Haorah J, Knipe B, Leibhart J, Ghorpade A, Persidsky Y
Department of Pharmacology, University of Nebraska Medical Center, Omaha, NE 68198-5215, USA.
J Leukoc Biol. 2005 Dec;78(6):1223-32. doi: 10.1189/jlb.0605340. Epub 2005 Oct 4.
Brain microvascular endothelial cells (BMVEC) connected by tight junctions (TJ) form a tight monolayer at the blood-brain barrier (BBB). We investigated the idea that BBB dysfunction seen in alcohol abuse is associated with oxidative stress stemming from ethanol (EtOH) metabolism in BMVEC. Exposure to EtOH induced catalytic activity/expression of EtOH-metabolizing enzymes, which paralleled enhanced generation of reactive oxygen species (ROS). EtOH-mediated oxidative stress led to activation of myosin light chain (MLC) kinase, phosphorylation of MLC and TJ proteins, decreased BBB integrity, and enhanced monocyte migration across BBB. Acetaldehyde or ROS donors mimicked changes induced by EtOH in BMVEC. Thus, oxidative stress resulting from alcohol metabolism in BMVEC can lead to BBB breakdown in alcohol abuse, serving as an aggravating factor in neuroinflammatory disorders.
通过紧密连接(TJ)相连的脑微血管内皮细胞(BMVEC)在血脑屏障(BBB)处形成紧密的单层结构。我们研究了一个观点,即酒精滥用中所见的血脑屏障功能障碍与BMVEC中乙醇(EtOH)代谢产生的氧化应激有关。暴露于EtOH会诱导EtOH代谢酶的催化活性/表达,这与活性氧(ROS)生成增加相平行。EtOH介导的氧化应激导致肌球蛋白轻链(MLC)激酶活化、MLC和TJ蛋白磷酸化、血脑屏障完整性降低以及单核细胞跨血脑屏障迁移增加。乙醛或ROS供体模拟了EtOH在BMVEC中诱导的变化。因此,BMVEC中酒精代谢产生的氧化应激可导致酒精滥用中的血脑屏障破坏,成为神经炎症性疾病的一个加重因素。