Dong Wen-Wen, Liu Yu-Jian, Lv Zhou, Mao Yan-Fei, Wang Ying-Wei, Zhu Xiao-Yan, Jiang Lai
Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, Peoples׳ Republic of China; School of Kinesiology, Key Laboratory of Exercise and Health Sciences, Ministry of Education, Shanghai University of Sport, Shanghai 200438, Peoples׳ Republic of China.
School of Kinesiology, Key Laboratory of Exercise and Health Sciences, Ministry of Education, Shanghai University of Sport, Shanghai 200438, Peoples׳ Republic of China.
Free Radic Biol Med. 2015 Nov;88(Pt B):404-416. doi: 10.1016/j.freeradbiomed.2015.05.004. Epub 2015 May 13.
High-mobility group box 1 (HMGB1) contributes to lung vascular hyperpermeability during ventilator-induced lung injury. We aimed to determine whether the natural antioxidant resveratrol protected against HMGB1-induced endothelial hyperpermeability both in vitro and in vivo. We found that HMGB1 decreased vascular endothelial (VE)-cadherin expression and increased endothelial permeability, leading to mitochondrial oxidative damage in primary cultured mouse lung vascular endothelial cells (MLVECs). Both the mitochondrial superoxide dismutase 2 mimetic MnTBAP and resveratrol blocked HMGB1-induced mitochondrial oxidative damage, VE-cadherin downregulation, and endothelial hyperpermeability. In in vivo studies, anesthetized male ICR mice were ventilated for 4h using low tidal volume (6 ml/kg) or high tidal volume (HVT; 30 ml/kg) ventilation. The mice were injected intraperitoneally with resveratrol immediately before the onset of ventilation. We found that resveratrol attenuated HVT-associated lung vascular hyperpermeability and HMGB1 production. HVT caused a significant increase in nuclear factor-erythroid 2-related factor 2 (Nrf2) nuclear translocation and Nrf2 target gene expression in lung tissues, which was further enhanced by resveratrol treatment. HMGB1 had no effect on Nrf2 activation, whereas resveratrol treatment activated the Nrf2 signaling pathway in HMGB1-treated MLVECs. Moreover, Nrf2 knockdown reversed the inhibitory effects of resveratrol on HMGB1-induced mitochondrial oxidative damage and endothelial hyperpermeability. The inhibitory effect of resveratrol on cyclic stretch-induced HMGB1 mRNA expression in primary cultured MLVECs was also abolished by Nrf2 knockdown. In summary, this study demonstrates that resveratrol protects against lung endothelial barrier dysfunction initiated by HVT. Lung endothelial barrier protection by resveratrol involves inhibition of mechanical stretch-induced HMGB1 release and HMGB1-induced mitochondrial oxidative damage. These protective effects of resveratrol might be mediated through an Nrf2-dependent mechanism.
高迁移率族蛋白B1（HMGB1）在呼吸机诱导的肺损伤过程中会导致肺血管通透性增加。我们旨在确定天然抗氧化剂白藜芦醇是否在体外和体内均能防止HMGB1诱导的内皮细胞通透性增加。我们发现，HMGB1会降低血管内皮（VE）-钙黏蛋白的表达并增加内皮细胞通透性，从而导致原代培养的小鼠肺血管内皮细胞（MLVECs）发生线粒体氧化损伤。线粒体超氧化物歧化酶2模拟物MnTBAP和白藜芦醇均能阻止HMGB1诱导的线粒体氧化损伤、VE-钙黏蛋白下调以及内皮细胞通透性增加。在体内研究中，对麻醉后的雄性ICR小鼠进行4小时的低潮气量（6 ml/kg）或高潮气量（HVT；30 ml/kg）通气。在通气开始前立即给小鼠腹腔注射白藜芦醇。我们发现，白藜芦醇可减轻HVT相关的肺血管通透性增加和HMGB1生成。HVT导致肺组织中核因子红细胞2相关因子2（Nrf2）核转位和Nrf2靶基因表达显著增加，白藜芦醇处理可进一步增强这一作用。HMGB1对Nrf2激活无影响，而白藜芦醇处理可激活HMGB1处理的MLVECs中的Nrf2信号通路。此外，Nrf2基因敲低可逆转白藜芦醇对HMGB1诱导的线粒体氧化损伤和内皮细胞通透性增加的抑制作用。Nrf2基因敲低也消除了白藜芦醇对原代培养的MLVECs中周期性拉伸诱导的HMGB1 mRNA表达的抑制作用。总之，本研究表明白藜芦醇可防止HVT引发的肺内皮屏障功能障碍。白藜芦醇对肺内皮屏障的保护作用涉及抑制机械拉伸诱导的HMGB1释放和HMGB1诱导的线粒体氧化损伤。白藜芦醇的这些保护作用可能是通过Nrf2依赖性机制介导的。
