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.

制造工厂的意外泄漏很常见，大量人员可能会暴露在高浓度的环境中。使用卤素气体作为化学武器的受害者也在增加。意外接触溴会导致呼吸窘迫、心脏骤停和循环衰竭研究。评估 Br2 暴露的急性和慢性后遗症的情况很少，并且治疗仍然是针对症状的，因为没有我们的研究表明，存在有效的应对措施，动物的心脏会受到严重损伤。耐受高剂量卤素 (Cl2/Br2) 吸入本应用的目的是鉴定生物性。负责这些事件的机制并根据令人兴奋的情况制定适当的对策。初步数据表明，溴化反应物（例如溴化脂质）是在肺部产生的。溴化反应物/脂质与含氧血液一起到达心脏，这些反应物会导致重要的失活。调节心跳的钙泵钙泵不活动会导致钙积累或钙泵。心脏细胞中的“钙超载” 钙超载是一个严重的问题，可能导致心脏病。增加的钙也会激活破坏性蛋白质，即破坏心脏超微结构的钙蛋白酶。因此，吸入 Br2 会产生高反应性中间体，激活 Ca2+ 敏感细胞钙蛋白酶导致细胞骨架和线粒体损伤以及心肌功能障碍，钙蛋白酶抑制将减轻 Br2 引起的心肺功能障碍和死亡。这些假设将通过完成进行检验。以下具体目标中概述的实验：描述由以下原因引起的心脏损伤和死亡。 Br2 吸入 SA#2：检验 Br2 和 Br2 反应物激活心脏钙蛋白酶并引起的假设。 SA#3：测试基于钙蛋白酶抑制剂的对策是否可以减轻细胞骨架和线粒体损伤。该项目的成果将确定有效的解毒剂。溴毒性并加强对意外或故意接触引起的紧急情况的准备。