Adenosinergic Signaling in the Immunoinflammatory Response After Cardiac Arrest

心脏骤停后免疫炎症反应中的腺苷信号传导

• 批准号: 10558715
• 负责人: David B. Seder
• 金额: $ 35.1万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-10 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558715
• 关键词: Acute; Adenosine; Adverse effects; Affect; Anti-Inflammatory Agents; Blood Vessels; Blood flow; Brain; Cardiopulmonary Resuscitation; Cell Separation; Cell physiology; Cells; Centers of Research Excellence; Cerebral Edema; Clinical; Clinical Research; Development; Elements; Emergency Care; Endothelial Cells; Endothelium; Enzymes; Event; Feedback; Functional disorder; Future; Generations; Grouping; Heart Arrest; Heart Injuries; Heterogeneity; Hour; Human; Hypoxic-Ischemic Brain Injury; Immune; Immune response; Impairment; Infarction; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention Trial; Ischemia; Knowledge; Laboratories; Lead; Lymphocyte; Lymphocyte Count; Lymphopenia; Mediating; Mediation; Medicine; Mentorship; Molecular; Myeloid Cells; Myocardial dysfunction; Names; Natural regeneration; Nervous System Trauma; Neurological outcome; Neurons; Neutrophil Activation; Organ; Organ failure; Outcome; Pathologic; Pathway interactions; Patient Care; Patient-Focused Outcomes; Patients; Peripheral; Phagocytosis; Phenotype; Physicians; Population; Production; Reactive Oxygen Species; Recovery; Reperfusion Injury; Research; Resuscitation; Risk; Scientist; Signal Transduction; Survivors; Syndrome; TNF gene; Testing; Time; Tissues; Translational Research; Variant; Work; acute care; career; cell injury; clinical phenotype; diversity and inclusion; endothelial dysfunction; experience; immunoregulation; improved; improved outcome; molecular phenotype; neuroprotection; neutrophil; novel; prevent; programs; regional difference; repaired; response; rural area; rural disparities; skills; survival outcome

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.

摘要 在美国每年约600，000例心脏骤停事件中，<7%的患者存活并具有良好的神经系统功能。 结果。患者异质性和急诊护理的变化影响缺血时间、复苏率， 和复苏后的结果。复苏后的早期是促进细胞增殖的关键窗口。 复苏该项目建立在一个强大的复苏后临床计划和我们以前的工作， 心脏骤停综合征患者中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，复苏后表达CD 73的（CD 73+）淋巴细胞数量较少，而表达CD 73的（CD 73+）淋巴细胞数量较多 中性粒细胞与CD 73+淋巴细胞的比值均与不良结局相关。CD 73是一种关键酶， 生成腺苷，其具有神经保护作用并调节血管反应性。因为持续时间的增加 缺血也增加了不良结局的风险，我们预测缺血时间越长， 生活在农村地区的患者心脏骤停将反映在更少的CD 73+循环淋巴细胞后， 复苏术我们预计，急救护理的地区差异有助于异质性， 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 除了我们的临床观察外，我们的研究还显示了CD 73+的关键免疫调节作用， 淋巴细胞对中性粒细胞活化的影响，特别是对高度炎症性中性粒细胞的新亚群的影响 我们命名为心脏骤停相关中性粒细胞（CAAN）。我们将描述分子信号 在中性粒细胞和内皮细胞功能方面与CD 73+淋巴细胞相关。我们假设 CD 73+淋巴细胞的活化是对全身缺血-再灌注的急性保护性反应 抑制全身缺血的炎症后果的损伤。此外，我们预测， 与病理性中性粒细胞活化和内皮功能受损相关， 导致血管末端区域的血流量减少和脑及其他组织梗塞 脆弱的器官我们的目的是：1）确定炎症特征和相关的临床表型 在具有不同水平的CD 73+淋巴细胞的心脏骤停患者中，和2）表征CD 73+淋巴细胞的作用 淋巴细胞对抗嗜中性粒细胞介导的对内皮细胞屏障的损伤。 这是第一次主要尝试表征心脏复苏后的细胞免疫反应， 逮捕，并代表了一个新的翻译研究方向博士大卫塞德，一个经验丰富的临床 trialist. 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， 人源性炎症细胞，并接受资深医生科学家的指导， 病人护理，学术医学，临床和转化研究（C。罗森和D.索耶）。 这项研究的完成将为改善心脏骤停结局的新型干预性试验奠定基础。