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.