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）是世界范围内死亡的主要原因之一。尽管心肺复苏（CPR）方法取得了进步，但这些骤停中有60-80%导致立即死亡，而剩下的人中，只有约5%成功复苏，恢复了有生产力的生活。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，具有一种典型的臭鸡蛋气味，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，并对各种靶点产生一系列生物效应，从而产生从细胞毒性到细胞保护作用的反应。据报道，H2S供体（Na2S）可以减轻啮齿动物和猪的心肌缺血再灌注（IR）损伤。在初步研究部分的研究中，我们观察到在心肺复苏术时给予Na2S可显著改善小鼠的心肌和神经功能以及CA/CPR后24小时的存活率。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缺乏所抵消。重要的是，活体小鼠的弥散加权MRI显示，Na2S可预防CA/CPR后24小时CA/CPR诱导的显著脑水肿的发生。本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合并心脏骤停综合征的预后。具体而言，我们建议：（目的1）在优化心脏骤停后护理的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对H2S对CA/CPR结果的保护作用。（目的4）阐明硫化氢在培养的神经元、内皮细胞和心肌细胞中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术的体内模型阐明基于硫化物的CA/CPR方法的独特保护作用。

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.