Immunomodulatory Therapy After Resuscitation From Cardiac Arrest

心脏骤停复苏后的免疫调节治疗

• 批准号: 10334812
• 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
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10334812
• 关键词: Acute; Address; Adult; Animal Model; Attenuated; Biology; Blood Circulation; Brain; Brain Injuries; Cardiopulmonary Resuscitation; Cardiovascular Physiology; Cardiovascular system; Clinical; Clinical Research; Critical Care; Development; Epinephrine; Event; Family suidae; Functional disorder; Heart; Heart Arrest; Heart Diseases; Heart Injuries; Hospitals; Immune; Immunology; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Injury to Kidney; Innate Immune Response; Innate Immune System; Intervention; Ischemia; Knowledge; Leukocytes; Leukocytosis; Life; Lipids; Mediating; Medicine; Micelles; Morbidity - disease rate; Neurologic; Operative Surgical Procedures; Organ; Patients; Pharmacology; Physiologic pulse; Play; Process; Prognosis; Public Health; Reperfusion Therapy; Research; Resuscitation; Role; Science; Severities; Spleen; Survival Rate; Syndrome; Testing; Tissues; Treatment Efficacy; United States; attenuation; beta-2 Adrenergic Receptors; chemokine receptor; design; effective therapy; experimental study; immune activation; immunomodulatory therapies; improved; inhibitor; insight; ischemic injury; macrophage; monocyte; monocyte chemoattractant protein 1 receptor; mortality; multidisciplinary; multiorgan damage; multiorgan injury; neutrophil; novel; novel strategies; novel therapeutic intervention; organ injury; porcine model; receptor-mediated signaling; systemic inflammatory response; therapeutic target; tissue injury; treatment strategy

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 每年在美国，近60万名成年人患有心脏骤停，大部分活动 突然发生在看似健康的人的院外环境中。尽管基本和 先进的生活支持增加了实现赞助商圈子（ROSC）回归的可能性， 从心脏骤停复苏后入院的患者中，将近70％会死亡 医院出院。最初达到ROSC的患者的发病率和死亡率高 主要归因于全身性损伤，涉及长时间的全身缺血和 尽管激活再灌注，但一种病理生理疾病称为“后心骤停综合征”。 先天免疫系统被认为是该综合征的重要组成部分， 由此产生的炎症反应导致后刺激性组织损伤仍然很差 理解。不幸的是，这种知识差距阻碍了有效治疗策略的发展 为心脏骤停综合征患者提供多器官保护。 本应用程序中提出的研究旨在通过检验中心假设来解决此问题 快速的白细胞增多和巨噬细胞膨胀是全身性后传播的积分成分 心脏骤停复苏后，炎症反应加剧了多器官损伤。 使用高度翻译的后心骤停综合症猪模型，外科手术和 将聘请药理学方法来确定脾白细胞释放的机械作用 传播后炎症和损伤（AIM 1），确定该过程是否被肾上腺素扩增 心肺复苏期间介导的β2-肾上腺素能受体（AIM 2），并评估 靶向方法的治疗效率，以减弱依赖CCR2的白细胞浸润。 逮捕综合症（AIM 3）。一种解决这些目标的综合研究方法是由 具有心血管生理学专业知识的多学科调查团队，大型心脏模型 疾病，白细胞生物学，免疫学和神经保护疗法。共同完成提议的 预计研究将显着提高我们对先天免疫系统介导的机械理解 心脏骤停复苏后的伤害，并确定新的治疗干预措施，以减轻多种 器官损害通过衰减后反应后的炎症反应，最终支持 开发新的策略，以提高心脏骤停患者的不可接受的低生存率 综合征。