Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation in Mdr2+/- mice
Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation in Mdr2+/- mice
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DOI：
10.1002/hep.21169
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发表时间：
2006-05-01
期刊：
影响因子：
13.5
通讯作者：
Clavien, PA
中科院分区：
文献类型：
--
作者：
Hoekstra, H;Porte, RJ;Clavien, PA
肝内胆管狭窄是原位肝移植术后的一个严重并发症。我们研究了内源性胆盐毒性在OLT后胆管损伤发病机制中的作用。将野生型小鼠和多药耐药2mdr2基因（Mdr2+/-）被破坏的杂合小鼠的肝脏移植到野生型受体小鼠体内。Mdr2+/-小鼠仅分泌正常量的50%的磷脂进入其胆汁，导致异常高的胆盐/磷脂比率。与纯合子Mdr2（-/-）小鼠相比，Mdr2+/-小鼠在正常条件下具有正常的肝脏组织学和功能。术后2周，通过光镜、电镜、分子及生化指标评估胆管损伤及胆汁淤积情况。野生型肝移植无胆管损伤或肝内胆汁淤积的迹象。然而，来自Mdr2+/-供者的肝移植物，在OLT后出现门静脉束增大、细胞损伤、小管增生、胆汁淤积和密集的炎症浸润。与此观察结果相似的是，与野生型肝脏受体相比，Mdr2+/-肝受体的血清转氨酶、碱性磷酸酶、总胆红素和胆盐水平明显更高。此外，肝脏胆汁转运蛋白的表达与OLT后Mdr2+/-移植物的生化和组织学胆汁淤积特征一致。综上所述，胆管移植后胆管损伤的发病机制中，胆盐/磷脂比值高的毒性胆汁成分与冷缺血协同作用。
Intrahepatic bile duct strictures are a serious complication after orthotopic liver transplantation (OLT). We examined the role of endogenous bile salt toxicity in the pathogenesis of bile duct injury after OLT. Livers from wild-type mice and mice heterozygous for disruption of the multidrug resistance 2 Mdr2 gene (Mdr2+/-) were transplanted into wild-type recipient mice. Mdr2+/- mice secrete only 50% of the normal amount of phospholipids into their bile, leading to an abnormally high bile salt/phospholipid ratio. In contrast to homozygous Mdr2(-/-) mice, the Mdr2+/- mice have normal liver histology and function under normal conditions. Two weeks after OLT, bile duct injury and cholestasis were assessed by light and electron microscopy, as well as through molecular and biochemical markers. There were no signs of bile duct injury or intrahepatic cholestasis in liver grafts from wild-type donors. Liver grafts from Mdr2+/- donors, however, had enlarged portal tracts with cellular damage, ductular proliferation, biliostasis, and a dense inflammatory infiltrate after OLT. Parallel to this observation, recipients of Mdr2+/- livers had significantly higher serum transaminases, alkaline phosphatase, total bilirubin, and bile salt levels, as compared with recipients of wild-type livers. In addition, hepatic bile transporter expression was compatible with the biochemical and histological cholestatic profile found in Mdr2+/- grafts after OLT. In conclusion, toxic bile composition, due to a high biliary bile salt/phospholipid ratio, acted synergistically with cold ischemia in the pathogenesis of bile duct injury after transplantation.