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

基本信息

批准号：
10348682
负责人：
David B. Seder
金额：
$ 34.85万
依托单位：
MAINEHEALTH
依托单位国家：
美国
项目类别：
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/10348682
关键词：
Acute Adenosine Adverse effects Affect Anti-Inflammatory Agents Blood Vessels Blood flow Brain Cardiopulmonary Resuscitation 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 base career cell injury clinical phenotype diversity and inclusion endothelial dysfunction experience immunoregulation improved improved outcome molecular phenotype neutrophil novel prevent programs regional difference repaired response rural area rural disparities skills survival outcome

项目摘要

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.

抽象的在美国举行的约600,000次年度心脏骤停事件中，<7％的神经系统可导致生存结果。患者异质性和急诊缺血时间的变化，复苏率，和震后结果。复苏后的凌晨是促进细胞的关键窗口恢复。该项目建立在强大的静止后临床计划的基础上，我们先前的工作确定独特的嗜中性粒细胞种群及其与“后心骤停综合症”中淋巴细胞的相互作用人类。在我们的患者中，复苏后的表达CD73（CD73+）淋巴细胞的数量少中性粒细胞与CD73+淋巴细胞比率各自与较差的预后有关。 CD73是关键酶腺苷的产生，神经保护性并调节血管反应性。因为增加了持续时间缺血也增加了预后不良的风险，我们预测与居住在农村地区的患者的心脏骤停将反映在更少的CD73+循环淋巴细胞中复苏。我们预计急诊护理区域差异会导致异质性炎症反应，强调了心脏骤停研究中多样性和包容性的重要性。在除了我们的临床观察结果，我们的研究显示了CD73+的关键免疫调节作用嗜中性粒细胞激活的淋巴细胞，特别是高度炎性嗜中性粒细胞的新型亚群我们命名了与心脏骤停相关的中性粒细胞（CAANS）。我们将表征分子信号与嗜中性粒细胞和内皮细胞功能相关的CD73+淋巴细胞相关。我们假设 CD73+淋巴细胞的激活是对全身缺血 - 再灌注的急性保护反应伤害全球性缺血的炎症后果。此外，我们预测数量很少 CD73+淋巴细胞与病理性嗜中性粒细胞活化和内皮功能受损相关，导致末端血管区域和大脑和其他组织梗塞的血液流量减少脆弱的器官。我们的目的是：1）确定炎症特征和相关的临床表型在心脏骤停患者中，CD73+淋巴细胞水平变化，2）表征CD73+的影响针对中性粒细胞介导的内皮细胞屏障损伤的淋巴细胞。这是表征心脏复苏后细胞免疫响应的第一次主要尝试逮捕，代表了经验丰富的临床戴维·塞德（David Seder）博士的新型翻译研究方向审判者。塞德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技能人类衍生的炎症细胞，并获得成功的高级身体科学家的心态患者护理，学术医学以及临床和翻译研究的职业（C. Rosen和D. Sawyer）。这项研究的完成将为新的介入试验奠定基础，以改善心脏骤停结果。