Immunomodulatory Therapy After Resuscitation From Cardiac Arrest

心脏骤停复苏后的免疫调节治疗

基本信息

批准号：
10543188
负责人：
Brian Raymond Weil
金额：
$ 45.56万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10543188
关键词：
Acute Address Adult Animal Model Attenuated Biology Brain Brain Injuries Cardiopulmonary Resuscitation Cardiovascular Physiology Cardiovascular system Circulation Clinical Clinical Research Critical Care Development Epinephrine Event Experimental Designs Family suidae Functional disorder Heart Heart Arrest Heart Diseases Heart Injuries Hospitals Immunology Individual Infiltration Inflammation Inflammatory Inflammatory Response Injury Injury to Kidney Innate Immune Response Innate Immune System Intervention Ischemia Knowledge Leucocytic infiltrate Leukocytes Leukocytosis Life Lipids Macrophage Mediating Medicine Micelles Morbidity - disease rate Nervous System Physiology Operative Surgical Procedures Organ Patient Admission Patients Physiologic pulse Play Process Prognosis Public Health Reperfusion Therapy Research Resuscitation Role Science Severities Spleen Survival Rate Syndrome Testing Tissues Treatment Efficacy United States White Blood Cell Count procedure attenuation beta-2 Adrenergic Receptors chemokine receptor cytokine effective therapy immune activation immunomodulatory therapies immunoregulation improved inhibitor insight ischemic injury monocyte monocyte chemoattractant protein 1 receptor mortality multidisciplinary multiorgan damage multiorgan injury neuroprotection neutrophil novel novel strategies novel therapeutic intervention organ injury pharmacologic porcine model receptor-mediated signaling systemic inflammatory response therapeutic target tissue injury treatment strategy

项目摘要

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.

抽象的在美国，每年有近 600,000 名成年人遭受心脏骤停，其中大多数事件尽管在基础和高级阶段，但在看似健康的个体中突然发生在院外环境中。先进的生命支持增加了实现自主循环（ROSC）恢复的可能性，近 70% 因心脏骤停复苏而入院的患者会在之前死亡最初实现 ROSC 的患者出院后发病率和死亡率较高。主要归因于伴随长期全身缺血的全身性多器官损伤再灌注，一种称为“心脏骤停后综合征”的病理生理状况。先天免疫系统被认为是该综合征的重要组成部分，其机制是由此产生的炎症反应导致复苏后组织损伤状况不佳不幸的是，这种知识差距阻碍了有效治疗策略的制定。为心脏骤停后综合征患者提供多器官保护。本申请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张是 ROSC 后全身恢复的重要组成部分心脏骤停复苏后加剧多器官损伤的炎症反应。使用心脏骤停后综合征的高度转化猪模型，结合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（目标 1），确定该过程是否被肾上腺素放大心肺复苏过程中介导的 ß2 肾上腺素能受体刺激（目标 2），并评估减轻心脏术后 CCR2 依赖性白细胞浸润的靶向方法的治疗效果逮捕综合症（目标 3）已由一个综合研究方法来解决这些目标。具有心血管生理学、大型动物心脏模型专业知识的多学科研究团队疾病、白细胞生物学、免疫学和神经保护疗法的共同完成。研究预计将显着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，并确定减轻多种损伤的新治疗干预措施通过减弱复苏后的炎症反应来减轻器官损伤，最终促进开发新策略以改善心脏骤停后患者的低得令人无法接受的生存率综合症。