Mitigation of Chlorine Injury to Mitochondria

氯（Cl 2）是一种刺激性和反应性气体，在世界各地大量生产。人类和 动物因工业事故或恐怖主义行为而暴露于Cl 2，会患上严重的反应性气道疾病， 肺水肿，甚至死于呼吸衰竭。那些存活下来的人有患慢性 肺部疾病，如肺纤维化和肺气肿，并容易感染。但 涉及的机制和改善急性和慢性肺损伤所需的对策仍然存在 难以捉摸在此，我们表明，小鼠暴露于Cl 2会损害其线粒体DNA（mtDNA）， 施用连接到细胞表面的DNA修复酶8-氧代鸟嘌呤-DNA糖基化酶1（OGG 1）， 线粒体靶向信号（mitoOGG 1或OGG 1融合蛋白）改善线粒体功能障碍， 氯致急性和慢性肺损伤。我们的R21应用程序的目标是：（1）建立 小鼠暴露于Cl 2损伤其mtDNA;（2）在Cl 2暴露后给予mitoOGG 1 通过修复线粒体DNA降低急性和慢性肺损伤和死亡率;（3）mitoOGG 1修复 线粒体的体外生物能量学。这些假设将通过完成全面的 一组实验概述了以下两个具体目标：1。评估mitoOGG 1的疗效 在小鼠暴露于Cl 2后给药，以降低急性肺损伤、死亡率和发展 肺纤维化的研究进展2.为了证明在Cl 2后给予肺细胞的mitoOGG 1 体外暴露逆转或至少减轻线粒体生物能量学和细胞损伤， 他们的mtDNA线粒体DNA的损伤将损害线粒体呼吸和膜电位， 凋亡和坏死。在血红素后给予mitoOGG 1，将逆转或至少减轻这些作用， 修复线粒体DNA先前的研究表明，线粒体DNA损伤在急性胰腺炎的发生中起着关键作用， 肺损伤mitoOGG 1过表达减轻心肌线粒体DNA损伤并保护心功能 失败），保护完整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，表明 mitoOGG 1可能被证明是暴露于Cl 2的患者的急性和慢性肺损伤的治疗剂， 以及其他卤素（如溴）和含氯化合物（如光气）。这些 研究联合收割机结合了两位资深研究人员（Matalon博士和吉莱斯皮博士）的专业知识， Cl 2诱导的肺损伤与修复及线粒体功能。

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.