Protective effects of leflunomide against ischemia-reperfusion injury of the rat liver
Protective effects of leflunomide against ischemia-reperfusion injury of the rat liver
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DOI：
10.1007/s00383-006-1668-x
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发表时间：
2006-05-01
影响因子：
1.8
通讯作者：
Yilmaz, Z
中科院分区：
文献类型：
--
作者：
Karaman, A;Fadillioglu, E;Yilmaz, Z
肝缺血再灌注损伤可发生在创伤、肝切除、失血性休克或肝移植等情况下。肝脏的I/R损伤引起肝细胞损伤，可能导致肝功能衰竭。大量证据表明，活性氧（ROS）和炎症反应可能是肝I/R中肝细胞损伤的原因之一。来氟米特是一种异恶唑衍生物，是一种独特的免疫调节剂。在本研究中，我们研究了来氟米特对中性粒细胞活化与氧化应激和一些抗氧化酶在大鼠肝脏I/R再灌注后的影响。32只大鼠随机分为4组：1组（对照组），来氟米特10 mg/kg，i.g.;第2组（假手术组），动物仅剖腹;第3组（肝脏I/R）和第4组（肝脏I/R +来氟米特）。第4组：来氟米特（10 mg/kg，i.g.）实验前两次注射。在第3组和第4组中，闭塞肝蒂60分钟诱导缺血和再灌注，此后允许60分钟。在再灌注期结束时，处死大鼠。测定肝组织中超氧化物歧化酶、过氧化氢酶、一氧化氮、黄嘌呤氧化酶、丙二醛、蛋白质羰基和髓过氧化物酶的含量，并进行组织学检查。第3组动物表现出肝脏形态严重恶化和显著的肝脏氧化应激。来氟米特预处理动物显着衰减的形态学改变和中性粒细胞活化，降低升高的氧化应激产物水平，并恢复耗尽的肝脏抗氧化酶。这些结果表明，活性氧在I/R诱导的肝损伤中起着重要作用，来氟米特可能通过清除自由基和抗氧化活性的抗炎作用来发挥肝保护作用。
Hepatic ischemia-reperfusion (I/R) injury may be developed in some conditions, such as trauma, major hepatic resection, hemorrhagic shock or liver transplantation. I/R injury of the liver causes hepatocellular damage that may lead to hepatic failure. A considerable body of evidence indicates that reactive oxygen species (ROS) and inflammation may contribute to hepatocellular injury in liver I/R. Leflunomide is an isoxazole derivative, and a unique immunomodulatory agent. In the present study, we examined the effects of leflunomide on the neutrophil activation with oxidative stress and some antioxidant enzymes in the reperfusion following I/R in the rat liver. Thirty-two rats divided into four groups: group 1 (control); was given leflunomide 10 mg/kg, i.g.; group 2 (SHAM), animals were only laparotomized; group 3 (liver I/R), and group 4 (liver I/R + Leflunomide). In group 4, rats were pretreated with leflunomide (10 mg/kg, i.g.) two doses prior to experiment. In groups 3 and 4, occluding the hepatic pedicel for 60 min induced ischemia and reperfusion was allowed thereafter for 60 min. At the end of the reperfusion period, rats were sacrificed. superoxide dismutase, catalase, nitric oxide, xanthine oxidase, malondialdehyde, protein carbonyl and myeloperoxidase levels were determined in hepatic tissue as well as histological examination with H and E staining. Group 3 animals demonstrated severe deterioration of liver morphology and a significant liver oxidative stress. Pretreatment of animals with leflunomide markedly attenuated morphological alterations and neutrophil activation, reduced elevated oxidative stress products levels and restored the depleted hepatic antioxidant enzyme. The findings imply that ROS play a causal role in I/R-induced hepatic injury, and leflunomide exerts hepatoprotective effects probably by the anti-inflammatory effect with radical scavenging and antioxidant activities.