Mitigation of Chlorine Injury to Mitochondria

减轻氯对线粒体的损伤

基本信息

批准号：
10480741
负责人：
Sadis Matalon
金额：
$ 18.62万
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：
2021
资助国家：
美国
起止时间：
2021-09-04 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10480741
关键词：
8-Oxoguanine DNA Glycosylase Acute Acute Lung Injury Air Airway Disease Alveolar Animals Apoptosis Arachidonic Acids Attenuated Bioenergetics Bromine Calcium Cell Line Cells Cessation of life Chlorine Chronic Lung Injury Chronic lung disease Cytoplasm DNA Repair Enzymes DNA glycosylase Data Defect Development Dinoprost Dyes Electron Spin Resonance Spectroscopy Epithelial Cells Exposure to F2-Isoprostanes FUS-1 Protein Gases Goals Halogens Heart failure Heme Hour Human Hydration status In Vitro Industrial Accidents Infection Injury Intramuscular Irritants Lipid Peroxidation Lung Measures Membrane Potentials Microvascular Permeability Mitochondria Mitochondrial DNA Mus Necrosis Oxidation-Reduction Oxygen Consumption Patients Phosgene Play Proteins Publishing Pulmonary Edema Pulmonary Emphysema Pulmonary Fibrosis Rattus Recovery Research Personnel Respiration Respiratory Failure Risk Signal Transduction Smooth Muscle Myocytes Structure of parenchyma of lung System Terrorism Testing Therapeutic Ventilator-induced lung injury airway hyperresponsiveness alveolar type II cell bronchial epithelium cell injury experimental study exposed human population extracellular heart function heart preservation in vivo indexing injury and repair lung injury methacholine mitochondrial dysfunction mitochondrial membrane mortality overexpression oxidation prevent repaired respiratory smooth muscle

项目摘要

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.

氯 (Cl2) 是一种刺激性反应性气体，全世界大量生产。人类和因工业事故或恐怖活动而接触 Cl2 的动物会患上严重的反应性气道疾病，肺水肿，甚至呼吸衰竭而死亡。那些幸存下来的人面临着患慢性病的风险肺部疾病，如肺纤维化和肺气肿，并且容易感染。然而，改善急性和慢性肺损伤所涉及的机制和所需的对策仍然存在难以捉摸。在此，我们证明小鼠暴露于 Cl2 会损害其线粒体 DNA (mtDNA)，从而施用 DNA 修复酶 8-氧代鸟嘌呤-DNA 糖基化酶 1 (OGG1)，该酶附着在线粒体靶向信号（mitoOGG1 或 OGG1 融合蛋白）改善线粒体功能障碍 Cl2 引起的急性和慢性肺损伤。我们 R21 应用程序的目标是：(1) 确定小鼠暴露于 Cl2 会损害其线粒体 DNA； (2) Cl2 暴露后给予 mitoOGG1 通过修复 mtDNA 减少急性和慢性肺损伤和死亡率，(3) mitoOGG1 修复体外线粒体生物能学。这些假设将通过完成全面的测试来检验以下两个具体目标概述的一组实验： 1. 评估 mitoOGG1 的功效在 Cl2 暴露后的小鼠中给药可降低急性肺损伤、死亡率和发展体内肺纤维化。 2. 证明 mitoOGG1 在 Cl2 后给予肺细胞体外暴露，通过修复逆转或至少减轻线粒体生物能和细胞损伤他们的线粒体DNA。 mtDNA 损伤会损害线粒体呼吸和膜电位，导致细胞凋亡和坏死。 mitoOGG1，在血红素后施用，将逆转或至少减轻这些影响修复线粒体DNA。先前的研究表明，线粒体DNA损伤在急性炎症的发生中起着关键作用。肺损伤。 mitoOGG1 的过度表达可减轻 mtDNA 损伤并保留心脏功能失败），保护完整小鼠免受呼吸机引起的肺损伤，并限制人类肺损伤循环死亡。因此，除了我们非常令人兴奋的初步数据外，这些已发表的研究表明 mitoOGG1 可能被证明可以治疗暴露于 Cl2 的患者的急性和慢性肺损伤，因为以及其他卤素（如溴）和含氯化合物（如光气）。这些研究结合了两位高级研究人员（Matalon 博士和 Gillespie 博士）的专业知识和重要的专业知识 Cl2 诱导的肺损伤和修复以及线粒体功能。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Chlorine inhalation induces acute chest syndrome in humanized sickle cell mouse model and ameliorated by postexposure hemopexin.

氯吸入会在人源化镰状细胞小鼠模型中诱发急性胸部综合征，并可通过暴露后血红素结合蛋白得到改善。

DOI：
发表时间：
2021-08
期刊：
影响因子：
11.4
作者：
Alishlash, Ammar Saadoon;Sapkota, Muna;Ahmad, Israr;Maclin, Kelsey;Ahmed, Noor A;Molyvdas, Adam;Doran, Stephen;Albert, Carolyn J;Aggarwal, Saurabh;Ford, David A;Ambalavanan, Namasivayam;Jilling, Tamas;Matalon, Sadis
通讯作者：
Matalon, Sadis

Reactive species generated by heme impair alveolar epithelial sodium channel function in acute respiratory distress syndrome.

血红素产生的反应物质会损害急性呼吸窘迫综合征中的肺泡上皮钠通道功能。

DOI：
发表时间：
2020
期刊：
影响因子：
11.4
作者：
Aggarwal, Saurabh;Lazrak, Ahmed;Ahmad, Israr;Yu, Zhihong;Bryant, Ayesha;Mobley, James A;Ford, David A;Matalon, Sadis
通讯作者：
Matalon, Sadis