Targeting cardiopulmonary calpains to mitigate toxicity of halogen gases.

针对心肺钙蛋白酶以减轻卤素气体的毒性。

• 批准号: 9754153
• 负责人: Shama Ahmad
• 金额: $ 39.46万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754153
• 关键词: Acute; Adult; Amines; Animals; Antidotes; Biochemical; Biological; Blood; Blood Circulation; Blood Gas Analysis; Bromine; Ca(2+)-Transporting ATPase; Calcium; Calpain; Cardiac; Cardiac Death; Cardiac Myocytes; Cardiopulmonary; Cardiotoxicity; Cell Death; Cessation of life; Chemical Weapons; Chlorine; Chronic; Clinical; Coronary; Corrosives; Data; Development; Distress; Dose; Echocardiography; Electrocardiogram; Emergency Situation; Epithelial; Evaluation; Event; Exposure to; Functional disorder; Gases; Goals; Halogens; Hazardous Substances; Heart; Heart Arrest; Heart Injuries; Heart failure; Homeostasis; Human; Impairment; In Vitro; Industrialization; Inhalation; Injury; Ions; Knowledge; Lead; Left; Lipids; Liquid substance; Lung; Mitochondria; Molecular; Morbidity - disease rate; Myocardial dysfunction; Myocardium; Outcome; Peptide Hydrolases; Peptides; Physiological; Plants; Plasma; Preparation; Production; Proteins; Public Health; Pulse Oximetry; Pump; Rattus; Readiness; Research; Respiratory distress; Reticulum; Shock; Surface; Telemetry; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Ventricular; base; calpain inhibitor; cardiopulmonary system; effective therapy; experience; experimental study; fatty aldehyde; heart cell; heart function; hemodynamics; improved; in vivo; injured; mortality; prevent; primary outcome; respiratory; secondary outcome; sudden cardiac death; time interval; treatment strategy; vascular bed

Accidental leaks from manufacturing plants are common and large groups of people may be exposed to high halogen (Cl2/Br2) concentrations. Use of halogen gases as chemical weapons is also on the rise. Victims of accidental bromine exposure experience respiratory distress, cardiac arrest and circulatory collapse. Studies evaluating acute and chronic sequelae of Br2 exposure are scant and treatment remains symptomatic as no effective countermeasures exist. Our studies have established that the heart is severely injured in animals that survive high dose halogen (Cl2/Br2) inhalation. The purpose of this application is to identify the biological mechanisms responsible for these events and develop appropriate countermeasures. Based on exciting preliminary data we propose that brominated reactants such as brominated lipids are produced in the lungs. Brominated reactants/lipids reach the heart along with oxygenated blood. These reactants inactivate important calcium pumps that regulate the heartbeats. Inactivity of calcium pumps causes calcium accumulation or “calcium overload” in the heart cells. Calcium overload is a serious problem and can lead to sudden cardiac death. Increased calcium also activates destructive proteins, the calpains that destroy cardiac ultrastructure. We therefore hypothesize that Br2 inhalation produces highly reactive intermediates that activate Ca2+ sensitive calpains leading to cytoskeletal and mitochondrial damage and myocardial dysfunction and that calpain inhibition will mitigate Br2-induced cardiopulmonary dysfunction and death. These hypotheses will be tested by completing the experiments outlined in the following specific aims. SA#1: Characterize cardiac injury and death induced by Br2 inhalation. SA#2: Test the hypothesis that Br2 and Br2 reactants activate cardiac calpains and cause cytoskeletal and mitochondrial damage. SA#3: Test whether calpain inhibitor based countermeasures mitigate acute and chronic effects caused by Br2 inhalation. The outcome from this project will identify an effective antidote for bromine toxicity and enhance readiness for emergencies arising from accidental or intentional exposures.

制造工厂的意外泄漏是很常见的，大量的人可能会接触到高放射性物质 卤素(Cl2/Br2)浓度。使用卤素气体作为化学武器的情况也在增加。受害者 意外接触溴会导致呼吸窘迫、心脏骤停和循环衰竭。研究 对BR2暴露的急性和慢性后遗症的评估很少，治疗仍然是无症状的 有效的对策是存在的。我们的研究已经证实，心脏受到严重损伤的动物 在大剂量卤素(Cl2/Br2)吸入中存活。这个应用的目的是为了识别生物 建立应对这些事件负责的机制，并制定适当的对策。基于激动人心的 初步数据我们认为，溴化反应物，如溴化脂，是在肺部产生的。 溴化反应物/脂质随含氧血液一起到达心脏。这些反应物灭活很重要 调节心跳的钙泵。钙泵不活动会导致钙积聚或 心脏细胞中的“钙超载”。钙超载是一个严重的问题，可能导致心脏骤停。 死亡。钙的增加还会激活破坏性蛋白，这种蛋白会破坏心脏的超微结构。我们 因此，假设吸入Br2会产生激活钙敏感的高活性中间体 钙蛋白酶导致细胞骨架和线粒体损伤以及心肌功能障碍，并抑制钙蛋白酶 将减轻BR2引起的心肺功能障碍和死亡。这些假设将通过以下方式进行测试 这些实验概述了以下具体目标。SA#1：描述由以下因素引起的心脏损伤和死亡 吸入BR2。SA#2：验证BR2和BR2反应物激活心脏钙痛并导致 细胞骨架和线粒体受损。SA#3：测试基于Calain抑制剂的对策是否可以缓解 吸入BR2引起的急性和慢性影响。这个项目的结果将确定一种有效的解毒剂 预防溴中毒，并加强对意外或故意暴露引起的紧急情况的准备。