Expression of Osteopontin Correlates with Portal Biliary Proliferation and Fibrosis in Biliary Atresia

Abstract

The acquired or perinatal form of biliary atresia is a Th1 fibro-inflammatory disease affecting both the extrahepatic and intrahepatic bile ducts. Osteopontin (OPN) is a Th1 cytokine implicated in several fibro-inflammatory and autoimmune diseases. We examined the expression of OPN in acquired biliary atresia in comparison to normal liver and several pediatric cholestatic liver diseases. We also assessed OPN expression by cultured human bile duct epithelial cells. We found that liver OPN mRNA and protein expression were significantly increased in biliary atresia versus normal and other cholestatic diseases. OPN expression in biliary atresia was localized to epithelium of proliferating biliary structures (ductules and/or ducts) and bile plugs contained therein. No portal biliary OPN expression could be demonstrated in normal liver, syndromic biliary atresia, biliary obstruction not due to biliary atresia, and idiopathic neonatal hepatitis. OPN expression by human bile duct epithelial cells in culture was responsive to IL-2 and TNF-␣. Our results demonstrate an up-regulation of OPN expression by interlobular biliary epithelium in biliary atresia, which correlates with biliary proliferation and portal fibrosis. These findings suggest a role for OPN in the pathogenesis of biliary atresia. Biliary atresia is the most common liver disease of infancy that leads to cirrhosis, end-stage liver disease and the need for liver transplantation (1). A small proportion of cases are thought to be congenital in that they are associated with other developmental anomalies, whereas most cases are diagnosed at 4 -8 wk of age and appear to represent a disease acquired in perinatal or neonatal life. The etiology and pathogenesis of biliary atresia remain unknown. A current working unifying hypothesis that can explain the clinical and pathologic features of the acquired form of biliary atresia is that some injury to the bile ducts, likely a perinatal viral infection, leads to an autonomous immune response that results in progressive bile duct injury and fibrosis (2). This progressive, inflammatory cholangiopathy results in extrahepatic bile duct obstruction (1,3). The extrahepatic bile duct is partially or entirely obliterated by fibrosis in association with inflammation within the fibrous remnant. The intrahepatic biliary system also appears to be affected by the primary disease process. Portal areas are expanded with fibrosis and exhibit marked proliferation of biliary elements (ductules and/or ducts) (4 -8). These duct structures often contain bile plugs. Biliary proliferation may still be a feature of the disease even at end-stage, but in some cases all duct structures disappear.Previous studies have shown that the mononuclear inflammatory infiltrate in the portal tracts comprises macrophages, CD4ϩ T-cells and NK cells (9 -13). We have shown that the inflammation is typically Th1 in character, in that it consists mainly of macrophages, CD4ϩ T-cells and CD8 ϩ T-cells with production of IL-2, IFN-␥, . The inciting agent leading to thi...

Osteopontin expression in normal and fibrotic liver. Altered liver healing in osteopontin-deficient mice

“…We suggest that osteopontin expressed by biliary epithelial cells may be involved in the management of the stress produced by bile duct ligation and bile stasis. In accordance with our data obtained in the bile duct ligation model, it was shown recently that, in biliary atresia, an up-regulation of osteopontin expression is observed in biliary epithelial cells, which correlates with biliary proliferation and portal fibrosis [19]. In the CCl 4 model, the early and strong increase in osteopontin mRNA expression is due to the numerous osteopontin-expressing inflammatory cells present in the necrotic areas around centrolobular veins.…”

Biliary atresia: interdisciplinary initiatives focus on a rare disease

“…A T cell-mediated inflammation can be observed in liver biopsies and support the observation that BA is an ongoing inflammatory process [21,22]. In the same specimens, the overexpression of cell adhesion molecules and cytokines, which are also part of the immune response, cannot be traced back to its starting point [23][24][25][26][27]. These observations show that BA is a disease which affects the intra-as well as the extrahepatic bile ducts and, with regard to its definition, the term ''extrahepatic'' should also be dropped.…”

Relationship of Proximal Renal Tubular Dysgenesis and Fetal Liver Injury in Neonatal Hemochromatosis

“…One section of each was stained with hematoxylin and eosin (H&E) and Perl's Prussian blue for detection of ferric iron. Using previously reported immunohistochemistry techniques (14), kidney sections were stained for epithelial membrane antigen (EMA; antihuman monoclonal mouse epithelial membrane antigen, Dako Corporation, Carpinteria, CA), which is an antigen known to be confined to the distal tubular epithelium (15), and fumarylacetoacetate hydrolase (FAH; monoclonal antibody kindly provided by RM Tanguay, Quebec Canada), which is confined to the proximal tubular epithelium (16,17), and liver sections were stained for AGT (anti-human angiotensinogen polyclonal rabbit serum, Sigma Chemical Co.-Aldrich, St. Louis, MO) and for human IgG (VECTASTAIN ABC kit for Human IgG, Vector Laboratories, Burlingame, CA). Sections were counterstained with hematoxylin.…”