Adenosinergic Signaling in the Immunoinflammatory Response After Cardiac Arrest

摘要 在美国每年约600,000例心脏骤停事件中，7%的患者存活下来，神经系统状况良好 结果。患者的异质性和急诊护理的差异会影响缺血时间、复苏率、 以及复苏后的结果。复苏后的最初几个小时是促进细胞生长的关键窗口 恢复。该项目建立在一个强大的复苏后临床计划和我们之前的工作确定 心跳骤停综合征患者独特的中性粒细胞群及其与淋巴细胞的相互作用 人类。在我们的患者中，复苏后低数量的CD73+(CD73+)淋巴细胞和高数量的 中性粒细胞/CD73+淋巴细胞比率均与不良预后相关。CD73是一种关键的酶。 产生腺苷，它具有神经保护作用，调节血管反应性。因为延长的持续时间 缺血也会增加不良预后的风险，我们预测缺血时间越长与 生活在农村地区的患者的心脏骤停将反映在CD73+循环淋巴细胞减少 复苏。我们预计急诊护理的地区差异将导致 炎症反应，强调多样性和包容性在心脏骤停研究中的重要性。在……里面 除了我们的临床观察，我们的研究表明CD73+具有关键的免疫调节作用 淋巴细胞对中性粒细胞的激活，特别是在一个新的高度炎症性中性粒细胞亚群上 我们将心脏骤停相关的中性粒细胞命名为(CAANs)。我们将描述分子信号 与CD73+淋巴细胞相关的中性粒细胞和内皮细胞功能。我们假设 CD73+淋巴细胞活化是对全身缺血再灌注的急性保护性反应 抑制全球缺血引起的炎症后果的损伤。此外，我们预测，较低的数字 CD73+淋巴细胞与病理性中性粒细胞活化和内皮功能受损有关， 导致血管末端区域的血流量减少和脑及其他部位的组织梗塞 脆弱的器官。我们的目标是：1)确定炎症特征和相关的临床表型 在心脏骤停患者中有不同水平的CD73+淋巴细胞，以及2)CD73+细胞的作用特征 淋巴细胞对抗中性粒细胞介导的内皮细胞屏障损伤。 这是首次对心脏复苏后的细胞免疫反应进行表征的重大尝试。 对于经验丰富的临床医生David Seder来说，这代表了一种新的翻译研究方向 三人组。Seder博士将把他的临床研究技能扩展到基于实验室的分子表型分析技能 人类来源的炎症细胞，并接受高级内科医生和科学家的指导，成功地 从事病人护理、学术医学以及临床和翻译研究(C.Rosen和D.Sawyer) 这项研究的完成将为新的介入试验改善心脏骤停结果奠定基础。

Abstract Of the ~600,000 annual cardiac arrest events in the USA, <7% result in survival with a good neurological outcome. Patient heterogeneity and variations in emergency care affect ischemia time, rates of resuscitation, and post-resuscitation outcomes. The early hours after resuscitation are a critical window to promote cell recovery. This project builds upon a robust post-resuscitation clinical program and our prior work identifying unique neutrophil populations and their interactions with lymphocytes in “post-cardiac arrest syndrome” in humans. In our patients, low numbers of CD73-expressing (CD73+) lymphocytes after resuscitation and a high neutrophil to CD73+ lymphocyte ratio are each associated with worse outcomes. CD73 is a key enzyme in the generation of adenosine, which is neuroprotective and regulates vasoreactivity. Because increased duration of ischemia also increases risk of poor outcome, we predict that the longer ischemic times associated with cardiac arrest in patients living in rural areas will be reflected in fewer CD73+ circulating lymphocytes post- resuscitation. We expect regional differences in emergency care to contribute to heterogeneity of the inflammatory response, emphasizing the importance of diversity and inclusion in cardiac arrest research. In addition to our clinical observations, our studies show critical immunomodulatory effects of CD73+ lymphocytes on neutrophil activation, specifically on a novel subpopulation of highly inflammatory neutrophils we have named cardiac arrest-associated neutrophils (CAANs). We will characterize molecular signaling associated with CD73+ lymphocytes with respect to neutrophil and endothelial cell function. We hypothesize that activation of CD73+ lymphocytes is an acute protective response to whole-body ischemia-reperfusion injury that dampens the inflammatory consequences of global ischemia. Further, we predict that low numbers of CD73+ lymphocytes correlate with pathological neutrophil activation and impaired endothelial function, leading to decreased blood flow at end-vascular territories and tissue infarction in the brain and other vulnerable organs. Our aims are to: 1) determine the inflammatory profiles and associated clinical phenotypes in cardiac arrest patients with varying levels of CD73+ lymphocytes, and 2) characterize the effects of CD73+ lymphocytes against neutrophil-mediated injury to the endothelial cell barrier. This is the first major attempt to characterize the cellular immune response after resuscitation from cardiac arrest, and represents a novel translational research direction for Dr. David Seder, an experienced clinical trialist. Dr. Seder will expand his clinical research skills into laboratory-based skills in molecular phenotyping of human-derived inflammatory cells, and receive mentorship from senior physician-scientists with successful careers in patient care, academic medicine, and clinical and translational research (C. Rosen and D. Sawyer). The completion of this study will set the stage for novel interventional trials to improve cardiac arrest outcomes.