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首页> 外文期刊>American Journal of Physiology >Mitochondrial-targeted DNA repair enzyme 8-oxoguanine DNA glycosylase 1 protects against ventilator-induced lung injury in intact mice
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Mitochondrial-targeted DNA repair enzyme 8-oxoguanine DNA glycosylase 1 protects against ventilator-induced lung injury in intact mice

机译：线粒体靶向DNA修复酶8-氧鸟嘌呤DNA糖基化酶1可以防止呼吸机诱发的完整小鼠肺损伤

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摘要

This study tested the hypothesis that oxidative mitochondrial-targeted DNA (mtDNA) damage triggered ventilator-induced lung injury (VILI). Control mice and mice infused with a fusion protein targeting the DNA repair enzyme, 8-oxoguanine-DNA glycosylase 1 (OGG1) to mitochondria were mechanically ventilated with a range of peak inflation pressures (PIP) for specified durations. In minimal VILI (1 h at 40 cmH_2O PIP), lung total extravascular albumin space increased 2.8-fold even though neither lung wet/dry (W/D) weight ratios nor bronchoalveolar lavage (BAL) macrophage inflammatory protein (MIP)-2 or IL-6 failed to differ from nonventilated or low PIP controls. This increase in albumin space was attenuated by OGG1. Moderately severe VILI (2 h at 40 cmH_1O PIP) produced a 25-fold increase in total extravascular albumin space, a 60% increase in W/D weight ratio and marked increases in BAL MIP-2 and IL-6, accompanied by oxidative mito-chondrial DNA damage, as well as decreases in the total tissue glutathione (GSH) and GSH/GSSH ratio compared with nonventilated lungs. All of these injury indices were attenuated in OGG1-treated mice. At the highest level of VILI (2 h at 50 cmH_2O PIP), OGG1 failed to protect against massive lung edema and BAL cytokines or against depletion of the tissue GSH pool. Interestingly, whereas untreated mice died before completing the 2-h protocol, OGG1-treated mice lived for the duration of observation. Thus mitochondri-ally targeted OGG1 prevented VILI over a range of ventilation times and pressures and enhanced survival in the most severely injured group. These findings support the concept that oxidative mtDNA damage caused by high PIP triggers induction of acute lung inflammation and injury.
机译：这项研究检验了以下假设：氧化线粒体靶向DNA（mtDNA）损伤引发了呼吸机诱发的肺损伤（VILI）。对照小鼠和注入靶向DNA修复酶，8-氧鸟嘌呤-DNA糖基化酶1（OGG1）到线粒体的融合蛋白的小鼠，在一定的持续时间内以一定范围的峰值充气压力（PIP）机械通气。在最小的VILI（在40 cmH_2O PIP下为1小时）中，即使肺湿/干（W / D）重量比或支气管肺泡灌洗（BAL）巨噬细胞炎性蛋白（MIP）-2或IL-6未能与非通风或低PIP控制有所不同。白蛋白空间的这种增加被OGG1减弱。中度严重的VILI（在40 cmH_1O PIP下2小时）使总血管外白蛋白空间增加了25倍，W / D重量比增加了60％，BAL MIP-2和IL-6明显增加，并伴有氧化性Mito与不通气的肺相比，线粒体DNA损伤以及总组织谷胱甘肽（GSH）和GSH / GSSH比率降低。在OGG1处理的小鼠中，所有这些损伤指数均减弱。在VILI最高水平（在50 cmH_2O PIP下2小时）时，OGG1未能针对大量肺水肿和BAL细胞因子或组织GSH池耗竭提供保护。有趣的是，未治疗的小鼠在完成2小时实验方案之前就死亡了，而经OGG1处理的小鼠在观察期间存活了下来。因此，线粒体靶向的OGG1在一定的通气时间和压力范围内可预防VILI，并在最严重的受伤组中提高了生存率。这些发现支持了由高PIP引起的氧化mtDNA损伤触发急性肺炎症和损伤诱导的概念。

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