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Immunosuppression after cardiac arrest and resuscitation

心脏骤停和复苏后的免疫抑制

基本信息

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
项目类别：
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

项目摘要

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.

摘要