Organ protection during cardiopulmonary arrest

心肺骤停时的器官保护

• 批准号: 7468129
• 负责人: BUDDHADEB DAWN
• 金额: $ 37万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7468129
• 关键词: Abbreviations; Ablation; Adenosine; Adenosine A1 Receptor; Adenoviruses; Affect; Agonist; American; Animals; Apoptosis; Blood Circulation; Brain; Cardiac; Cardiac Myocytes; Cardiopulmonary; Cardiopulmonary Arrest; Clinical Research; Congestive Heart Failure; Development; Dose; Effectiveness of Interventions; Endothelial Cells; Engineering; Exercise; Exposure to; Female; Gene Targeting; Gene Transfer; Genetic; Goals; Health; Heart; Heart Arrest; Human; Inhibition of Apoptosis; Injury; Intervention; Intestines; Ischemia; Ischemic Preconditioning; Kidney; Lead; Left; Length; Life; Mediating; Mediator of activation protein; Molecular Biology; Mus; Muscle; Myocardial; Myocardial Ischemia; Myocardium; NS-398; Neurologic; Neuronal Injury; Nitric Oxide; Opioid; Organ; Outcome; PTGS2 gene; Pathology; Patients; Personal Satisfaction; Phase; Physiological; Physiology; Protein Chemistry; Protein Overexpression; Public Health; Quality of life; Reactive Oxygen Species; Recovery; Research; Risk; Role; Stress; Testing; Therapeutic; Time; Transgenic Mice; Transgenic Organisms; Up-Regulation; Ventricular; Ventricular Fibrillation; celecoxib; clinically relevant; cyclooxygenase 2; experience; gene therapy; heme oxygenase-1; human NOS2A protein; improved; inhibitor/antagonist; interdisciplinary approach; mimetics; mortality; mouse model; neuron apoptosis; novel; novel therapeutics; outcome forecast; preconditioning; pressure; prevent; protective effect; receptor; response

DESCRIPTION (provided by applicant): No intervention is currently available to prevent the consequences of organ damage associated with cardiopulmonary arrest. While the protective effects of preconditioning (PC) during regional ischemic injury to several organs have been well-documented, it remains unknown whether this phenomenon can be utilized to improve the outcome following cardiac arrest. The overall objective of this proposal is to evaluate the efficacy of physiologic and pharmacologic late PC-mimetic interventions in preventing cardiac and neuronal injury during cardiopulmonary arrest. Our fundamental hypothesis is that the heart and brain can be preconditioned to tolerate the ischemic injury during cardiac arrest by using clinically-feasible PC-mimetic interventions that can be given prophylactically to patients at risk for cardiopulmonary arrest. Specifically, we will test the hypothesis that exposure to exercise, adenosine A1 receptor agonists, opioid ?1 receptor agonists, and NO donors induces delayed antistunning and antiapoptotic effects that result in improved outcome following cardiopulmonary arrest, and that these salubrious effects are mediated by a coordinated upregulation of iNOS, COX-2, and HO-1. This study will utilize a broad multidisciplinary approach that will involve integrative physiology, protein chemistry, molecular biology, and gene targeting. All studies will be carried out in a well-characterized mouse model of cardiac arrest using genetically-engineered animals, which will provide conclusive information. In Aim 1, the efficacy of exercise, CCPA, TAN-67, and DETA/NO in conferring protection during cardiac arrest will be carefully characterized and the mechanism of the antiapoptotic effects will be elucidated. Aim 2 will investigate the role of iNOS in organ protection during cardiopulmonary arrest. Both iNOS-/- and iNOS transgenic mice will be used to determine whether iNOS is necessary and sufficient to confer protection. In Aim 3, the beneficial role of COX-2 will be conclusively established by genetic ablation and pharmacologic inhibition. Aim 4 will elucidate the role of HO-1 as a co-mediator of protection using HO-1-/- mice and HO-1 transgenic mice. Aim 5 will determine the utility of adenovirus-mediated gene transfer of iNOS, COX-2, and HO-1 in recapitulating the beneficial effects. This proposal will yield new and important information regarding the role of clinically-relevant agents in inducing protection against a devastating and common health problem. This information may eventually lead to the development of novel therapeutic strategies to save human lives. PUBLIC HEALTH RELEVANCE Approximately 500,000 Americans are affected by cardiopulmonary arrest every year. Despite decades of research, the survival and prognosis after cardiac arrest remain dismal. Although the phenomenon of preconditioning (PC) has been shown to protect various organs during ischemic injury, its role in cardiac arrest remains unclear. The primary goal of this proposal is to examine whether PC-mimetic physiologic and pharmacologic interventions can protect against cardiac and neurologic injury sustained during cardiac arrest. These results would have enormous therapeutic implications for patients with cardiac arrest. The results of the proposed studies will therefore be highly relevant for improving public health, and improving the length and quality of life of thousands of patients with cardiac arrest.

描述（由申请人提供）：目前尚无干预措施以防止与心肺逮捕有关的器官损害的后果。尽管有充分记录的几个器官的区域性缺血性损伤期间预处理（PC）的保护作用（PC）尚不清楚这种现象是否可以用于改善心脏骤停后的结果。该提案的总体目的是评估生理和药理学晚期PC模拟干预措施在心脏肺停滞期间预防心脏和神经元损伤方面的功效。我们的基本假设是，可以通过使用临床上可行的PC模拟干预措施来预防心脏骤停期间的心脏和大脑在心脏骤停期间忍受缺血性损伤，这些干预措施可以预防性地对有心肺停滞风险的患者进行预防。 Specifically, we will test the hypothesis that exposure to exercise, adenosine A1 receptor agonists, opioid ?1 receptor agonists, and NO donors induces delayed antistunning and antiapoptotic effects that result in improved outcome following cardiopulmonary arrest, and that these salubrious effects are mediated by a coordinated upregulation of iNOS, COX-2, and HO-1.这项研究将利用一种广泛的多学科方法，该方法将涉及综合生理学，蛋白质化学，分子生物学和基因靶向。所有研究都将在使用遗传学工程动物的心脏骤停的小鼠模型中进行，这将提供结论性信息。在AIM 1中，将仔细表征运动在心脏骤停期间提供的锻炼，CCPA，TAN-67和DETA/NO的疗效，并将阐明抗凋亡作用的机制。 AIM 2将调查iNOS在心肺骤停过程中的器官保护中的作用。 iNOS - / - 和iNOS转基因小鼠都将用于确定iNOS是否需要且足以提供保护。在AIM 3中，COX-2的有益作用将通过遗传消融和药理抑制来确定。 AIM 4将使用HO-1 - / - 小鼠和HO-1转基因小鼠阐明HO-1作为保护者的作用。 AIM 5将确定腺病毒介导的iNOS，COX-2和HO-1基因转移的效用，以概括有益作用。该提案将产生有关临床上与临床相关的代理在诱发毁灭性和常见健康问题保护方面的作用的新的重要信息。这些信息最终可能导致发展新型治疗策略以挽救人类生命。 公共卫生相关性约有50万美国人每年受到心肺逮捕的影响。尽管进行了数十年的研究，但心脏骤停后的生存和预后仍然令人沮丧。尽管已显示预处理现象（PC）在缺血性损伤期间可以保护各种器官，但其在心脏骤停中的作用尚不清楚。该提案的主要目的是检查PC模拟生理和药理干预措施是否可以预防心脏骤停期间遭受的心脏和神经系统损伤。这些结果对心脏骤停患者具有巨大的治疗意义。因此，拟议研究的结果将与改善公共卫生以及改善数千名心脏骤停患者的寿命长度和质量相关。