Taylor Sarah A, Yeap Xin-Yi, Wang Jiao-Jing, Gromer Kyle D, Kriegermeier Alyssa, Green Richard M, Zhang Zheng J
Department of Pediatrics, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA.
Department of Surgery, Northwestern University, Chicago, IL, USA.
Physiol Rep. 2020 May;8(10):e14446. doi: 10.14814/phy2.14446.
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.
以慢性胆管梗阻和胆汁流动恢复为特征的胆汁淤积性肝病的小鼠模型有限。虽然小鼠胆管结扎术（BDL）是一种成熟的梗阻性胆汁淤积模型，但目前的BDL逆转（BDLR）模型会改变胆管解剖结构。我们旨在开发一种更符合生理的BDLR模型，以评估胆管梗阻后肝损伤恢复的时间进程和机制。在本研究中，我们使用生物相容性PE - 50导管在小鼠BDL后将胆汁流入十二指肠，而不破坏胆囊。在建立该技术后，BDL后7天或14天进行BDLR的总体存活率为88%。对对照小鼠进行假手术。比较BDL、BDLR和对照小鼠的实验室数据、肝脏组织学和肝脏基因表达。在BDL后第7天观察到胆汁淤积性肝损伤的实验室证据，并且在BDLR后48小时内迅速改善。BDLR后胆汁酸转运蛋白Abcb11的基因表达也增强，然而，胆管增殖持续存在。免疫反应评估显示，与BDL小鼠相比，BDLR小鼠中一般免疫细胞标志物Cd45的基因和蛋白表达增加，提示BDLR后有修复性免疫反应。总之，我们建立了一种新型的BDLR小鼠模型，该模型可用于研究梗阻性胆汁淤积后负责肝脏修复的胆汁酸和免疫途径。使用我们的模型进行的未来研究可能会确定新疗法的靶点，以改善儿童和成人胆汁淤积性肝病的预后。
