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

基本信息

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
项目类别：
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

项目摘要

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）：心脏骤停每年影响大约 500,000 名美国人，只有不到 25% 的患者能够存活到出院，这在很大程度上是由于严重的中枢神经系统损伤造成的。组织缺血和缺血再灌注损伤（IRI）的延迟效应先天免疫反应的激活是延迟微血管损伤、血管增加的主要介质。特别是，阻断白细胞向中枢神经系统的募集可显着降低缺血性挑战后观察到的脑损伤程度。在本提案中，我们研究了周围炎症对全脑缺血的病理后果，重点关注其中的关系。这些研究基于我们的观察，即针对 II 型肺细胞的细胞外超氧化物歧化酶 (EC-SOD) 的表达会减弱中性粒细胞的转运。在本提案中，我们测试了肺内 EC-SOD 的表达通过减少损伤相关分子模式 (DAMP) 的产生以及内皮和 PMN 所需的 TLR4 激活水平来抑制 IRI 的假设。成功证明肺-脑耦合通过对中性粒细胞启动的影响调节迟发性脑损伤，可能为心脏骤停后出现的患者提供新的治疗策略。