Immunomodulatory Therapy After Resuscitation From Cardiac Arrest

摘要 在美国，每年有近60万成年人患有心脏骤停，其中大多数事件 在看似健康的个体中突然发生在院外环境中。尽管基础设施和 先进的生命支持增加了实现自主循环恢复（ROSC）的可能性， 近70%的心脏骤停复苏后入院的患者将在 出院最初达到ROSC的患者的高发病率和死亡率一直是 主要归因于全身性、多器官损伤，伴随着长时间的全身缺血， 再灌注，一种被称为“心脏骤停后综合征”的病理生理状况。虽然激活 先天免疫系统被认为是该综合征的重要组成部分，其机制是 所产生的炎症反应导致复苏后组织损伤仍然很差 明白不幸的是，这种知识差距阻碍了有效治疗策略的发展 为心脏骤停后综合征患者提供多器官保护。 本申请中提出的研究旨在通过检验中心假设来解决这个问题 快速白细胞增多和巨噬细胞扩增是ROSC后系统性 在心脏骤停复苏后加重多器官损伤炎症反应。 使用心脏骤停综合征的高度平移猪模型，手术和 将采用药理学方法来确定脾白细胞释放在 ROSC后炎症和损伤（目的1），确定这一过程是否被肾上腺素放大- 介导的β 2-肾上腺素能受体的刺激在心肺复苏（目的2），并评估 靶向方法减轻心脏术后CCR 2依赖性白细胞浸润的疗效 停搏综合征（目的3）。一个综合的研究方法，以解决这些目标已经制定了一个 具有心血管生理学专业知识的多学科研究团队，大型心脏动物模型 疾病，白细胞生物学，免疫学和神经保护疗法。总体而言，完成拟议的 这项研究有望显著推进我们对先天免疫系统介导的 心脏骤停复苏后的损伤，并确定新的治疗干预，减轻多- 通过减弱复苏后炎症反应，最终促进 开发新的策略，以提高心脏骤停后患者不可接受的低生存率 综合征

Abstract Nearly 600,000 adults suffer from cardiac arrest in the United States each year, with the majority of events occurring suddenly in an out-of-hospital setting in seemingly healthy individuals. Although advances in basic and advanced life support have increased the likelihood of achieving return of spontaneous circulation (ROSC), nearly 70% of patients that are admitted to the hospital following resuscitation from cardiac arrest will die before hospital discharge. The high morbidity and mortality rate of patients who initially achieve ROSC has been attributed primarily to systemic, multi-organ injury that accompanies prolonged whole-body ischemia and reperfusion, a pathophysiological condition referred to as “post-cardiac arrest syndrome”. Although activation of the innate immune system is recognized to be an important component of this syndrome, the mechanisms by which the resulting inflammatory response contributes to post-resuscitation tissue injury remain poorly understood. Unfortunately, this knowledge gap has hindered the development of effective treatment strategies to provide multi-organ protection in patients with post-cardiac arrest syndrome. The studies proposed in the present application aim to address this problem by testing the central hypothesis that rapid leukocytosis and macrophage expansion are integral components of the systemic post-ROSC inflammatory response that exacerbate multi-organ injury following resuscitation from cardiac arrest. Using a highly translational porcine model of post-cardiac arrest syndrome, a combination of surgical and pharmacological approaches will be employed to identify the mechanistic role of splenic leukocyte release in post-ROSC inflammation and injury (Aim 1), determine whether this process is amplified by epinephrine- mediated stimulation of ß2-adrenergic receptors during cardiopulmonary resuscitation (Aim 2), and evaluate the therapeutic efficacy of a targeted approach to attenuate CCR2-dependent leukocyte infiltration in post-cardiac arrest syndrome (Aim 3). An integrated research approach to address these aims has been developed by a multi-disciplinary investigative team with expertise in cardiovascular physiology, large animal models of heart disease, leukocyte biology, immunology, and neuroprotective therapies. Collectively, completion of the proposed studies is expected to significantly advance our mechanistic understanding of innate immune system-mediated injury following resuscitation from cardiac arrest and identify novel therapeutic interventions that mitigate multi- organ damage by attenuating the post-resuscitation inflammatory response, ultimately facilitating the development of novel strategies to improve the unacceptably low survival rate of patients with post-cardiac arrest syndrome.