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

• 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
• 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

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）是全球死亡的主要原因之一。尽管心肺复苏（CPR）方法的进展，但其中60-80％的逮捕导致了立即死亡，而剩余的逮捕方法只有大约5％的人成功复苏了，以至于它们恢复了生产力。需要创新的方法来改善心脏骤停和CPR的结果。 硫化氢是一种无色的气体，具有在各种天然和工业来源中发现的特征性腐烂的气味。最近的研究表明，H2S是内源产生的，并对各种靶标发挥了许多生物学作用，从而产生了从细胞毒性到细胞保护作用的反应。据报道，施用H2S供体（NA2S）会减轻啮齿动物和猪的心肌缺血 - 再灌注（IR）损伤。在“初步研究”部分提出的研究中，我们观察到，在小鼠中，CA/CPR后，心肺复苏术时的NA2S显着改善了24H。 Na2s的强大保护作用与氧化应激，神经元死亡和没有信号增强有关。值得注意的是，NA2S的保护作用被NOS3缺乏消除了。重要的是，在活小鼠中扩散加权MRI证明，在CA/CPR之后，NA2S的给药可阻止CA/CPR诱导的24H脑水肿的发育。 该提案的总体目标是阐明H2S的作用，并制定新的治疗策略，以改善CA/CPR的结局，使后心骤停综合征复杂化。具体而言，我们建议：（目标1）在CA/CPR的小鼠模型中表征神经和心肌功能障碍和全身性炎症的时间相关的演变，并具有优化的心脏骤停后护理（目标2），以定义硫化物对神经和心肌功能的影响的影响（目标2），该影响的影响3）（ca/ca）的保护性（Aim cpr）的影响（Aim cpr）（Aim cpr）（Aim cpr）的影响（Aim cpr）（Aim cpr）（Aim cpr）（Aim cpr）（Aim cpr）（Aim cpr）的影响（aive of Aert）（AIM CPR）（AIM CPR）（AIM CPR）的影响（AIM CPR）（AIM CPR）的影响（ H2S关于CA/CPR的结果，（目标4）阐明了负责硫化氢在培养的神经元，内皮细胞和心肌细胞中硫化氢的保护作用的分子信号传导机制。 我们预计拟议的研究将使用我们的创新体内鼠心脏骤停模型和CPR来阐明基于硫化物的CA/CPR方法的独特保护作用。 公共卫生相关性：突然心脏骤停（CA）是全球死亡的主要原因之一。尽管心肺复苏（CPR）方法的进展，但其中60-80％的逮捕导致了立即死亡，而剩余的逮捕方法只有大约5％的人成功复苏了，以至于它们恢复了生产力。需要创新的方法来改善心脏骤停和CPR的结果。该提案的总体目标是阐明H2S的作用，并制定新的治疗策略，以改善CA/CPR的结局，使后心骤停综合征复杂化。我们预计拟议的研究将使用我们的创新体内鼠心脏骤停模型和CPR来阐明基于硫化物的CA/CPR方法的独特保护作用。