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。

基本信息

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
项目类别：
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

项目摘要

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.

制造厂的意外泄漏很常见，大量人可能会暴露于高处卤素（CL2/BR2）浓度。使用卤素气体作为化学武器也正在上升。受害者意外的溴暴露经历呼吸窘迫，心脏骤停和回路崩溃。研究评估BR2暴露的急性和慢性后遗症很少，治疗仍然有症状，因为没有存在有效的对策。我们的研究确定，心脏在动物中受到严重伤害存活高剂量卤素（CL2/BR2）吸入。该应用程序的目的是识别生物学负责这些事件的机制并开发适当的对策。基于令人兴奋的我们提出的初步数据表明，在肺部产生了诸如溴化脂质之类的经纪反应物。溴反应物/脂质与含氧血液一起到达心脏。这些反应物使重要的重要调节心跳的钙泵。钙泵的不活跃会导致钙的积累或心脏细胞中的“钙过载”。钙超负荷是一个严重的问题，可能导致心脏突然死亡。增加的钙还激活破坏性蛋白，这是破坏心脏超微结构的钙蛋白酶。我们因此，假设BR2吸入会产生激活Ca2+敏感的高反应性中间体导致细胞骨架和线粒体损伤和心肌功能障碍以及钙蛋白酶抑制作用的钙蛋白酶会减轻BR2引起的心肺功能障碍和死亡。这些假设将通过完成以下特定目的概述了实验。 SA＃1：特征是心脏损伤和死亡 BR2吸入。 SA＃2：测试BR2和BR2反应物激活心脏钙的假设并导致细胞骨架和线粒体损伤。 SA＃3：测试基于Calpain抑制剂的对策是否减轻由BR2吸入引起的急性和慢性作用。该项目的结果将确定有效的解毒剂对于溴的毒性并增强因意外或故意暴露引起的紧急情况的准备。