Mitochondrial Bioenergetic Dysfunction and Chlorine Toxicity

线粒体生物能功能障碍和氯毒性

基本信息

批准号：
8608361
负责人：
VICTOR M DARLEY-USMAR
金额：
$ 36.75万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-24 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8608361
关键词：
Acute Air Airway Resistance Animals Antioxidants Apoptosis Asthma Autophagocytosis Biochemical Bioenergetics Breathing Cells Cessation of life Chlorine Chronic Obstructive Airway Disease Clara cell Clinical Data Dental Pulp Depressed mood Disaccharides Distal Environmental Health Epithelial Epithelial Cells Excision Exposure to Extracellular Matrix F2-Isoprostanes Functional disorder Gases Generations Genus Hippocampus Glucose Glucosides Glycolysis Human Immunosuppressive Agents In Vitro Industrial Accidents Inflammatory Injury Irritants Lead Life Link Liquid substance Lung Measurement Measures Membrane Potentials Metabolic Mitochondria Morbidity - disease rate Mus Necrosis Organ Organelles Outcome Oxidative Stress Oxygen Pathology Pathway interactions Peripheral Pharmacologic Substance Physiological Plasma Proteins Post-Translational Protein Processing Proteins Public Health Publishing Quality Control Reactive Oxygen Species Recovery Research Personnel Sanitation Sirolimus Structure of parenchyma of lung System Terrorism Testing Therapeutic Intervention Tissues Toxic effect Transplantation Transportation Trehalose Unsaturated Fatty Acids Weight Wheezing adduct alveolar type II cell base chemokine cytokine effective therapy exposed human population extracellular human FRAP1 protein improved in vivo indexing lung injury male mortality novel strategies oxidative damage planetary Atmosphere prevent public health relevance repaired research study wasting wet lung

项目摘要

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.

描述（由申请人提供）：氯 (Cl2) 是一种高刺激性和反应性气体，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。吸入后也会对公众健康构成重大威胁。接触在运输和工业事故以及恐怖主义行为期间释放到大气中的 Cl2 会导致人类和动物显着发病和死亡。没有安全的 Cl2 暴露：即使在家庭中暴露于低水平的 Cl2 也可能导致喘息并加剧哮喘和慢性阻塞性肺病的临床结果。吸入后，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，然后继续延长最初接触 Cl2 的毒性并导致长期病理学。在本提案中，我们将测试以下假设：这些次级反应物质以线粒体为目标，从而降低线粒体质量并导致生物能功能障碍，从而延迟组织恢复和修复。基于这些数据，我们假设线粒体是肺上皮细胞中 Cl2 毒性的关键靶标，通过线粒体靶向抗氧化剂（例如 MitoQ）预防线粒体氧化损伤与增强线粒体自噬（雷帕霉素和海藻糖）的联合策略将是有益的改善Cl2毒性。这一假设将通过完成这两个高度集成的具体目标中强调的体外和体内研究来检验：SA-1：确定人气道细胞体外暴露于 Cl2 后线粒体损伤和自噬的机制和生理后遗症。 SA-2：确定小鼠在 Cl2 后给予 MitoQ、雷帕霉素和海藻糖是否会降低 Cl2 诱导的死亡率和肺损伤并改善线粒体生物能功能。这些实验的完成将为进一步的研究提供合理的基础，以针对人类面临的主要环境和公共卫生威胁建立有效的治疗方法。