A novel murine model of reversible bile duct obstruction demonstrates rapid improvement of cholestatic liver injury

Autor: Jiao Jing Wang, Sarah A. Taylor, Zheng J. Zhang, Kyle D. Gromer, Xin Yi Yeap, Alyssa Kriegermeier, Richard M. Green
Rok vydání: 2020
Předmět:
Zdroj: Physiological Reports, Vol 8, Iss 10, Pp n/a-n/a (2020)
Physiological Reports
ISSN: 2051-817X
DOI: 10.14814/phy2.14446
Popis: 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.
We have established a novel surgical murine model of reversible bile duct ligation that is more physiologic than prior models of bile duct ligation reversal. Our model demonstrates acute hepatic injury from 7‐day bile duct ligation with rapid improvement after restoration of bile flow, including changes in immune, bile acid, and fibrotic pathways during this response. Further studies with this model may identify novel therapeutic targets for pediatric and adult cholestatic liver disease.
Databáze: OpenAIRE
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