To be published in PLOS ONE: Comparing animal well-being between bile duct ligation models

A prevailing animal model currently used to study severe human diseases like obstructive cholestasis, primary biliary or sclerosing cholangitis, biliary atresia, and acute liver injury is the common bile duct ligation (cBDL). Modifications of this model include ligation of the left hepatic bile duct (pBDL) or ligation of the left bile duct with the corresponding left hepatic artery (pBDL+pAL). Both modifications induce cholestasis only in the left liver lobe. After induction of total or partial cholestasis in mice, the well-being of these animals was evaluated by assessing burrowing behavior, body weight, and a distress score. To compare the pathological features of these animal models, plasma levels of liver enzymes, bile acids, bilirubin, and within the liver tissue, necrosis, fibrosis, inflammation, as well as expression of genes involved in the synthesis or transport of bile acids were assessed. The survival rate of the animals and their well-being was comparable between pBDL+pAL and pBDL. However, surgical intervention by pBDL+pAL caused confluent necrosis and collagen depositions at the edge of necrotic tissue, whereas pBDL caused focal necrosis and fibrosis in between portal areas. Interestingly, pBDL animals had a higher survival rate and their well-being was significantly improved compared to cBDL animals. On day 14 after cBDL liver aspartate, as well as alanine aminotransferase, alkaline phosphatase, glutamate dehydrogenase, bile acids, and bilirubin were significantly elevated, but only glutamate dehydrogenase activity was increased after pBDL. Thus, pBDL may be primarily used to evaluate local features such as inflammation and fibrosis or regulation of genes involved in bile acid synthesis or transport but does not allow to study all systemic features of cholestasis. The pBDL model also has the advantage that fewer mice are needed, because of its high survival rate, and that the well-being of the animals is improved compared to the cBDL animal model.

当前用于研究梗阻性胆汁淤积、原发性胆汁性胆管炎、硬化性胆管炎、胆道闭锁及急性肝损伤等人类重症疾病的主流动物模型为胆总管结扎术（common bile duct ligation, cBDL）。该模型的改良方案包括左肝管结扎术（left hepatic bile duct ligation, pBDL），以及左肝管联合对应左肝动脉结扎术（pBDL+pAL）；上述两种改良模型仅会在左侧肝叶诱发胆汁淤积。在对小鼠实施完全或部分胆汁淤积造模后，研究人员通过评估掘洞行为、体重及窘迫评分，对动物的健康状况进行评价。为对比各动物模型的病理特征，本研究检测了血浆肝酶、胆汁酸、胆红素水平，以及肝组织内的坏死、纤维化、炎症情况，同时检测了参与胆汁酸合成或转运的基因表达水平。pBDL+pAL组与pBDL组的动物存活率及健康状况无显著差异。但pBDL+pAL手术会造成坏死组织边缘出现融合性坏死及胶原沉积，而pBDL仅会引发门静脉区之间的局灶性坏死与纤维化。值得注意的是，与cBDL组相比，pBDL组动物存活率更高，健康状况也显著改善。造模后第14天，cBDL组小鼠的血浆天冬氨酸氨基转移酶、丙氨酸氨基转移酶、碱性磷酸酶、谷氨酸脱氢酶、胆汁酸及胆红素水平均显著升高；而pBDL组仅谷氨酸脱氢酶活性出现升高。因此，pBDL模型主要可用于评估炎症、纤维化等局部特征，或调控胆汁酸合成与转运的相关基因，但无法用于研究胆汁淤积的全部全身性特征。此外，pBDL模型的优势还在于其存活率更高，相较于cBDL模型可减少实验小鼠的使用量，且动物的健康状况更佳。