Immunomodulatory Therapy After Resuscitation From Cardiac Arrest

摘要 在美国，每年有近60万成年人遭受心脏骤停，其中大多数事件 突然发生在看似健康的个体的院外环境中。尽管在基础和技术方面的进展 先进的生命支持增加了实现自主循环恢复(ROSC)的可能性， 在心脏骤停复苏后入院的患者中，近70%的人会在 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，伴随着长期的全身缺血和 再灌注，一种被称为“心脏骤停后综合征”的病理生理状态。尽管激活了 先天免疫系统被认为是这种综合征的重要组成部分，其机制是通过 其中导致的炎症反应对复苏后组织损伤的影响仍然很小 明白了。不幸的是，这一知识差距阻碍了有效治疗策略的发展。 为心脏骤停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一问题 快速白细胞增多和巨噬细胞扩张是全身性ROSC后的重要组成部分 心脏骤停复苏后加重多器官损伤的炎症反应。 使用高度翻译的猪心脏骤停后综合征模型，外科手术和 将使用药理学方法来确定脾白细胞释放的机制作用 ROSC后炎症和损伤(目标1)，确定这一过程是否被肾上腺素放大- 在心肺复苏期间介导性的2-肾上腺素能受体的刺激(目标2)，并评估 靶向治疗心脏术后CCR2依赖性白细胞浸润的疗效观察 停滞综合征(目标3)。为了解决这些目标，一种综合的研究方法已经由一个 多学科研究团队，在心血管生理学、心脏大型动物模型方面具有专业知识 疾病、白细胞生物学、免疫学和神经保护疗法。总体上，完成拟议的 研究有望显著推进我们对先天免疫系统介导的机制的理解 心脏骤停复苏后的损伤，并确定新的治疗干预措施，以减轻多 通过减轻复苏后的炎症反应造成器官损伤，最终促进 开发新的策略来改善心脏骤停后患者不可接受的低存活率 综合症。

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.