Mitochondrial Bioenergetic Dysfunction and Chlorine Toxicity

描述（由申请人提供）：氯（Cl2）是一种高度刺激性的活性气体，在世界各地大量生产，广泛用于纸浆漂白，废物卫生和各种药品的制造。吸入后还会对公众健康构成重大威胁。在交通运输和工业事故以及恐怖主义行为中，暴露于释放到大气中的Cl2会导致人类和动物的严重发病率和死亡率。没有安全的Cl2暴露：即使在家中暴露于低水平的Cl2也可能导致喘息，并加剧哮喘和慢性阻塞性肺疾病的临床结果。吸入时，Cl2首先与肺上皮衬里液（ELF）中的抗氧化剂发生反应；当抗氧化剂耗尽时，它会与蛋白质、细胞外基质成分和不饱和脂肪酸形成相对稳定的加合物，然后继续延长初始Cl2暴露的毒性，并导致长期病理。在本提案中，我们将验证这些次级活性物质以线粒体为目标，从而降低线粒体质量并导致生物能量功能障碍，从而延迟组织恢复和修复的假设。基于这些数据，我们假设线粒体是肺上皮细胞Cl2毒性的关键靶点，通过线粒体靶向抗氧化剂（如MitoQ）和增强线粒体自噬（雷帕霉素和海藻糖）预防线粒体氧化损伤的联合策略将有利于改善Cl2毒性。这一假设将通过完成这两个高度整合的特定目标所强调的体外和体内研究来验证：SA-1：确定体外暴露于人气道细胞Cl2后线粒体损伤和自噬的机制和生理后遗症。SA-2：确定Cl2后给予小鼠MitoQ、雷帕霉素和海藻糖是否能降低Cl2诱导的死亡率和肺损伤，并改善线粒体生物能量功能。这些实验的完成将为进一步的研究提供合理的基础，以便为人类面临的重大环境和公共卫生威胁确立有效的治疗方法。

DESCRIPTION (provided by applicant): Chlorine (Cl2) is a highly irritant and reactive gas produced in large quantities throughout the world and used extensively for pulp bleaching, waste sanitation and in the manufacturing of various pharmaceuticals. It also poses a significant threat to public health when inhaled. Exposure to Cl2, released into the atmosphere during transportation and industrial accidents, as well as acts of terrorism resulted in significant morbidity and mortality to both humans and animals. There is no safe exposure to Cl2: Even domestic exposure to low levels of Cl2 may result in wheezing and exacerbate the clinical outcome of asthma and chronic obstructive pulmonary disease. When inhaled, Cl2 first reacts with antioxidants in the lung epithelial lining fluid (ELF); when antioxidants are depleted, it fors relatively stable adducts with proteins, components of the extracellular matrix and unsaturated fatty acids which then proceed to prolong the toxicity of the initial Cl2 exposure and contribute t the long term pathology. In this proposal we will test the hypothesis that these secondary reactive species target the mitochondrion and so decrease mitochondrial quality and cause bioenergetic dysfunction which delays tissue recovery and repair. Based upon these data we hypothesize that mitochondria are a critical target for Cl2 toxicity in lung epithelial cells and te combined strategy of preventing mitochondrial oxidative damage by mitochondrial targeted antioxidants (such as MitoQ) with enhancing mitophagy (by rapamycin and trehalose), will be beneficial in ameliorating Cl2 toxicity. This hypothesis will be tested by completing the in vitro and in vivo studies highlighted in these two highly integrated specific aims: SA-1: Determine the mechanisms and physiological sequelae of mitochondria injury and autophagy following exposure of human airway cells to Cl2 in vitro. SA-2: Determine if post Cl2 administration of MitoQ, rapamycin and trehalose in mice decreases Cl2 induced mortality and lung injury and improves mitochondrial bioenergetics function. Completion of these experiments will provide the rational basis for additional studies to establish effective therapies for a major environmental and public health threat to humans.