Lung endothelial barrier protection by resveratrol involves inhibition of HMGB1 release and HMGB1-induced mitochondrial oxidative damage via an Nrf2-dependent mechanism
Lung endothelial barrier protection by resveratrol involves inhibition of HMGB1 release and HMGB1-induced mitochondrial oxidative damage via an Nrf2-dependent mechanism
复制标题
白藜芦醇对肺内皮屏障的保护涉及通过 Nrf2 依赖性机制抑制 HMGB1 释放和 HMGB1 诱导的线粒体氧化损伤
DOI：
10.1016/j.freeradbiomed.2015.05.004
复制
发表时间：
2015-11-01
影响因子：
7.4
通讯作者：
Jiang, Lai
中科院分区：
文献类型：
--
作者：
Dong, Wen-Wen;Liu, Yu-Jian;Jiang, Lai
高迁移率族蛋白1(HMGB1)参与了呼吸机所致肺损伤时肺血管的高通透性。我们的目的是确定天然抗氧化剂白藜芦醇在体外和体内是否对HMGB1诱导的内皮高通透性具有保护作用。我们发现HMGB1降低了原代培养的小鼠肺血管内皮细胞(MLVECs)血管内皮细胞(VE)-钙粘附素的表达，增加了内皮细胞的通透性，导致线粒体氧化损伤。线粒体超氧化物歧化酶2模拟物MnTBAP和白藜芦醇均可阻断HMGB1诱导的线粒体氧化损伤、VE-钙粘附素下调和内皮高通透性。在体内实验中，麻醉的雄性ICR小鼠分别用小潮气量(6ml/kg)和大潮气量(HVT：30ml/kg)进行4h的机械通气。在开始换气之前，立即给小鼠腹腔注射白藜芦醇。我们发现，白藜芦醇可抑制HVT相关的肺血管高通透性和HMGB1的产生。高压氧可引起肺组织核因子-红系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HMGB1对Nrf2活化的影响，而白藜芦醇处理可激活Nrf2信号通路。此外，Nrf2基因敲除逆转了白藜芦醇对HMGB1诱导的线粒体氧化损伤和内皮高通透性的抑制作用。白藜芦醇对周期性牵张诱导的MLVECs HMGB1mRNA表达的抑制作用也可被Nrf2基因敲除。综上所述，本研究表明白藜芦醇对HVT所致的肺内皮细胞屏障功能障碍具有保护作用。白藜芦醇对肺内皮细胞屏障的保护作用包括抑制机械牵张诱导的HMGB1释放和HMGB1诱导的线粒体氧化损伤。白藜芦醇的上述保护作用可能是通过Nrf2依赖机制实现的。(C)2015 Elsevier Inc.保留所有权利
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 4 h 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. (C) 2015 Elsevier Inc. All rights reserved