Abstract
There are limited murine models of cholestatic liver diseases characterized by chronic biliary obstruction and resumption of bile flow. While murine bile duct ligation (BDL) is a well‐established model of obstructive cholestasis, current models of BDL reversal (BDLR) alter biliary anatomy. We aimed to develop a more physiologic model of BDLR to evaluate the time course and mechanism for resolution of hepatic injury after biliary obstruction. In the present study, we restored bile flow into the duodenum without disruption of the gall bladder after murine BDL using biocompatible PE‐50 tubing. After establishing the technique, overall survival for BDLR at 7 or 14 days after BDL was 88%. Sham laparotomy was performed in control mice. Laboratory data, liver histology, and hepatic gene expression were compared among BDL, BDLR, and controls. Laboratory evidence of cholestatic liver injury was observed at day 7 after BDL and rapid improvement occurred within 48 hr of BDLR. After BDLR there was also enhanced gene expression for the bile acid transporter Abcb11, however, bile duct proliferation persisted. Assessment of the immune response showed increased gene and protein expression for the general immune cell marker Cd45 in BDLR versus BDL mice suggesting a reparative immune response after BDLR. In summary, we have established a novel murine model of BDLR that allows for the investigation into bile acid and immune pathways responsible for hepatic repair following obstructive cholestasis. Future studies with our model may identify targets for new therapies to improve outcome in pediatric and adult cholestatic liver disease.
Highlights
Obstructive cholangiopathies remain a leading indication for pediatric and adult liver transplantation and represent an unmet need for the development of new therapeutic strategies.There are few effective medical therapies for primary biliary cholangitis (PBC) that slow disease progression and there are no effective medical therapies for primary sclerosing cholangitis (PSC)
We have developed a novel murine model that represents more physiologic restoration of bile flow after obstruction than prior models using a cholecystojejunostomy (Yang et al, 2014)
Our murine model of the acute phase of hepatic injury after bile duct ligation (BDL) for 7 days shows a rapid improvement in cholestatic inflammatory liver injury after restoration of bile flow that has not previously been demonstrated
Summary
This work was supported by: the George Ferry Young Investigator Award from the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (SAT), NIH/NIDDK 5R011DK093807-06 (RMG), The Max Goldenberg Foundation (RMG), The George Lockerbie Liver Cancer Foundation (RMG), and Northwestern Core Facilities Development Pilot Grant (ZJZ).
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