Lithocholic acid feeding induces segmental bile duct obstruction and destructive cholangitis in mice
Lithocholic acid feeding induces segmental bile duct obstruction and destructive cholangitis in mice
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DOI：
10.2353/ajpath.2006.050404
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发表时间：
2006-02-01
影响因子：
6
通讯作者：
Trauner, M
中科院分区：
文献类型：
--
作者：
Fickert, P;Fuchsbichler, A;Trauner, M
我们确定了石胆酸（LCA）喂养的小鼠，越来越多地使用的胆汁淤积性肝损伤模型的肝胆损伤的机制。Swiss白化病小鼠接受对照饲料或1%（w/w）伊卡饲料（持续1、2和4天），随后评估肝脏形态和超微结构、紧密连接、纤维化标志物和肝胆功能的关键蛋白以及胆汁流量和组成。正如预期的那样伊卡喂养导致胆汁梗死，随后是破坏性胆管炎，伴导管周围肌成纤维细胞活化和增殖。在超微结构水平上，小胆管经常被晶体阻塞。胆汁分泌的荧光标记熊去氧胆酸在胆汁梗死中积累，而大多数梗死没有被注入胆总管的印度墨水染色;这两个结果都表明部分胆道梗阻。主要基底外侧胆汁酸摄取蛋白（钠-牛磺胆酸盐协同转运蛋白和有机阴离子转运多肽1）的表达减少，小管转运蛋白胆盐输出泵和多药相关蛋白2被保留，基底外侧转运蛋白多药相关蛋白3和解毒酶磺基转移酶2a 1被诱导。因此，我们证明，伊卡喂养小鼠导致节段性胆管阻塞，破坏性胆管炎，导管周围纤维化，和适应性转运蛋白和代谢酶的反应。
We determined the mechanisms of hepatobiliary injury in the lithocholic acid (LCA)-fed mouse, an increasingly used model of cholestatic liver injury. Swiss albino mice received control diet or 1% (w/w) ICA diet (for 1, 2, and 4 days), followed by assessment of liver morphology and ultrastructure, tight junctions, markers of fibrosis and key proteins of hepatobiliary function, and bile flow and composition. As expected ICA feeding led to bile infarcts, which were followed by a destructive cholangitis with activation and proliferation of periductal myofibroblasts. At the ultrastructural level, small bile ducts were frequently obstructed by crystals. Biliary-excreted fluorescence-labeled ursodeoxycholic acid accumulated in bile infarcts, whereas most infarcts did not stain with India ink injected into the common bile duct; both findings are indicative of partial biliary obstruction. Expression of the main basolateral bile acid uptake proteins (sodium-taurocholate cotransporter and organic anion-transporting polypeptide 1) was reduced, the canalicular transporters bile salt export pump and multidrug-related protein 2 were preserved, and the basolateral transporter multidrug-related protein 3 and the detoxifying enzyme sulfotransferase 2a1 were induced. Thus, we demonstrate that ICA feeding in mice leads to segmental bile duct obstruction, destructive cholangitis, periductal fibrosis, and an adaptive transporter and metabolic enzyme response.