CONTRIBUTION OF HEPATIC PARENCHYMAL AND NONPARENCHYMAL CELLS TO HEPATIC FIBROGENESIS IN BILIARY ATRESIA

Extrahepatic biliary atresia is a severe neonatal liver disease result ing from a sclerosing cholangiopathy of unknown etiology. Although bil iary obstruction may be surgically corrected by a ''Kasai'' hepatoport oenterostomy, most patients still develop progressive hepatic fibrosis , although the source of increased collagen deposition is unclear, Thi s study examined the role of hepatic stellate cells (HSCs) and assesse d the source of transforming growth factor-beta (TGF-beta) production in hepatic fibrogenesis in patients with biliary atresia. Liver biopsi es from 18 biliary atresia patients (including 5 pre- and post-Kasai) were subjected to immunohistochemistry for alpha-smooth muscle actin a nd in situ hybridization for either procollagen alpha(1) (I) mRNA or T GF-beta, mRNA. Sections were also subjected to immunohistochemistry fo r active TGF-beta(1) protein. The role of Kupffer cells in TGF-beta(1) production was assessed by immunohistochemistry for CD68, Procollagen alpha(1) (I) mRNA was colocalized to alpha-smooth muscle actin-positi ve HSCs within the region of increased collagen protein deposition in fibrotic septa and surrounding hyperplastic bile ducts, The number of activated HSCs was decreased in only one post-Kasai biopsy, TGF-beta(1 ) mRNA expression was demonstrated in bile duct epithelial cells and a ctivated HSCs and in hepatocytes in close proximity to fibrotic septa. Active TGF-beta(1) protein was demonstrated in bile duct epithelial c ells and activated HSCs. This study provides evidence that activated H SCs are responsible for increased collagen production in patients with biliary atresia and therefore play a definiti e role in the fibrogeni c process. We have also shown that bile duct epithelial cells, HSCs, a nd hepatocytes are all involved in the production of the profibrogenic cytokine, TGF-beta(1).