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:
- 金额:$ 41.45万
- 依托单位:
- 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:
- 关键词:AcuteAddressAdrenal GlandsAnti-Inflammatory AgentsAntibiotic TherapyB-LymphocytesBacterial CountsBlood specimenBrainCardiopulmonary ResuscitationCessation of lifeClinicalClinical ResearchDataDevelopmentDiseaseFutureGeneticGlucocorticoid ReceptorGlucocorticoidsGoalsHealthHealthcareHeart ArrestHomeostasisHourHypothalamic structureImmuneImmune System DiseasesImmune responseImmune systemImmunosuppressionImpairmentIncidenceInfectionInflammasomeInflammationInflammatoryInflammatory ResponseIntensive Care UnitsKnockout MiceKnowledgeLinkLiteratureLungLymphocyteLymphocyte FunctionLymphopeniaLymphopoiesisMediatingMissionModelingMorbidity - disease rateMusNeurosecretory SystemsOutcomeOutcome StudyPathologyPathway interactionsPatientsPharmacologyPhasePhenotypePilot ProjectsPituitary GlandPrognosisPublic HealthRecovery of FunctionReportingResearchResourcesResuscitationRoleStressSurvivorsSyndromeT-LymphocyteTestingUnited States National Institutes of HealthWorkagedapoptosis in lymphocytesbasebiobankclinical outcome measuresclinically relevantclinically significantcytokinefunctional outcomeshypothalamic-pituitary-adrenal axisimmunomodulatory strategyimmunopathologyimmunoregulationimprovedimproved outcomeinfection rateinsightmortalitymouse modelnovelnovel therapeutic interventionolder patientpatient populationprophylacticresuscitative caresextool
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
由于复苏方面的相当大的进步,在最初的复苏中存活的心脏骤停(CA)患者的数量增加了。
被捕并被送入重症监护室(ICU)的人数一直在稳步增加。然而,在这不断增长的
患者人群中,发病率和死亡率仍然高得令人无法接受。这主要归功于
CA后综合征,其中不平衡的免疫应答是关键组成部分。使用我们的临床相关
最近,我们在小鼠CA和心肺复苏(CA/CPR)模型中发现,
在CA/CPR中,存在从良好建立的CA后急性促炎免疫应答到CA/CPR后急性促炎免疫应答的明显转变。
鲜为人知的抗炎免疫反应,最终演变成严重的免疫抑制,
状态此外,我们的初步数据清楚地支持这种免疫抑制状态与CA后
感染和功能恢复差。重要的是,这一观点得到了临床观察的证实,
感染性并发症发生在高比例的CA幸存者中,并且认为复苏后感染
增加发病率和死亡率。因此,更好地了解术后并发症具有重要的临床意义。
CA免疫抑制。我们的长期目标是开发新的治疗策略,以改善CA的预后。
本研究的目的是分析CA后免疫抑制的机制,并确定其作用机制。
针对CA后免疫抑制对CA结局的影响,包括感染发生率和长期
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,表明激活的
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
中心假设是CA和复苏激活了大脑中的炎性小体,这反过来又激活了大脑中的神经元。
HPA轴,导致免疫抑制和CA预后差。这一假设是基于我们强大的
初步数据和大量文献有关的疾病引起的免疫抑制。我们将测试我们的
通过追求以下具体目标的中心假设:1)确定HPA轴在CA后的作用
2)通过HPA轴确定炎性小体在CA后免疫抑制中的作用;
和3)确定调节CA后免疫抑制对CA结果的影响。拟议
研究意义重大,因为我们从这项研究中获得的知识有望为未来的发展提供信息
新的复苏后护理策略,以减轻CA后免疫功能障碍的有害影响,
改善整体CA预后。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Wei Yang其他文献
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{{ truncateString('Wei Yang', 18)}}的其他基金
Immunosuppression after cardiac arrest and resuscitation
心脏骤停和复苏后的免疫抑制
- 批准号:
10543113 - 财政年份:2022
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