IMPACT OF HYDROGEN SULFIDE ON OUTCOME OF CARDIAC ARREST AND CARDIOPULMONARY RESUS

硫化氢对心脏骤停和心肺复苏结果的影响

基本信息

批准号：
8236893
负责人：
FUMITO ICHINOSE
金额：
$ 42.89万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-05 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8236893
关键词：
Address Animal Model Animals Attenuated Basic Science Biological Brain Brain Injuries Brain region Breathing Cardiac Cardiac Myocytes Cardiopulmonary Cardiopulmonary Resuscitation Caring Cause of Death Cerebral Edema Cessation of life Characteristics Clinical Clinical Research Defibrillators Development Diffusion Endothelial Cells Evolution Exhibits Failure Family suidae Functional disorder Gases Goals Heart Arrest Hydrogen Sulfide Imaging Techniques Inflammation Injury Interdisciplinary Study Life Magnetic Resonance Imaging Methods Modeling Molecular Mus Myocardial Myocardial Ischemia Myocardial dysfunction Nervous System Physiology Neurologic Dysfunctions Neurological outcome Neurons Nitric Oxide Odors Outcome Oxidative Stress Production Radiology Specialty Reperfusion Injury Reporting Research Rodent Role Signal Transduction Source Structure Study Section Sulfides Syndrome Techniques Testing Therapeutic Time Translating Translational Research Trauma Weight base bioimaging cytotoxic egg human NOS3 protein imaging modality improved in vivo Model innovation mouse model multidisciplinary natural hypothermia novel novel strategies novel therapeutics pre-clinical prevent protective effect public health relevance research study response sodium sulfide water diffusion

项目摘要

DESCRIPTION (provided by applicant): Sudden cardiac arrest (CA) is one of the leading causes of death worldwide. Despite advances in cardiopulmonary resuscitation (CPR) methods, 60-80% of these arrests result in immediate death, and of the remaining, only about 5 percent are successfully resuscitated to the extent that they are returned to productive lives. Innovative approach is needed to improve the outcome of cardiac arrest and CPR. Hydrogen sulfide is a colorless gas with a characteristic rotten-egg odor found in various natural and industrial sources. Recent studies suggested that H2S is endogenously produced and exerts a host of biological effects on various targets, resulting in responses that range from cytotoxic to cytoprotective effects. It has been reported that administration of an H2S donor (Na2S) attenuates myocardial ischemia-reperfusion (IR) injury in rodents and pig. In studies presented in the Preliminary Studies section, we observed that administration of Na2S at the time of CPR markedly improved myocardial and neurological function and survival 24h after CA/CPR in mice. The robust protective effect of Na2S was associated with attenuated oxidative stress, neuronal death, and enhanced NO signal. Of note, the protective effects of Na2S were abolished by NOS3 deficiency. Importantly, administration of Na2S prevented CA/CPR-induced development of marked cerebral edema 24h after CA/CPR as demonstrated by diffusion-weighted MRI in live mice. The overall goal of this proposal is to elucidate the role of H2S and develop novel therapeutic strategies to improve outcomes of CA/CPR complicated with post-cardiac arrest syndrome. Specifically, we propose: (Aim 1) To characterize time-dependent evolution of neurological and myocardial dysfunction and systemic inflammation in a mouse model of CA/CPR with optimized post-cardiac arrest care, (Aim 2) To define the impact of hydrogen sulfide on the evolution of neurological and myocardial dysfunction after CA/CPR, (Aim 3) To define the role of NOS for the protective effects of H2S on outcome of CA/CPR, and (Aim 4) To elucidate the molecular signaling mechanisms responsible for the protective effects of hydrogen sulfide in cultured neurons, endothelial cells, and cardiomyocytes. We anticipate that proposed studies will illuminate the unique protective effects of sulfide-based approach to CA/CPR using our innovative in vivo model of murine cardiac arrest and CPR. PUBLIC HEALTH RELEVANCE: Sudden cardiac arrest (CA) is one of the leading causes of death worldwide. Despite advances in cardiopulmonary resuscitation (CPR) methods, 60-80% of these arrests result in immediate death, and of the remaining, only about 5 percent are successfully resuscitated to the extent that they are returned to productive lives. Innovative approach is needed to improve the outcome of cardiac arrest and CPR. The overall goal of this proposal is to elucidate the role of H2S and develop novel therapeutic strategies to improve outcomes of CA/CPR complicated with post-cardiac arrest syndrome. We anticipate that proposed studies will illuminate the unique protective effects of sulfide-based approach to CA/CPR using our innovative in vivo model of murine cardiac arrest and CPR.

描述（由申请人提供）：心脏骤停（CA）是全世界死亡的主要原因之一。尽管心肺复苏 (CPR) 方法取得了进步，但 60-80% 的逮捕会导致立即死亡，而在其余的人中，只有约 5% 能够成功复苏并恢复正常生活。需要创新方法来改善心脏骤停和心肺复苏的结果。硫化氢是一种无色气体，具有典型的臭鸡蛋气味，存在于各种天然和工业来源中。最近的研究表明，H2S 是内源产生的，并对各种靶标产生多种生物效应，产生从细胞毒性到细胞保护作用的反应。据报道，给予 H2S 供体 (Na2S) 可减轻啮齿动物和猪的心肌缺血再灌注 (IR) 损伤。在“初步研究”部分中介绍的研究中，我们观察到在 CPR 时给予 Na2S 可显着改善小鼠 CA/CPR 后 24 小时的心肌和神经功能以及存活率。 Na2S 的强大保护作用与氧化应激减弱、神经元死亡和 NO 信号增强有关。值得注意的是，Na2S 的保护作用因 NOS3 缺乏而消失。重要的是，在活体小鼠中进行弥散加权 MRI 证实，在 CA/CPR 24 小时后，施用 Na2S 可以防止 CA/CPR 诱导的明显脑水肿的发展。该提案的总体目标是阐明 H2S 的作用并开发新的治疗策略，以改善 CA/CPR 并发心脏骤停后综合征的结果。具体来说，我们建议：（目标 1）通过优化的心脏骤停后护理来表征 CA/CPR 小鼠模型中神经和心肌功能障碍以及全身炎症的时间依赖性演变，（目标 2）确定硫化氢的影响CA/CPR 后神经和心肌功能障碍的演变，（目标 3）确定 NOS 在 H2S 对 CA/CPR 结局的保护作用中的作用，以及（目标 4）阐明负责硫化氢对培养的神经元、内皮细胞和心肌细胞的保护作用的分子信号机制。我们预计，拟议的研究将利用我们创新的小鼠心脏骤停和心肺复苏体内模型，阐明基于硫化物的方法对 CA/CPR 的独特保护作用。公共卫生相关性：心脏骤停 (CA) 是全世界死亡的主要原因之一。尽管心肺复苏 (CPR) 方法取得了进步，但 60-80% 的逮捕会导致立即死亡，而在其余的人中，只有约 5% 能够成功复苏并恢复正常生活。需要创新方法来改善心脏骤停和心肺复苏的结果。该提案的总体目标是阐明 H2S 的作用并开发新的治疗策略，以改善 CA/CPR 并发心脏骤停后综合征的结果。我们预计，拟议的研究将利用我们创新的小鼠心脏骤停和心肺复苏体内模型，阐明基于硫化物的方法对 CA/CPR 的独特保护作用。