Uesugi T, Froh M, Arteel G E, Bradford B U, Gäbele E, Wheeler M D, Thurman R G
Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599-7365, USA.
Hepatology. 2001 Dec;34(6):1149-57. doi: 10.1053/jhep.2001.29400.
Chronic alcohol administration increases gut-derived endotoxin in the portal blood, which activates Kupffer cells through nuclear factor kappaB (NF-kappaB) to produce toxic mediators such as proinflammatory cytokines, leading to liver injury. Therefore, a long-term intragastric ethanol feeding protocol was used here to test the hypothesis that NF-kappaB inhibition would prevent early alcohol-induced liver injury. Adenoviral vectors encoding either the transgene for IkappaB superrepressor (AdIkappaB-SR) or the bacterial beta-galactosidase reporter gene (AdlacZ) were administered intravenously to Wistar rats. Animals were fed a high-fat liquid diet with either ethanol or isocaloric maltose-dextrin (control) for 3 weeks. There was no significant difference in mean urine alcohol concentrations between the groups fed ethanol. IkappaB-SR expression was increased for up to 2 weeks after injection, but was undetectable at 3 weeks. NF-kappaB activation was increased by ethanol and associated with up-regulation of tumor necrosis factor alpha (TNF-alpha). These increases were blunted significantly up to 2 weeks by AdIkappaB-SR. Dietary alcohol significantly increased liver to body weight ratios and serum alanine transaminase (ALT) levels in AdlacZ-treated animals, effects that were blunted significantly in AdIkappaB-SR-treated rats. Ethanol caused severe steatosis, inflammation, and focal necrosis in AdlacZ-treated animals. These pathologic changes were significantly decreased by AdIkappaB-SR. The protective effects of IkappaB-SR were significant 2 weeks after injection, but were lost at 3 weeks when IkappaB-SR was no longer expressed. Ethanol increased 4-hydroxynonenal as a maker of oxidative stress in both AdlacZ and AdIkappaB groups. These data support the hypothesis that NF-kappaB inhibition prevents early alcohol-induced liver injury even in the presence of oxidative stress.
长期摄入酒精会增加门静脉血中源自肠道的内毒素，内毒素通过核因子κB（NF-κB）激活库普弗细胞，使其产生如促炎细胞因子等毒性介质，进而导致肝损伤。因此，本研究采用长期胃内灌注乙醇的方案来验证NF-κB抑制可预防早期酒精性肝损伤这一假说。将编码IkappaB超抑制剂转基因（AdIkappaB-SR）或细菌β-半乳糖苷酶报告基因（AdlacZ）的腺病毒载体静脉注射给Wistar大鼠。动物被喂食含乙醇或等热量麦芽糖糊精（对照）的高脂液体饮食3周。喂食乙醇的各组之间平均尿酒精浓度无显著差异。注射后长达2周IkappaB-SR表达增加，但在3周时检测不到。乙醇会增加NF-κB的激活，并与肿瘤坏死因子α（TNF-α）的上调相关。AdIkappaB-SR可使这些增加在长达2周的时间内显著减弱。在AdlacZ处理的动物中，饮食中的酒精显著增加了肝脏与体重的比值以及血清丙氨酸转氨酶（ALT）水平，而在AdIkappaB-SR处理的大鼠中，这些影响显著减弱。乙醇在AdlacZ处理的动物中导致严重的脂肪变性、炎症和局灶性坏死。AdIkappaB-SR可使这些病理变化显著减少。IkappaB-SR的保护作用在注射后2周时显著，但在3周时当IkappaB-SR不再表达时消失。乙醇在AdlacZ组和AdIkappaB组中均增加了作为氧化应激标志物的4-羟基壬烯醛。这些数据支持了NF-κB抑制即使在存在氧化应激的情况下也能预防早期酒精性肝损伤这一假说。
