Immunosuppression after cardiac arrest and resuscitation

心脏骤停和复苏后的免疫抑制

• 批准号: 10367177
• 负责人: Wei Yang
• 金额: $ 41.45万
• 依托单位: DUKE UNIVERSITY
• 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 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367177
• 关键词: Acute; Address; Adrenal Glands; Anti-Inflammatory Agents; Antibiotic Therapy; B-Lymphocytes; Bacterial Counts; Blood specimen; Brain; Cardiopulmonary Resuscitation; Cessation of life; Clinical; Clinical Research; Data; Development; Disease; Future; Genetic; Glucocorticoid Receptor; Glucocorticoids; Goals; Health; Healthcare; Heart Arrest; Homeostasis; Hour; Hypothalamic structure; Immune; Immune System Diseases; Immune response; Immune system; Immunosuppression; Impairment; Incidence; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Intensive Care Units; Knockout Mice; Knowledge; Link; Literature; Lung; Lymphocyte; Lymphocyte Function; Lymphopenia; Lymphopoiesis; Mediating; Mission; Modeling; Morbidity - disease rate; Mus; Neurosecretory Systems; Outcome; Outcome Study; Pathology; Pathway interactions; Patients; Pharmacology; Phase; Phenotype; Pilot Projects; Pituitary Gland; Prognosis; Public Health; Recovery of Function; Reporting; Research; Resources; Resuscitation; Role; Stress; Survivors; Syndrome; T-Lymphocyte; Testing; United States National Institutes of Health; Work; aged; apoptosis in lymphocytes; base; biobank; clinical outcome measures; clinically relevant; clinically significant; cytokine; functional outcomes; hypothalamic-pituitary-adrenal axis; immunomodulatory strategy; immunopathology; immunoregulation; improved; improved outcome; infection rate; insight; mortality; mouse model; novel; novel therapeutic intervention; older patient; patient population; prophylactic; resuscitative care; sex; tool

Abstract Due to considerable advances in resuscitation, the number of cardiac arrest (CA) patients who survive the initial arrest and are admitted to the intensive care unit (ICU) has been steadily increasing. However, among this growing patient population, the morbidity and mortality rates remain unacceptably high. This has been attributed primarily to post-CA syndrome of which an imbalanced immune response is a key component. Using our clinically relevant murine model of CA and cardiopulmonary resuscitation (CA/CPR), we recently discovered that following CA/CPR, there is a clear shift from the well-established acute post-CA pro-inflammatory immune response to the less-known anti-inflammatory immune response, which eventually evolves into a severe immunosuppressive state. Further, our preliminary data clearly support a link between this immunosuppressive state, and post-CA infection and poor functional recovery. Importantly, this notion is corroborated by clinical observations that infectious complications occur in a high percentage of CA survivors, and post-resuscitation infection is believed to increase morbidity and mortality. Therefore, it is of tremendous clinical significance to better understand post- CA immunosuppression. Our long-term goal is to develop novel therapeutic strategies to improve CA prognosis. The objective here is to dissect mechanisms that underpin post-CA immunosuppression, and to determine the effects of targeting post-CA immunosuppression on CA outcome, including incidence of infections and long-term functional recovery. Notably, our pilot studies have provided compelling evidence indicating that activation of the hypothalamic-pituitary-adrenal (HPA) axis is a primary mechanism that drives post-CA immunosuppression. Our central hypothesis is that CA and resuscitation activates inflammasomes in the brain, which in turn activates the HPA axis, leading to immunosuppression and poor CA outcome. This hypothesis is based on our strong preliminary data and on substantial literature related to disease-induced immunosuppression. We will test our central hypothesis by pursuing the following specific aims: 1) Determine the role of the HPA axis in post-CA immunosuppression; 2) Determine the role of inflammasomes in post-CA immunosuppression via the HPA axis; and 3) Determine the effects of modulating post-CA immunosuppression on CA outcomes. The proposed research is significant because knowledge we will gain from this study is expected to inform future development of new post-resuscitation care strategies to mitigate detrimental effects of post-CA immune dysfunction and thus, improve overall CA prognosis.

抽象的 由于复苏的巨大进步，生存初始的心脏骤停（CA）患者数量 逮捕并被接受重症监护室（ICU）已稳步增加。但是，其中不断增长 患者人数，发病率和死亡率仍然不可接受。这主要归因于 CA后综合征的免疫反应不平衡是关键成分。使用我们的临床相关 CA和心肺复苏的鼠模型（CA/CPR），我们最近发现以下是 CA/CPR，从公认的急性CA后促炎性免疫反应到 鲜为人知的抗炎免疫反应，最终演变成严重的免疫抑制作用 状态。此外，我们的初步数据清楚地支持了这种免疫抑制状态与CA之后的联系 感染和功能恢复不良。重要的是，通过临床观察证明了这一观念 感染性并发症发生在CA幸存者的高百分比中，并且据信后引起感染感染 提高发病率和死亡率。因此，更好地了解之后更好地理解 - CA免疫抑制。我们的长期目标是制定新的治疗策略来改善CA预后。 这里的目的是剖析基于CA后免疫抑制的机制，并确定 靶向CA后免疫抑制对CA结果的影响，包括感染的发生率和长期 功能恢复。值得注意的是，我们的试点研究提供了令人信服的证据，表明激活 下丘脑 - 垂体 - 肾上腺（HPA）轴是驱动CA后免疫抑制的主要机制。我们的 中心假设是CA和复苏会激活大脑中的炎症，从而激活 HPA轴，导致免疫抑制和CA结果不佳。这个假设是基于我们的强大 初步数据和与疾病诱导的免疫抑制有关的大量文献。我们将测试我们的 通过追求以下特定目的：1）确定HPA轴在CA后CA中的作用 免疫抑制； 2）确定通过HPA轴通过HPA轴的CA后免疫抑制的作用； 3）确定调节CA后免疫抑制对CA结果的影响。提议 研究很重要，因为我们将从这项研究中获得的知识有望为未来的发展提供信息 新的引起弹药后护理策略，以减轻CA后免疫功能障碍的有害影响，因此 改善总体ca预后。