Department of Medicine II, Hospital of the Ludwig-Maximilians University (LMU) of Munich, Campus Grosshadern, Munich, Germany.
Lab Invest. 2013 Dec;93(12):1288-94. doi: 10.1038/labinvest.2013.115. Epub 2013 Sep 23.
Kupffer cells (KCs) have a major role in liver injury, and cysteinyl-leukotrienes (Cys-LTs) are known to be involved as well. The KC-mediated pathways for the production and secretion of Cys-LT in cholestatic liver injury have not yet been elucidated. Here, we hypothesized that KC activation by Toll-like receptor ligands results in Cys-LT-mediated microcirculatory alterations and liver injury in acute cholestasis. We hypothesized further that this situation is associated with changes in the secretion and production of Cys-LT. One week after bile duct ligation (BDL), livers showed typical histological signs of cholestatic liver injury. Associated microcirculatory disturbances caused increased basal and maximal portal pressure following KC activation. These differences were determined in BDL livers compared with sham-operated livers in vivo (KC activation by LPS 4 mg/kg b.w.) and in isolated perfused organs (KC activation by Zymosan A, 150 μg/ml). Treatment with the 5-lipoxygenase inhibitor MK-886 alone did not alter portal perfusion pressure, lactate dehydrogenase (LDH) efflux, or bile duct proliferation in BDL animals. Following KC activation, portal perfusion pressure increased. The degree of cell injury was attenuated by MK-886 (3 μM) treatment as estimated by LDH efflux. In normal rats, a large amount of Cys-LT efflux was found in the bile. Only a minor amount was found in the effluent perfusate. In BDL livers, the KC-mediated Cys-LT efflux into the sinusoidal system increased, although the absolute Cys-LT level was still grossly lower than the biliary excretion in sham-operated livers. In conclusion, our results indicate that treatment with Cys-LT inhibitors might be a relevant target for attenuating cholestatic liver damage.
枯否细胞（KCs）在肝损伤中起主要作用，已知半胱氨酰白三烯（Cys-LTs）也参与其中。在胆汁淤积性肝损伤中，KC 介导的 Cys-LT 产生和分泌途径尚未阐明。在这里，我们假设 Toll 样受体配体激活 KC 导致 Cys-LT 介导的微循环改变和急性胆汁淤积性肝损伤。我们进一步假设这种情况与 Cys-LT 的分泌和产生变化有关。胆管结扎（BDL）后 1 周，肝脏显示出典型的胆汁淤积性肝损伤组织学特征。伴随的微循环紊乱导致 KC 激活后基础和最大门静脉压升高。这些差异是在体内 BDL 肝脏（KC 通过 LPS 4mg/kg b.w.激活）和分离灌注器官（KC 通过 Zymosan A，150μg/ml 激活）中与假手术肝脏进行比较确定的。单独用 5-脂氧合酶抑制剂 MK-886 治疗不会改变 BDL 动物的门静脉灌注压、乳酸脱氢酶（LDH）外渗或胆管增殖。KC 激活后，门静脉灌注压增加。MK-886（3μM）治疗可减轻细胞损伤程度，LDH 外渗评估。在正常大鼠中，大量的 Cys-LT 从胆汁中流出。在流出的灌流液中只发现少量。在 BDL 肝脏中，KC 介导的 Cys-LT 流入窦状系统增加，尽管绝对 Cys-LT 水平仍远低于假手术肝脏的胆汁排泄量。总之，我们的结果表明，用 Cys-LT 抑制剂治疗可能是减轻胆汁淤积性肝损伤的一个相关靶点。
