Masuda Yuichi, Vaziri Nosratola D, Takasu Chie, Li Shiri, Robles Lourdes, Pham Christine, Le Aimee, Vo Kelly, Farzaneh Seyed H, Stamos Michael J, Ichii Hirohito
Department of Surgery, Medicine, University of California, Irvine, CA, USA.
Gastroenterol Hepatol (Que). 2014;1(1):1-7. doi: 10.3968/5206.
Ischemia-reperfusion injury (IRI) is a common phenomenon occurring during liver surgery, transplantation, and trauma. IRI causes oxidative stress which plays a critical role in causing organ damage. The Nrf2 is the master regulator of numerous genes, encoding antioxidant, detoxifying, and cytoprotective molecules. Nrf2 dysfunction has been implicated in the pathogenesis of several inflammatory disorders, cancer, and aging. This study was undertaken to investigate the effect of Nrf2 pathway activator (dh404) on warm liver IRI in a rodent model.
Ten Sprague-Dawley rats were treated with dh404 or vehicle. Dh404 was dissolved in sesame oil and was given orally (1.5mg/kg) the night before and 5 hours before procedures. Rat livers were subjected to 60 minutes of 70% ischemia followed by 3 hours of reperfusion. Serum ALT and Malondialdehyde (MDA) were determined and liver tissue was processed for histological examination, and determination of apoptosis, myeloperoxidase (MPO) activity, ADP/ATP ratio, and expressions of Nrf2, eNOS, anti-oxidant enzymes, and inflammatory mediators.
Serum ALT and MDA levels and tissue MPO activity were significantly lower, expression of the anti-oxidant enzyme, glutamate cysteine ligase were significantly higher, whereas expression of NFkB and COX-2 was unchanged in the dh404-treated group. Although the total Suzuki histology score did not differ significantly, the extent of sinusoidal congestion, vacuolization, and apoptosis was significantly reduced in the dh404 treated compared to the untreated group (P<0.01).
Pre-treatment with dh404 resulted in partial attenuation of hepatic ischemia reperfusion injury in rats.
缺血再灌注损伤（IRI）是肝脏手术、移植及创伤过程中常见的现象。IRI会引发氧化应激，而氧化应激在导致器官损伤中起关键作用。核因子E2相关因子2（Nrf2）是众多基因的主要调节因子，可编码抗氧化、解毒及细胞保护分子。Nrf2功能障碍与多种炎症性疾病、癌症及衰老的发病机制有关。本研究旨在探究Nrf2通路激活剂（dh404）对啮齿动物模型中温缺血肝脏IRI的影响。
将10只斯普拉格-道利大鼠分为dh404处理组或对照组。dh404溶于芝麻油，在手术前一晚及手术前5小时经口给予（1.5mg/kg）。大鼠肝脏经历70%缺血60分钟，随后再灌注3小时。测定血清谷丙转氨酶（ALT）和丙二醛（MDA）水平，并对肝组织进行组织学检查，测定凋亡、髓过氧化物酶（MPO）活性、ADP/ATP比值以及Nrf2、内皮型一氧化氮合酶（eNOS）、抗氧化酶和炎症介质的表达。
在dh404处理组中，血清ALT和MDA水平以及组织MPO活性显著降低，抗氧化酶谷氨酸半胱氨酸连接酶的表达显著升高，而核因子κB（NFkB）和环氧化酶-2（COX-2）的表达未发生变化。尽管铃木组织学总评分无显著差异，但与未处理组相比，dh404处理组的肝血窦充血、空泡化及凋亡程度显著降低（P<0.01）。
dh404预处理可部分减轻大鼠肝脏缺血再灌注损伤。
