Mechanisms of lung-dependent neutrophil priming in global cerebral ischemia-reperfusion injury

肺依赖性中性粒细胞启动在全脑缺血再灌注损伤中的机制

• 批准号: 8913387
• 负责人: MARC W HALTERMAN
• 金额: $ 35.03万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8913387
• 关键词: Acute; Affect; Alveolar; American; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Attenuated; Biological; Biological Assay; Blood - brain barrier anatomy; Brain; Brain Injuries; Breathing; Bypass; Caring; Cerebral Edema; Cerebral Ischemia; Cerebrovascular Circulation; Cerebrum; Coupling; Cues; Endotoxemia; Endotoxins; Exhibits; Extracellular Matrix; Extracellular Matrix Degradation; Free Radicals; Functional disorder; Gases; Generations; Heart Arrest; Hippocampus (Brain); Hospitals; Immune; Immune response; Induced Heart Arrest; Inflammation; Inflammatory; Injury; Ischemia; Leukocytes; Lung; Lung Inflammation; Mediating; Mediator of activation protein; Mesentery; Modeling; Molecular; Mus; Nerve Degeneration; Nervous System Trauma; Neuronal Injury; Organ failure; Oxygen; Patients; Pattern; Peripheral; Physiological; Play; Population; Production; Receptor Signaling; Relative (related person); Reperfusion Injury; Reperfusion Therapy; Resuscitation; Role; Route; Serum; Severities; Signal Transduction; Superoxide Dismutase; Syndrome; System; TLR4 gene; Testing; Theoretical model; Time; Tissues; Toxic effect; Travel; Vascular Permeabilities; alveolar epithelium; alveolar type II cell; base; central nervous system injury; extracellular; in vivo; lung injury; migration; mortality; mouse model; neuroprotection; neurotoxicity; neurovascular unit; neutrophil; pneumocyte; public health relevance; relating to nervous system; research study; spatiotemporal; toll-like receptor 4; trafficking; treatment strategy

 DESCRIPTION (provided by applicant): Cardiac arrest affects an estimated 500,000 Americans annually, and fewer than 25% patients will survive to discharge due in large part to overwhelming CNS injury. The post-resuscitation syndrome following cardiac arrest (PCAS) encompasses the damaging effects of tissue ischemia and the delayed effects of ischemic reperfusion injury (IRI). Activation of the innate immune response is a prime mediator of the delayed microvascular damage, increased vascular permeability and progressive tissue damage observed after resuscitation. In particular, blocking leukocyte recruitment to the CNS significantly reduces the extent of brain injury observed after ischemic challenge. In this proposal we investigate the pathological consequences of peripheral inflammation on global cerebral ischemia, focusing on the relationship between lung inflammation, neutrophil priming and delayed CNS injury. These studies are based on our observation that expression of extracellular superoxide dismutase (EC-SOD) targeted to type II pneumocytes blunts neutrophil trafficking into the post-ischemic brain and confers marked neuroprotection. In this proposal we test the hypothesis that expression of EC-SOD within the lung inhibits IRI by reducing the production of damage associated molecular patterns (DAMPs) and levels of TLR4 activation required for endothelial and PMN activation. Successful demonstration that lung-brain coupling modulates delayed cerebral injury through effects on neutrophil priming may suggest new treatment strategies for patients presenting after cardiac arrest.

 描述（由申请人提供）：心脏骤停每年影响估计500，000名美国人，并且由于在很大程度上压倒性的CNS损伤，只有不到25%的患者能够存活到出院。心脏骤停后复苏综合征（PCAS）包括组织缺血的损伤效应和缺血再灌注损伤（IRI）的延迟效应。先天性免疫应答的激活是复苏后观察到的延迟性微血管损伤、增加的血管渗透性和进行性组织损伤的主要介质。特别是，阻断白细胞向CNS募集显著降低了缺血性激发后观察到的脑损伤程度。在这个建议中，我们调查周围炎症对全脑缺血的病理后果，重点是肺部炎症，中性粒细胞启动和迟发性中枢神经系统损伤之间的关系。这些研究是基于我们的观察，即针对II型肺细胞的细胞外超氧化物歧化酶（EC-SOD）的表达减弱了中性粒细胞进入缺血后脑的运输，并赋予显着的神经保护作用。在这个建议中，我们测试的假设，肺内的EC-SOD的表达抑制IRI通过减少产生的损伤相关的分子模式（DAMP）和TLR 4激活所需的内皮细胞和PMN激活的水平。肺-脑偶联通过影响中性粒细胞启动调节迟发性脑损伤的成功证明可能为心脏骤停后出现的患者提供新的治疗策略。