Inducible nitric oxide synthase is required in alcohol-induced liver injury:: Studies with knockout mice
Inducible nitric oxide synthase is required in alcohol-induced liver injury:: Studies with knockout mice
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DOI：
10.1053/j.gastro.2003.08.030
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发表时间：
2003-12-01
期刊：
影响因子：
29.4
通讯作者：
Arteel, GE
中科院分区：
文献类型：
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作者：
McKim, SE;Gäbele, E;Arteel, GE
背景与目的：氧化应激参与早期酒精性肝损伤，超氧阴离子（O-2（.）-）NADPH氧化酶的产生起着关键作用。然而，自由基一氧化氮（NO.）诱导型一氧化氮合酶（iNOS）也可能参与其中。研究方法：为了验证这一假设，给iNOS敲除小鼠（B6.129P2-Nos 2（tm 1 Lau））和野生型小鼠喂食高脂肪对照或含乙醇饮食4周。结果如下：治疗组之间的平均体重增加没有显著差异，野生型和iNOS敲除小鼠的平均尿乙醇浓度相似。4周后，在野生型小鼠中，肠内乙醇（113 +/- 20）使血清丙氨酸氨基转移酶（ALT）水平显著增加，约为对照值（29 +/- IU/L）的4倍;在iNOS敲除小鼠中，乙醇的这种作用显著减弱（50 +/- 9）。如果野生型小鼠用iNOS抑制剂N-（3-氨甲基）苄基-乙脒（1400 W）治疗，则观察到类似的抗肝损伤保护作用。肠内乙醇还引起野生型小鼠肝脏中严重的脂肪堆积、轻度炎症和坏死，但对iNOS敲除小鼠没有影响。在iNOS基因敲除小鼠中，由酒精引起的4-羟基壬烯醛（脂质过氧化）和3-硝基酪氨酸（活性氮物质形成）蛋白加合物的积累被完全阻断。结论：这些数据有力地支持了这样的假设，即通过产生一氧化氮衍生的促氧化剂（例如，过氧亚硝酸盐）。
Background & Aims: Oxidative stress contributes to early alcohol-induced liver injury, and superoxide (O-2(.)-) production from NADPH oxidase plays a key role. However, the production of the free radical nitric oxide (NO.) by inducible nitric oxide synthase (iNOS) could also be involved. Methods: To test this hypothesis, iNOS knockout (B6.129P2-Nos2(tm1 Lau)) and wild-type mice were fed high-fat control or ethanol-containing diets for 4 weeks. Results: Mean body weight gains were not significantly different between treatment groups, and average urine ethanol concentrations were similar in wild-type and iNOS knockout mice. After 4 weeks, serum alanine aminotransferase (ALT) levels were increased significantly about 4-fold over control values (29 +/- IU/L) by enteral ethanol (113 +/- 20) in wild-type mice; this effect of ethanol was significantly blunted in iNOS knockout mice (50 +/- 9). Similar protective effects against liver damage were observed if wild-type mice were treated with the iNOS inhibitor N-(3-aminomethyl)benzyl-acetamindine (1400W). Enteral ethanol also caused severe fatty accumulation, mild inflammation, and necrosis in the liver in wild-type mice but had no effect in iNOS knockout mice. The accumulation of 4-hydroxynonenal (lipid peroxidation) and 3-nitrotyrosine (reactive nitrogen species formation) protein adducts caused by alcohol was completely blocked in iNOS knockout mice. Conclusions: These data strongly support the hypothesis that iNOS is required for the pathogenesis of early alcohol-induced hepatitis by production of nitric oxide-derived pro-oxidants (e.g., peroxynitrite).