Mitigation of Chlorine Injury to Mitochondria

氯(Cl2)是一种刺激性和反应性气体，在世界各地大量产生。人类和 因工业事故或恐怖主义行为而暴露于Cl2的动物，会患上严重的反应性呼吸道疾病， 肺水肿，甚至死于呼吸衰竭。那些幸存下来的人有患慢性病的风险 肺部疾病，如肺纤维化和肺气肿，易受感染。然而， 涉及的机制(S)和改善急、慢性肺损伤所需的对策仍然存在 难以捉摸。在这里，我们证明了小鼠暴露在Cl2中会损伤它们的线粒体DNA(MtDNA)，这种线粒体DNA 给药DNA修复酶，8-氧鸟嘌呤-DNA糖基酶1(OGG1)，连接到 线粒体靶向信号(mitoOGG1或OGG1融合蛋白)改善线粒体功能障碍和 Cl2诱导的急性和慢性肺损伤。我们的R21应用程序的目标是：(1)建立 小鼠暴露于Cl2会损害其线粒体DNA；(2)Cl2暴露后给予mitoOGG1 通过修复线粒体DNA和(3)mitoOGG1修复来减少急慢性肺损伤和死亡率 线粒体在体外的生物能量学。这些假设将通过完成全面的 以下两个具体目标中概述的一系列实验：1.评估mitoOGG1的疗效 Cl2暴露后小鼠给药可减少急性肺损伤、死亡率和发病 活体内的肺纤维化。2.证明Cl2后给肺细胞注射mitoOGG1 体外暴露，逆转或至少减轻线粒体生物能量学和通过修复细胞损伤 他们的线粒体DNA。线粒体DNA的损伤会损害线粒体的呼吸和膜电位，导致 细胞凋亡和坏死。在血红素后给予mitoOGG1将逆转或至少减轻这些影响，方法是 修复线粒体DNA。先前的研究表明，线粒体DNA的损伤在急性白血病的发生发展中起着关键作用。 肺损伤。过表达mitoOGG1减轻心肌线粒体DNA损伤并保护心功能 失败)，保护完整的小鼠免受呼吸机诱导的肺损伤，并在 循环系统死亡。因此，这些发表的研究，除了我们非常令人兴奋的初步数据外，还表明 MitoOGG1可能被证明对接触Cl2、AS的患者的急性和慢性肺损伤具有治疗作用。 以及其他卤素(如溴)和含氯化合物(如光气)。这些 研究结合了两位高级研究员(马塔隆博士和吉莱斯皮博士)的专业知识和重要的专业知识。 在Cl2诱导的肺损伤修复和线粒体功能方面。

Chlorine (Cl2) is an irritant and reactive gas produced in large quantities throughout the world. Humans and animals exposed to Cl2 from industrial accidents or acts of terrorism, develop severe reactive airway disease, pulmonary edema and even death from respiratory failure. Those that survive are at risk of developing chronic lung diseases, such as pulmonary fibrosis and emphysema and be susceptive to infections. However, the mechanism(s) involved and the countermeasures required to ameliorate acute and chronic lung injury remain elusive. Herein we show that exposure of mice to Cl2 damages their mitochondria DNA (mtDNA) that administration of the DNA repair enzyme, 8-oxoguanine-DNA glycosylase 1 (OGG1), attached to the mitochondrial targeting signal (mitoOGG1 or OGG1 fusion protein) ameliorated mitochondrial dysfunction and Cl2-induced acute and chronic lung injury. The goals of our R21 application are: (1) to establish that exposure of mice to Cl2 damages their mtDNA; (2) administration of mitoOGG1 post Cl2 exposure decrease acute and chronic lung injury and mortality by repairing mtDNA and (3) that mitoOGG1 repairs the mitochondria bioenergetics in vitro. These hypotheses will be tested by completing the comprehensive set of experiments outlined in the following two Specific Aims: 1. Assess the efficacy of mitoOGG1 administered in mice post Cl2 exposure to decreases acute lung injury, mortality and the development of pulmonary fibrosis in vivo. 2. To demonstrate that mitoOGG1, administered to lung cells post Cl2 exposure in vitro, reverses, or at least mitigates, mitochondria bioenergetics and cell injury by repairing their mtDNA. Injury to mtDNA will compromise mitochondria respiration and membrane potential resulting in apoptosis and necrosis. mitoOGG1, administered post-heme, will reverse, or at least mitigate, these effects by repairing mtDNA. Previous studies have shown that injury to mtDNA plays a key role in the development of acute lung injury. Overexpression of mitoOGG1 attenuated mtDNA damage and preserved cardiac function in heart failure), protected against ventilator-induced lung injury in intact mice and limited human lung injury after circulatory death. Thus, these published studies, in addition to our highly exciting preliminary data, indicated that mitoOGG1 may prove to be a therapeutic for acute and chronic lung injury in patients exposed to Cl2, as well as other halogens (such as Bromine) and chlorine-containing compounds (such as Phosgene). These studies combine the expertise of two senior investigators (Drs. Matalon and Gillespie) with significant expertise in Cl2 induced lung injury and repair and mitochondrial function.