hepatic fibrosis liver tissue stained strongly for both types I and II receptors. The distribution of staining showed marked increase in hepatocyte expression for both types I and II. Cholangiocytes lacked expression of type II receptor but stained strongly for type I. Whole liver expression of type I and II receptor as analyzed by Western blot and optical densitometry showed increased expression of both type I and II receptors. The ratio of type I/II receptor expression was markedly different from normal liver. Conclusions. In congenital hepatic fibrosis, expression of TGF β1 receptors is increased. This reflects the increased expression of the cytokine itself. The distribution of types I and II receptor expression is markedly different between hepatocytes and biliary epithelial cells. The absence of type II receptor expression in the ectatic biliary epithelium of the fibrotic livers suggests that the epithelial hyperplasia may be related to the loss of the growth inhibitory response of TGF β1. This phenomenon of resistance to the inhibitory effect of TGF β1 is known in several cancer cell lines. Further in vitro studies on isolated cholangiocytes and hepatocytes are under way to further define these findings.