Karaman Abdurrahman, Iraz Mustafa, Kirimlioglu Hale, Karadag Nese, Tas Erkan, Fadillioglu Ersin
Department of Pediatric Surgery, Turgut Ozal Medical Center, Faculty of Medicine, Inonu University, 44280, Malatya, Turkey.
Pediatr Surg Int. 2006 Sep;22(9):701-8. doi: 10.1007/s00383-006-1744-2. Epub 2006 Aug 5.
Cholestasis, or impaired bile flow, occurs in a wide variety of liver diseases and causes hepatic damage by retention and accumulation of toxic hydrophobic bile salts inducing persistent inflammation and oxidative stress. In the present research, we studied the effect of leflunomide, a novel immunosuppressive and anti-inflammatory agent against autoimmune disease, on hepatic damage produced by double ligature of the extrahepatic biliary duct in Wistar Albino rats. Cholestasis was done by double ligature and section of the extrahepatic biliary duct (BDL). Leflunomide was given i.g. 10 mg/kg/day. The severity of cholestasis and hepatic injury was determined by changes in the plasma enzyme activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and levels of direct bilirubin. Malondialdehyde (MDA), protein carbonyl (PC), nitric oxide (NO), catalase (CAT) and superoxide dismutase (SOD) were determined to the oxidative status in the liver tissue. Myeloperoxidase (MPO) activity and levels of tissue hydroxyproline (HPR) were determined to neutrophil activation and collagen accumulation, respectively. Further, histological changes were studied. Treatment with leflunomide markedly reduced serum transaminase activities as compared to BDL rats. At the same time leflunomide significantly inhibited increases in liver MDA, PC and NO levels and also attenuated the depletion of CAT and SOD in the liver after bile duct ligation. Similarly, increase in tissue MPO activity and HPR due to BDL was also attenuated by leflunomide treatment. These findings were supported by histopathological findings. These findings suggested that leflunomide can attenuate hepatic damage in extrahepatic cholestasis by prevention of oxidative stress and inflammatory process.
胆汁淤积，即胆汁流动受损，发生于多种肝脏疾病中，并通过有毒疏水性胆汁盐的潴留和蓄积导致肝损伤，进而引发持续的炎症和氧化应激。在本研究中，我们研究了来氟米特（一种用于治疗自身免疫性疾病的新型免疫抑制剂和抗炎药）对Wistar白化大鼠肝外胆管双重结扎所致肝损伤的影响。通过双重结扎和切断肝外胆管（BDL）来造成胆汁淤积。来氟米特经口给予，剂量为10 mg/kg/天。通过丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）的血浆酶活性变化以及直接胆红素水平来确定胆汁淤积和肝损伤的严重程度。测定丙二醛（MDA）、蛋白质羰基（PC）、一氧化氮（NO）、过氧化氢酶（CAT）和超氧化物歧化酶（SOD）以评估肝组织的氧化状态。分别测定髓过氧化物酶（MPO）活性和组织羟脯氨酸（HPR）水平以评估中性粒细胞活化和胶原蓄积情况。此外，还研究了组织学变化。与BDL大鼠相比，来氟米特治疗显著降低了血清转氨酶活性。同时，来氟米特显著抑制了胆管结扎后肝脏MDA、PC和NO水平的升高，并减轻了肝脏中CAT和SOD的消耗。同样，来氟米特治疗也减弱了BDL所致的组织MPO活性和HPR的升高。这些发现得到了组织病理学结果的支持。这些结果表明，来氟米特可通过预防氧化应激和炎症过程减轻肝外胆汁淤积中的肝损伤。
