The hedgehog pathway regulates remodelling responses to biliary obstruction in rats
- 1Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, USA
- 2Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, USA
- Dr A M Diehl, Duke University Medical Center, Division of Gastroenterology, GSRB 1, 595 LaSalle Street, Suite 1073, Box 3256, Durham, NC 27710, USA;
- Revised 15 February 2008
- Accepted 5 March 2008
- Published Online First 28 March 2008
Background: Chronic biliary obstruction provokes fibrosis and accumulation of immature ductular cells. This fibroductular reaction resolves following biliary decompression, suggesting that it may also be involved in the repair of biliary damage. The hedgehog (Hh) pathway becomes activated in liver after bile duct ligation (BDL), and might modulate hepatic remodelling because Hh ligands are potent morphogens.
Objective: To study the induction of the Hh pathway during progression and resolution of biliary fibrosis, and to clarify whether Hh signalling regulates accumulation of bile duct progenitor cells.
Design and main outcome measures: Livers from rats with BDL were examined by quantitative real-time polymerase chain reaction analysis and immunohistochemistry to identify factors that might stimulate Hh signalling. BDL rats were subjected to Roux-en-Y hepaticojejunostomy (R-Y) to relieve biliary obstruction in order to determine whether these factors and Hh signalling declined as ductular populations and concomitant fibrosis regressed. Cultures of immature ductular cells were treated with putative Hh inducers and Hh ligands to confirm their functional relevance.
Results: BDL increased expression of platelet-derived growth factor-BB (PDGF-BB) and sonic hedgehog (Shh), downregulated hedgehog-interacting protein (Hip), activated Hh signalling, and expanded populations of Hh-responsive ductular cells that expressed pancyotkeratin, a liver progenitor cell marker. After R-Y, Hip remained suppressed, expression of PDGF-BB and Shh gradually declined, and populations of hedgehog-responsive ductular cells regressed. In cultured ductular cells, PDGF-BB treatment induced Shh expression, and incubation with Shh inhibited apoptotic activity.
Conclusions: These results identify a mechanism for activation of the Hh pathway during cholestasis and suggest that Hh signalling regulates ductular cell accumulation after biliary injury.
See Commentary, p 1198
Funding: This work was supported by National Institutes of Health Grants 5RO1-AA010154-11 and 5RO1-DK053792-07 to AMD. AO is a recipient fellow of Dottorato di Ricerca in and Alimenti e salute (VI ciclo), Universita’ Politecnica delle Marche, Ancona, Italy.
Competing interests: None.
Ethics approval: Experiments using rats were approved by the Government of Lower Franconia, Germany, and the Institutional Review Board of Beth Israel Deaconess Medical Center on the 8 February 2007.