Yang Ying-Ying, Lee Kuei-Chuan, Huang Yi-Tsau, Wang Ying-Wen, Hou Ming-Chih, Lee Fa-Yauh, Lin Han-Chieh, Lee Shou-Dong
Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital Taipei, Taiwan.
J Hepatol. 2008 Jul;49(1):25-33. doi: 10.1016/j.jhep.2008.02.012. Epub 2008 Mar 14.
BACKGROUND/AIMS: Increased intrahepatic resistance (IHR) in cirrhosis is due to fibrosis and hepatic endothelial dysfunction (HED). Besides producing fibrosis, increased reactive oxygen species (ROS) promotes ROS-related nitration of anti-oxidative enzymes in cirrhotic livers. Tyrosine nitration (nitrotyrosilation)-related inactivation of anti-oxidative enzymes is increased in cirrhotic livers. This study investigates effects of N-acetylcysteine (NAC) administrations in bile-duct-ligation (BDL) rats.
This study measured portal venous pressure (PVP), IHR, hepatic endothelial function, hepatic levels of anti-oxidants and oxidants, type III procollagen (PIIIP), proteins expression of thromboxane synthase (TXS), nitrotyrosine, manganese superoxide dismutase (MnSOD), and hepatic NOx and thromboxane A(2) (TXA(2)) production in perfusates.
The improvement of HED was associated with decreased PVP and IHR, hepatic protein and mRNA levels of PIIIP, protein expression of TXS and nitrotyrosine, oxidants and production of TXA(2) in NAC-treated BDL rat livers. Conversely, hepatic NOx production, anti-oxidants, and protein expression of MnSOD were increased in NAC-treated BDL rat livers.
In NAC-treated cirrhotic rats, the decrease in IHR was mainly caused by its anti-oxidative effect-related prevention of hepatic fibrogenesis associated with the decrease of oxidants-related nitrotyrosilation and improvement of HED.
背景/目的：肝硬化时肝内阻力（IHR）增加是由于纤维化和肝内皮功能障碍（HED）所致。除了产生纤维化外，活性氧（ROS）增加还会促进肝硬化肝脏中抗氧化酶的ROS相关硝化作用。肝硬化肝脏中与酪氨酸硝化（硝基酪氨酸化）相关的抗氧化酶失活增加。本研究探讨了N-乙酰半胱氨酸（NAC）给药对胆管结扎（BDL）大鼠的影响。
本研究测量了门静脉压力（PVP）、IHR、肝内皮功能、肝脏抗氧化剂和氧化剂水平、III型前胶原（PIIIP）、血栓素合酶（TXS）、硝基酪氨酸、锰超氧化物歧化酶（MnSOD）的蛋白表达，以及灌注液中肝脏NOx和血栓素A2（TXA2）的产生。
在NAC处理的BDL大鼠肝脏中，HED的改善与PVP和IHR降低、PIIIP的肝脏蛋白和mRNA水平、TXS和硝基酪氨酸的蛋白表达、氧化剂以及TXA2产生减少有关。相反，NAC处理的BDL大鼠肝脏中肝脏NOx产生、抗氧化剂和MnSOD的蛋白表达增加。
在NAC处理的肝硬化大鼠中，IHR降低主要是由于其抗氧化作用相关地预防了与氧化剂相关的硝基酪氨酸化减少和HED改善相关的肝纤维化。
