Pathophysiological roles of peroxynitrite in circulatory shock.
Pathophysiological roles of peroxynitrite in circulatory shock.
复制标题
DOI：
10.1097/shk.0b013e3181e7e9ba
复制
发表时间：
2010-09
期刊：
影响因子：
--
通讯作者：
Módis K
中科院分区：
文献类型：
--
作者：
Szabó C;Módis K
过氧亚硝酸盐是一种由一氧化氮（NO）和超氧化物产生的活性氧化剂，它与蛋白质、脂质和DNA反应，促进细胞毒性和促炎症反应。在这里，我们概述了过氧亚硝酸盐在各种形式的循环休克中的作用。免疫组织化学和生化证据表明，在啮齿动物和大型动物的各种内毒素和失血性休克实验模型中，过氧亚硝酸盐的产生。此外，在循环休克后的人体组织中也发现了过氧亚硝酸盐的生物标志物。过氧亚硝酸盐在体内和体外都能引发毒性氧化反应。脂质过氧化的启动、线粒体呼吸链酶的直接抑制、甘油醛-3-磷酸脱氢酶的失活、膜Na+/K+ atp酶活性的抑制、膜钠通道的失活以及其他氧化蛋白修饰都有助于过氧亚硝酸盐的细胞毒性作用。此外，过氧亚硝酸盐是DNA链断裂的有力触发器，随后激活核酶聚（adp -核糖）聚合酶（PARP），从而促进细胞能量崩溃和细胞坏死。过氧亚硝酸盐导致休克发病的其他作用包括儿茶酚胺和儿茶酚胺受体失活（导致血管衰竭）、内皮和上皮损伤（导致内皮和上皮超通透性和屏障功能障碍）以及心肌细胞损伤（导致心脏收缩功能丧失）。中和过氧亚硝酸盐与有效的过氧亚硝酸盐分解催化剂提供细胞保护和有益的作用在啮齿动物和大型动物循环休克模型。
Peroxynitrite is a reactive oxidant produced from nitric oxide (NO) and superoxide, which reacts with proteins, lipids and DNA and promotes cytotoxic and pro-inflammatory responses. Here we overview the role of peroxynitrite in various forms of circulatory shock. Immunohistochemical and biochemical evidence demonstrate the production of peroxynitrite in various experimental models of endotoxic and hemorrhagic shock, both in rodents and in large animals. In addition, biological markers of peroxynitrite have been identified in human tissues after circulatory shock. Peroxynitrite can initiate toxic oxidative reactions in vitro and in vivo. Initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3-phosphate dehydrogenase, inhibition of membrane Na+/K+ ATP-ase activity, inactivation of membrane sodium channels, and other oxidative protein modifications contribute to the cytotoxic effect of peroxynitrite. In addition, peroxynitrite is a potent trigger of DNA strand breakage, with subsequent activation of the nuclear enzyme poly (ADP-ribose) polymerase (PARP), which promotes cellular energetic collapse and cellular necrosis. Additional actions of peroxynitrite that contribute to the pathogenesis of shock include inactivation of catecholamines and catecholamine receptors (leading to vascular failure), endothelial and epithelial injury (leading to endothelial and epithelial hyper-permeability and barrier dysfunction) as well as myocyte injury (contributing to loss of cardiac contractile function). Neutralization of peroxynitrite with potent peroxynitrite decomposition catalysts provides cytoprotective and beneficial effects in rodent and large animal models of circulatory shock.