Ronis Martin J J, Butura Angelica, Korourian Soheila, Shankar Kartik, Simpson Pippa, Badeaux Jamie, Albano Emanuele, Ingelman-Sundberg Magnus, Badger Thomas M
Department of Pharmacology & Toxicology, University of Arkansas for Medical Sciences, 1120 Marshall Street, Little Rock, AR 72202, USA.
Exp Biol Med (Maywood). 2008 Mar;233(3):344-55. doi: 10.3181/0707-RM-203.
To determine the temporal relationship between alcohol-induced changes in cytokines and chemokines, development of liver pathology and stimulation of hepatocyte proliferation, male Sprague-Dawley rats were intragastrically fed low carbohydrate-containing ethanol (EtOH) diets via total enteral nutrition (TEN) for up to 49 d. Induction of EtOH metabolism and appearance of steatosis preceded development of oxidative stress, inflammation, and cell death. A transitory peak of tumor necrosis factor (TNFalpha) and interferon gamma (IFN gamma) was observed at 14 d followed by reduced expression of TNFalpha, IFN gamma and another Th1 cytokine IL-12 accompanied by reduced expression of the Th1 regulators T-bet and STAT4. After 35-49 d of EtOH, at a time when hepatocyte proliferation was stimulated, IL-12 returned to control values and a second peak of TNFalpha occurred. The Th2 cytokine IL-4 remained suppressed throughout the study and was accompanied by reductions in the Th2 regulator GATA3. There was no temporal effect of EtOH on expression of IL-6 or TGFbeta. IL-5 and IL-13 mRNA were undetectable. Chemokine CXCL-2 expression increased progressively up to 35 d and preceded the appearance of inflammatory infiltrates. These data suggest that steatosis, increased ethanol metabolism, a transient induction of the innate immune response and suppression of Th2 responses were acute consequences of ethanol treatment and were followed by suppression of Th1 responses. However, the majority of necrosis, apoptosis and a late peak of TNFalpha only occurred after 6-7 weeks of ethanol, coincided with the appearance of inflammatory infiltrates and were associated with stimulation of hepatocyte proliferation.
为了确定酒精诱导的细胞因子和趋化因子变化、肝脏病理发展以及肝细胞增殖刺激之间的时间关系，通过全肠内营养（TEN）给雄性Sprague-Dawley大鼠经胃内喂食含低碳水化合物的乙醇（EtOH）饮食，持续49天。EtOH代谢的诱导和脂肪变性的出现先于氧化应激、炎症和细胞死亡的发展。在第14天观察到肿瘤坏死因子（TNFα）和干扰素γ（IFNγ）出现短暂峰值，随后TNFα、IFNγ和另一种Th1细胞因子IL-12的表达降低，同时Th1调节因子T-bet和STAT4的表达也降低。在EtOH处理35 - 49天后，即肝细胞增殖受到刺激时，IL-12恢复到对照值，并且TNFα出现第二个峰值。Th2细胞因子IL-4在整个研究过程中一直受到抑制，同时Th2调节因子GATA3也减少。EtOH对IL-6或TGFβ的表达没有时间效应。未检测到IL-5和IL-13 mRNA。趋化因子CXCL-2的表达在35天前逐渐增加，并先于炎症浸润的出现。这些数据表明，脂肪变性、乙醇代谢增加、先天免疫反应的短暂诱导和Th2反应的抑制是乙醇处理的急性后果，随后是Th1反应的抑制。然而，大多数坏死、凋亡和TNFα的晚期峰值仅在乙醇处理6 - 7周后出现，与炎症浸润的出现同时发生，并与肝细胞增殖的刺激有关。
