Mast cell activation as a determinant of neurologic injury after cardiac arrest

肥大细胞激活是心脏骤停后神经损伤的决定因素

• 批准号: 10042316
• 负责人: Jorn Karhausen
• 金额: $ 25.43万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10042316
• 关键词: Acute; Adult; Affect; Animals; Astrocytes; Blood - brain barrier anatomy; Blood Circulation; Blood flow; Brain; Brain Injuries; Cardiopulmonary Resuscitation; Cause of Death; Cell physiology; Cells; Chymase; Clinical; Complex; Critical Care; Critical Illness; Data; Deductibles; Development; Effector Cell; Ensure; Event; Goals; Healthcare; Heart Arrest; Histamine; Human; Immune; Induced Heart Arrest; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Ischemia; Knowledge; Link; Mediating; Meninges; Modeling; Mus; Nervous System Physiology; Nervous System Trauma; Neuraxis; Neuronal Injury; Neurons; Organ; Outcome; Outcome Study; Pathology; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Pericytes; Peripheral; Plasma; Potassium Chloride; Process; Reperfusion Therapy; Research; Resources; Resuscitation; Role; Sampling; Sentinel; Severities; Shapes; Shock; Source; Stroke; Survivors; Testing; Tryptase; Ursidae Family; Work; Yang; allergic response; base; biobank; blood-brain barrier disruption; catalyst; cellular targeting; clinically relevant; disability; improved; innovation; insight; mast cell; mouse model; neuroimaging; neuroinflammation; neurological recovery; neuron development; neuropathology; novel; novel diagnostics; novel therapeutics; out-of-hospital cardiac arrest; preservation; prevent; reconstitution; recruit; response; tissue stress; tool

Abstract: Brain injury is a major determinant of outcomes in patients after out of hospital cardiac arrest (OHCA). Because neuronal damage shows a typical, delayed course, it has been deducted that components of post–cardiac arrest neuronal injury are potentially treatable. However, considerable gaps in knowledge exist on the mechanisms that mediate neuronal injury in this setting. Mast cells (MCs) are perivascular immune sentinel cells best known to trigger acute inflammation and shock in allergic responses. Supported by our preliminary findings, we hypothesize that MCs are also central effectors in development of neuro-inflammation and neuronal injury after OHCA. As such, we documented robust MC activation after cardiac arrest in both a mouse model and in recovering patients. Furthermore, MC-deficient mice displayed reduced disruption of their blood brain barrier and less infiltration of inflammatory cells indicating that they may be protected from harmful secondary responses after cardiac arrest. Consequently, the objective of our work is to establish several independent lines of research in mice and in patients in order to comprehensively characterize the MC contribution to neuroinflammation and neuronal injury following cardiac arrest. This project constitutes a crucial step towards our long-term goal to establish MCs as key cellular targets of the harmful responses to cardiac arrest and to develop novel therapeutic and diagnostic tools that improve the care of these critically ill patients.

摘要： 脑损伤是院外心脏骤停（OHCA）患者预后的主要决定因素。 由于神经元损伤表现出典型的延迟过程，因此可以推断， 心脏骤停后神经元损伤的组分是潜在可治疗的。然而，在这方面， 在这方面，关于介导神经元损伤的机制存在相当大的知识空白。 设置. 肥大细胞（MC）是血管周围的免疫哨兵细胞，最为人所知的是触发急性炎症 和过敏反应中的休克根据我们的初步研究结果，我们假设MC 也是OHCA后神经炎症和神经元损伤发展的中枢效应物。 因此，我们在小鼠模型和小鼠模型中记录了心脏骤停后MC的强烈激活。 康复患者此外，MC缺陷小鼠显示其血液破坏减少 脑屏障和炎性细胞浸润较少，表明它们可能受到保护， 心脏骤停后有害的继发反应。因此，我们工作的目标是 在小鼠和患者中建立几个独立的研究线， 全面表征MC对神经炎症和神经元损伤的贡献 心脏骤停后 这个项目是我们实现长期目标的关键一步，即建立MC作为关键的蜂窝网络。 靶点的有害反应心脏骤停，并开发新的治疗和诊断 改善这些重症患者护理的工具。