Mitochondrial Bioenergetic Dysfunction and Chlorine Toxicity

线粒体生物能功能障碍和氯毒性

• 批准号: 8740480
• 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
• 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/8740480
• 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

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.

说明(申请人提供)：氯(Cl2)是一种在世界各地大量生产的高度刺激性和反应性气体，广泛用于纸浆漂白、废物卫生和各种药品的制造。吸入还会对公众健康构成重大威胁。在运输和工业事故中释放到大气中的Cl2以及恐怖主义行为导致人和动物的严重发病率和死亡率。没有安全的Cl2暴露：即使在国内暴露在低水平的Cl2中也可能导致喘息，并加剧哮喘和慢性阻塞性肺疾病的临床结局。吸入时，Cl2首先与肺上皮衬里液(ELF)中的抗氧化剂反应；当抗氧化剂耗尽时，它与蛋白质、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。在这项提案中，我们将检验这一假设，即这些次级反应物种以线粒体为目标，因此降低线粒体质量，并导致生物能量功能障碍，从而延迟组织的恢复和修复。基于这些数据，我们假设线粒体是Cl2对肺上皮细胞毒性的关键靶点，通过线粒体靶向抗氧化剂(如MitoQ)防止线粒体氧化损伤与增强有丝分裂吞噬(通过雷帕霉素和海藻糖)相结合的策略，将有助于减轻Cl2毒性。这一假说将通过完成这两个高度整合的特定目标的体外和体内研究来验证：SA-1：确定体外培养的人呼吸道细胞暴露于Cl2后线粒体损伤和自噬的机制和生理后遗症。SA-2：确定Cl2后给予小鼠MitoQ、雷帕霉素和海藻糖是否降低了Cl2诱导的死亡率和肺损伤，并改善了线粒体生物能量学功能。这些实验的完成将为进一步的研究提供合理的基础，以建立针对对人类的重大环境和公共健康威胁的有效疗法。