Contribution of Hepatic Parenchymal and Nonparenchymal Cells to Hepatic Fibrogenesis in Biliary Atresia

Abstract

Extrahepatic biliary atresia is a severe neonatal liver disease resulting from a sclerosing cholangiopathy of unknown etiology. Although biliary obstruction may be surgically corrected by a "Kasai" hepatoportoenterostomy , most patients still develop progressive hepatic fibrosis , although the source of increased collagen deposition is unclear. This study examined the role of hepatic stellate cells (HSCs) and assessed the source of transforming growth factor-␤ (TGF-␤) production in hepatic fibrogenesis in patients with biliary atresia. Liver biopsies from 18 biliary atresia patients (including 5 pre-and post-Kasai) were subjected to immunohistochemistry for ␣-smooth muscle actin and in situ hybridization for either procollagen ␣ 1 (I) mRNA or TGF-␤ 1 mRNA. Sections were also subjected to immunohistochemistry for active TGF-␤ 1 protein. The role of Kupffer cells in TGF-␤ 1 production was assessed by immunohistochemistry for CD68. Procollagen ␣ 1 (I) mRNA was colocalized to ␣-smooth muscle actin-positive 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-␤ 1 mRNA expression was demonstrated in bile duct epithelial cells and activated HSCs and in hepatocytes in close proximity to fibrotic septa. Active TGF-␤ 1 protein was demonstrated in bile duct epithelial cells and activated HSCs. This study provides evidence that activated HSCs are responsible for increased collagen production in patients with biliary atresia and therefore play a definitive role in the fibrogenic process. We have also shown that bile duct epithelial cells , HSCs , and hepatocytes are all involved in the production of the profibrogenic cytokine , TGF-␤ 1 . (Am J Pathol 1998, 153:527-535)Extrahepatic biliary atresia is a progressive, sclerosing, inflammatory process in neonates, causing atresia of all or part of the extrahepatic biliary system and rapidly extending to involve the major intrahepatic biliary ducts.

Fibrogenesis in pediatric cholestatic liver disease: Role of taurocholate and hepatocyte-derived monocyte chemotaxis protein-1 in hepatic stellate cell recruitment #

“…16 Bound antibody was detected using a biotinylated rabbit anti-goat secondary antibody (Dako, Denmark), followed by streptavidin-peroxidase (StrepABC; Dako) as previously described. 7,8 Negative control used nonimmune anti-human antisera (Dako) in place of primary antibody. Immunohistochemistry was also performed for ␣-smooth muscle actin (␣-SMA) and cytokeratin-7 (CK-7) on human liver sections to assess the role of HSCs and liver progenitor cells, 17 respectively, in MCP-1 expression.…”

“…We previously demonstrated that activated hepatic stellate cells (HSCs) and periportal myofibroblasts are the principal collagen-producing cells causing cirrhosis in CFLD 7 and BA. 8 It is generally recognized that in normal liver, HSCs exist in a quiescent phenotype in a perisinusoidal location, closely associated with hepatocytes. 9 In liver injury, HSCs are recruited and activated into "myofibroblast-like" cells which have a central role in the deposition of fibrillar collagens and fibrotic matrix and expression of proinflammatory and profibrogenic cytokines and associated receptors.…”

“…Both cholangiocytes and hepatocytes may produce soluble factors capable of both activating HSCs and causing their recruitment, 11 and we have demonstrated the expression of transforming growth factor-␤ 1 in peri-scar hepatocytes in association with disease progression in CFLD 7 and in BA. 8 However, the search for earlier events in cholestasis which might stimulate recruitment of portal fibroblasts and perisinusoidal HSCs, thus initiating fibrogenesis, might reveal potential targets for therapy. 11,12 In particular, HSCs are known to respond to a variety of chemokines in vitro, with monocyte chemotaxis protein-1 (MCP-1) being one of the most potent.…”

Effects of selective bile duct ligation on liver parenchyma in young animals: histologic and molecular evaluations

“…The mechanisms of increased collagen production and liver parenchyma fibrosis are poorly understood [1,2]. These phenomena are particularly observed in children with biliary obstruction (BO) in whom the evolution to biliary cirrhosis and hepatic failure leads to the need for liver transplantation.…”

Persistent Elevation of Hepatocyte Growth Factor Activator Inhibitors in Cholangiopathies Affects Liver Fibrosis and Differentiation

“…To test whether increased HAI-1 or HAI-2 expression plays a role in the fibrosis process in BA livers, portal fibroblasts (PFs) (Fig. 4A) and stellate cells, 20 two major cell types responsible for cholestasis-related fibrosis, 29,30 were treated with conditioned media from Hep3B cells stably overexpressing HAI-1 or HAI-2 (Fig. 4B) or control media (green fluorescent protein [GFP] or vector) to assay their effects on the fibrogenic activity.…”