Increased expression of transforming growth factor-beta(1) and thrombospondin-1 in congenital hepatic fibrosis: Possible role of the hepatic stellatecell

Background: Congenital hepatic fibrosis is a rare disease characterized by portal tract fibrosis and biliary duct ectasia. It is associated with autos omal recessive polycystic kidney disease and rarely progresses to cirrhosis . The activated stellate cell has been implicated in the pathogenesis of al cohol- or inflammation-mediated cirrhosis through fibrogenic proteins such as transforming growth factor-beta(1); however, the role of the stellate ce ll in pun, noninflammatory fibrosis is unknown. It has been hypothesized th at Fibrosis in congenital hepatic fibrosis may be caused by upregulation of transforming growth factor-beta, and thrombospondin-1, and that the hepati c stellate cell may be the mediator of these proteins. Methods: Human liver tissue samples from patients with congenital hepatic f ibrosis (n = 9) and from normal patients (n = 3) were analyzed. Tissue homo genates from both groups were analyzed for transforming growth factor-beta( 1) protein and mRNA by Western blot analysis and in situ hybridization, res pectively. Immunolocalization studies were performed in fixed tissue sectio ns from both groups. Stellate cells were cultured from livers exhibiting co ngenital hepatic fibrosis and confirmed by desmin staining. The cells were cultured in serum-free medium for 48 hours, and media were collected and an alyzed by Western blot analysis for thrombospondin-1 and transforming growt h factor-beta(1). Results: Congenital hepatic fibrosis liver tissue homogenates had higher le vels of thrombospondin-1 and transforming growth factor-beta(1) protein tha n in normal livers. In congenital hepatic fibrosis tissue, transforming gro wth factor-beta(1) was more highly expressed in the ectatic biliary epithel ium and the perisinusoidal space, whereas thrombospondin-1 localized most i ntensely to the hepatocytes and spared the bile ducts. Congenital hepatic f ibrosis-derived stellate cells secreted both thrombospondin-1 and transform ing growth factor-beta(1) in vitro. Conclusions: Transforming growth factor-beta(1) and thrombospondin-1 may pl ay a role in the pathogenesis of liver fibrosis in patients with congenital hepatic fibrosis. One potential source of these fibrogenic proteins is the hepatic stellate cell.