Delivery of the Cu/Zn-superoxide dismutase gene with adenovirus reduces early alcohol-induced liver injury in rats.
Delivery of the Cu/Zn-superoxide dismutase gene with adenovirus reduces early alcohol-induced liver injury in rats.
复制标题
DOI：
10.1053/gast.2001.23253
复制
发表时间：
2001-04
期刊：
影响因子：
29.4
通讯作者：
M. Wheeler;Hiroshi Kono;Ming Yin;Ivan Rusyn;M. Froh;H. Connor;Ronald P. Mason;R. Samulski;R. G. Thurman
中科院分区：
文献类型：
--
作者：
M. Wheeler;Hiroshi Kono;Ming Yin;Ivan Rusyn;M. Froh;H. Connor;Ronald P. Mason;R. Samulski;R. G. Thurman
背景和目的酒精性肝损伤与多种可能来源的氧化剂增加有关。因此，我们推测抗氧化酶Cu/ zn -超氧化物歧化酶（SOD1）的增加和稳定表达可以减少氧自由基，减轻酒精性肝损伤。方法采用含Cu/ zn超氧化物歧化酶（Ad.SOD1）或β -半乳糖苷酶（Ad.lacZ）的重组腺病毒给药，灌胃乙醇3周。结果感染3周后，肝细胞和库普弗细胞中SOD水平均较内源性水平显著升高3-5倍。Ad患者血清转氨酶水平及病理指标均显著升高。lacz处理动物采用灌胃饲养模型。这种效果在Ad中明显减弱。SOD1-infected动物。重要的是，SOD1过表达也降低了乙醇引起的电子自旋共振可检测的自由基加合物。此外，乙醇引起的核因子κ b （NFkappaB）、肿瘤坏死因子α (tnf - α)和白细胞介素1信使RNA （mRNA）的升高被Ad.SOD1所钝化。结论：这些数据支持了一种假设，即氧化剂的产生在早期酒精性肝损伤中起关键作用，抗氧化酶的基因传递可能有助于预防和治疗。
BACKGROUND AND AIMS Alcohol-induced liver injury is associated with an increase in oxidants from a variety of possible sources. Therefore, it was hypothesized that increased and stable expression of the antioxidant enzyme Cu/Zn-superoxide dismutase (SOD1) would diminish oxygen free radicals and reduce alcohol-induced liver injury. METHODS To test this hypothesis, rats were given recombinant adenovirus containing Cu/Zn-superoxide dismutase (Ad.SOD1) or beta-galactosidase (Ad.lacZ) and fed ethanol enterally for 3 weeks. RESULTS SOD was increased significantly 3-5-fold over endogenous levels in both hepatocytes as well as Kupffer cells 3 weeks after infection. Serum transaminase levels and pathology were elevated significantly in Ad.lacZ-treated animals by using an intragastric feeding model. This effect was blunted significantly in Ad.SOD1-infected animals. Importantly, electron spin resonance-detectable free-radical adducts caused by ethanol were also decreased by SOD1 overexpression. Moreover, the increase in nuclear factor kappaB (NFkappaB), tumor necrosis factor alpha (TNF-alpha), and interleukin 1 messenger RNA (mRNA) caused by ethanol was blunted in animals treated with Ad.SOD1. CONCLUSIONS These data support the hypothesis that oxidant production is critical in early alcohol-induced liver injury and that gene delivery of antioxidant enzymes may be useful in prevention and treatment.