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)是全球主要的死亡原因之一。尽管心肺复苏(CPR)方法取得了进展，但这些逮捕中有60%-80%会导致立即死亡，而在其余的人中，只有大约5%的人成功复苏，恢复正常生活。需要创新的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，带有一种典型的臭鸡蛋味，存在于各种天然和工业来源中。最近的研究表明，硫化氢是由内源性产生的，并在不同的靶点上产生一系列的生物效应，导致从细胞毒性到细胞保护的各种反应。有报道称，给予硫化氢供体(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》部分介绍的研究中，我们观察到，在心肺复苏时给予Na2S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时间。Na2S的强大保护作用与减轻氧化应激、神经元死亡和增强NO信号有关。值得注意的是，Na2S的保护作用被NOS3缺乏所消除。重要的是，在活体小鼠的弥散加权磁共振显示，给予Na2S可以阻止CA/CPR后24小时CA/CPR诱导的显著脑水肿的发展。这项建议的总体目标是阐明硫化氢的作用，并开发新的治疗策略，以改善CA/CPR合并心脏骤停后综合征的预后。具体地说，我们建议：(目的1)描述心跳骤停后优化护理的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)确定一氧化氮合酶在硫化氢对CA/CPR结局的保护作用中的作用，以及(目的4)阐明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，拟议的研究将使用我们创新的小鼠心脏骤停和CPR活体模型来阐明基于硫化物的CA/CPR方法的独特保护效果。 公共卫生相关性：心脏骤停(CA)是世界范围内主要的死亡原因之一。尽管心肺复苏(CPR)方法取得了进展，但这些逮捕中有60%-80%会导致立即死亡，而在其余的人中，只有大约5%的人成功复苏，恢复正常生活。需要创新的方法来改善心脏骤停和心肺复苏的结果。这项建议的总体目标是阐明硫化氢的作用，并开发新的治疗策略，以改善CA/CPR合并心脏骤停后综合征的预后。我们预计，拟议的研究将使用我们创新的小鼠心脏骤停和CPR活体模型来阐明基于硫化物的CA/CPR方法的独特保护效果。

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.