Fibrogenesis in pediatric cholestatic liver disease: Role... : Hepatology (original) (raw)

Autoimmune, Cholestatic and Biliary Disease

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

Ramm, Grant A.1*†; Shepherd, Ross W.2; Hoskins, Anita C.1; Greco, Sonia A.1; Ney, Agnieszka D.1; Pereira, Tamara N.1; Bridle, Kim R.3; Doecke, James D.4; Meikle, Peter J.5; Turlin, Bruno6; Lewindon, Peter J.1,7

1 The Hepatic Fibrosis Group, The Queensland Institute of Medical Research, Brisbane, Australia

2 Biostatistics Unit, The Queensland Institute of Medical Research, Brisbane, Australia

3 Department of Pediatrics, Washington University School of Medicine, St. Louis, MO

4 School of Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia

5 Baker IDI Heart and Diabetes Institute, Melbourne, Australia

6 Department of Pathology, Hospital Pontchaillou, Rennes, France

7 Department of Pediatrics and Child Health, University of Queensland, Brisbane, Australia

* Hepatic Fibrosis Group, The Queensland Institute of Medical Research, PO Royal Brisbane and Women's Hospital, Brisbane, QLD, 4029, Australia

Email:[email protected];

Received April 11, 2008; accepted September 10, 2008.

Published online 19 September 2008 in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: National Health and Medical Research Council (NHMRC) of Australia; Grant Number: 290220; Grant sponsor: Australian Cystic Fibrosis Research Trust; Grant sponsor: Royal Children's Hospital Foundation, Brisbane, Australia; Grant Numbers: 913-003 913-005 972-011 972-017; Grant sponsor: National Institutes of Health; Grant Number: 5U01DK62452; Grant sponsor: Senior Research Fellowship from the NHMRC of Australia; Grant Number: 241913.

# Potential conflict of interest: Nothing to report.

† Fax: +61-7-3362 0191.

Abstract

Cholestatic liver diseases, such as cystic fibrosis (CF) liver disease and biliary atresia, predominate as causes of childhood cirrhosis. Despite diverse etiologies, the stereotypic final pathway involves fibrogenesis where hepatic stellate cells (HSCs) are recruited, producing excess collagen which initiates biliary fibrosis. A possible molecular determinant of this recruitment, monocyte chemotaxis protein-1 (MCP-1), an HSC-responsive chemokine, was investigated in CF liver disease and biliary atresia. The bile-duct-ligated rat and in vitro coculture models of cholestatic liver injury were used to further explore the role of MCP-1 in HSC recruitment and proposed mechanism of induction via bile acids. In both CF liver disease and biliary atresia, elevated hepatic MCP-1 expression predominated in scar margin hepatocytes, closely associated with activated HSCs, and was also expressed in cholangiocytes. Serum MCP-1 was elevated during early fibrogenesis. Similar observations were made in bile-duct-ligated rat liver and serum. Hepatocytes isolated from cholestatic rats secreted increased MCP-1 which avidly recruited HSCs in coculture. This HSC chemotaxis was markedly inhibited in interventional studies using anti-MCP-1 neutralizing antibody. In CF liver disease, biliary MCP-1 was increased, positively correlating with levels of the hydrophobic bile acid, taurocholate. In cholestatic rats, increased MCP-1 positively correlated with taurocholate in serum and liver, and negatively correlated in bile. In normal human and rat hepatocytes, taurocholate induced MCP-1 expression. Conclusion: These observations support the hypothesis that up-regulation of hepatocyte-derived MCP-1, induced by bile acids, results in HSC recruitment in diverse causes of cholestatic liver injury, and is a key early event in liver fibrogenesis in these conditions. Therapies aimed at neutralizing MCP-1 or bile acids may help reduce fibro-obliterative liver injury in childhood cholestatic diseases. (Hepatology 2008.)