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

描述（由申请人提供）：心脏骤停（CA）是全球主要死亡原因之一。尽管心肺复苏（CPR）方法取得了进展，但这些骤停中有60-80%导致立即死亡，而在其余的人中，只有约5%成功复苏，恢复了生产性生活。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是内源性产生的，并对各种靶点产生许多生物学效应，导致从细胞毒性到细胞保护作用的反应。据报道，施用H2S供体（Na 2S）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Na 2S显著改善了小鼠CA/CPR后24小时的心肌和神经功能以及存活率。Na 2S的强大保护作用与减弱的氧化应激、神经元死亡和增强的NO信号有关。值得注意的是，Na 2S的保护作用被NOS 3缺乏所消除。重要的是，如通过活体小鼠中的扩散加权MRI所证明的，施用Na 2S防止CA/CPR后24小时CA/CPR诱导的显著脑水肿的发展。 本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局。具体而言，我们建议：（目的1）在具有优化的心脏骤停后护理的CA/CPR小鼠模型中表征神经和心肌功能障碍以及全身炎症的时间依赖性演变，（目的2）确定硫化氢对CA/CPR后神经和心肌功能障碍演变的影响，（目的3）确定NOS在H2S对CA/CPR结果的保护作用中的作用，目的4）阐明硫化氢对培养的神经细胞、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，拟议的研究将阐明独特的保护作用的硫化物为基础的方法CA/CPR使用我们的创新的小鼠心脏骤停和CPR的体内模型。 公共卫生相关性：心脏骤停（CA）是全球主要死亡原因之一。尽管心肺复苏（CPR）方法取得了进展，但这些骤停中有60-80%导致立即死亡，而在其余的人中，只有约5%成功复苏，恢复了生产性生活。需要创新的方法来改善心脏骤停和CPR的结果。本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局。我们预计，拟议的研究将阐明独特的保护作用的硫化物为基础的方法CA/CPR使用我们的创新的小鼠心脏骤停和CPR的体内模型。

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.