Hoekstra Harm, Porte Robert J, Tian Yinghua, Jochum Wolfram, Stieger Bruno, Moritz Wolfgang, Slooff Maarten J H, Graf Rolf, Clavien Pierre A
Swiss HPB Center, Department of Visceral and Transplant Surgery, University Hospital Zurich, Switzerland.
Hepatology. 2006 May;43(5):1022-31. doi: 10.1002/hep.21169.
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.
肝内胆管狭窄是原位肝移植（OLT）后的一种严重并发症。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2（Mdr2）基因破坏杂合型小鼠（Mdr2+/-）的肝脏移植到野生型受体小鼠体内。Mdr2+/-小鼠胆汁中分泌的磷脂量仅为正常量的50%，导致胆盐/磷脂比例异常升高。与纯合Mdr2-/-小鼠不同，Mdr2+/-小鼠在正常条件下肝脏组织学和功能正常。OLT后两周，通过光镜和电镜以及分子和生化标志物评估胆管损伤和胆汁淤积情况。来自野生型供体的肝移植中没有胆管损伤或肝内胆汁淤积的迹象。然而，来自Mdr2+/-供体的肝移植在OLT后出现门静脉区扩大，伴有细胞损伤、小胆管增生、胆汁淤积和密集的炎性浸润。与此观察结果一致，与野生型肝脏受体相比，Mdr2+/-肝脏受体的血清转氨酶、碱性磷酸酶、总胆红素和胆盐水平显著更高。此外，肝胆汁转运体表达与OLT后Mdr2+/-移植物中发现的生化和组织学胆汁淤积特征相符。总之，由于胆汁中胆盐/磷脂比例高导致的毒性胆汁成分，在移植后胆管损伤的发病机制中与冷缺血协同作用。
