Role of lung-brain coupling on neutrophil priming and reperfusion injury following global cerebral ischemia

肺脑耦合在全脑缺血后中性粒细胞启动和再灌注损伤中的作用

基本信息

批准号：
9240675
负责人：
Nguyen Mai
金额：
$ 4.86万
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：
2015-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9240675
关键词：
Adrenal gland hypofunction Affect Attenuated Biological Assay Blood - brain barrier anatomy Blood Circulation Blood Coagulation Disorders Brain Brain Injuries Caring Cerebral Ischemia Cerebrovascular system Coculture Techniques Coupling Critical Care Disease Endothelium Enzymes Evolution Extravasation Fluorescence-Activated Cell Sorting Functional disorder Heart Arrest Hospital Mortality Human ITGAM gene Immunologics In Vitro Individual Inflammation Inflammatory Response Injury Ischemia Kinetics Leukocytes Link Lung Lung Inflammation Measures Mechanical ventilation Mediating Modeling NADPH Oxidase Nature Nervous System Trauma Neuraxis Neuronal Injury Neurons Neutrophil Activation Organ Patients Peripheral Peroxidases Physiology Reactive Oxygen Species Reperfusion Injury Reperfusion Therapy Role Site Stimulus Superoxide Dismutase Symptoms Syndrome Testing Therapeutic Intervention Time Tissues Toxic effect Transfusion Transgenic Mice Travel United States Venous Work alveolar type II cell antioxidant enzyme cytokine experimental study extracellular in vivo induced hypothermia insight migration mimetics mouse model multiorgan injury neuroinflammation neurological recovery neurotoxic neurotoxicity neutrophil new therapeutic target overexpression prevent public health relevance spatiotemporal targeted treatment trafficking

项目摘要

DESCRIPTION (provided by applicant): Neurologic recovery after cardiac arrest is complicated by a constellation of organ dysfunction and systemic inflammation known as Post Cardiac Arrest Syndrome (PCAS). After return of spontaneous circulation, reperfusion of the brain is accompanied by the migration of "primed," neurotoxic neutrophils (PMNs) that cause blood-brain-barrier dysfunction and damage to local tissue with the release of degradative enzymes, cytokines, and reactive oxygen species. Recent work in the fields of pulmonary and critical care suggests that priming is reversible and mediated at the PMN-pulmonary endothelium interface. Our lab has found that targeted expression of extracellular superoxide dismutase (SOD3, an antioxidant enzyme) in the lung alters PMN kinetics and neuronal injury after ischemia-reperfusion. In this proposal we investigate the link between lung inflammation, PMN activation, and cerebral ischemia-reperfusion injury in a mouse model of PCAS that combines the effects of global cerebral ischemia-reperfusion and systemic inflammation. We hypothesize that PCAS induces PMN priming, and that the level of SOD3 activity and inflammation in the lung in turn modulates their histotoxic effects of as they traverse the post-ischemic cerebrovasculature. The experiments proposed will test the effects of manipulating SOD3 activity on: 1) the spatiotemporal trafficking of PMNs and degree of ischemic injury to the CNS observed, 2) PMN neurotoxicity in vitro, and 3) whether the lung can effectively "de-prime" PMNs exposed to priming stimuli ex vivo and reintroduced to the systemic circulation by transfusion. These studies highlight the potential role of lung-brain coupling in ischemia-reperfusion injury and focus on the PMN priming circuit as a potential target for therapeutic intervention. Given its salient role in modulating the inflammatory response to ischemia-reperfusion injury, the lung is an easily accessible target in which putative neuroprotective strategies may be tested.

描述（由适用提供）：心脏骤停后的神经系统恢复是通过器官功能障碍和全身性炎症（称为心脏后骤停综合征（PCAS））组成的。基于赞助者的循环返回后，大脑的再灌注是通过“启动”，神经毒性神经粒细胞（PMN）迁移来实现的，这些神经毒性神经粒细胞（PMN）通过释放降解性酶，细胞因子，细胞因子和反应性氧释放而引起血脑屏障功能障碍和对局部组织的损害来实现。肺和重症监护领域的最新工作表明，在PMN-Purmonary内皮界面上启动是可逆的和介导的。我们的实验室发现，肺部超氧化物歧化酶（SOD3，一种抗氧化酶）的靶向表达在缺血 - 再灌注后改变了PMN动力学和神经元损伤。在该提案中，我们研究了肺部炎症，PMN激活和脑缺血再灌注损伤之间的联系，这结合了全球脑缺血 - 再生灌注和全身性炎症的影响。我们假设PCA会诱导PMN启动，并且肺中的SOD3活性和炎症水平又调节了它们的组织毒性作用，因为它们穿越了缺血后的脑血管造影。提出的实验将测试操纵SOD3活性对：1）PMN的空间临时运输以及观察到的CNS的缺血性损伤程度，2）PMN PMN神经毒性在体外，3）3）肺是否可以有效地“ pMN” pMN，以驱动刺激刺激和依次驱动循环。这些研究强调了肺脑耦合在缺血 - 再灌注损伤中的潜在作用，并专注于PMN启动回路，这是治疗干预的潜在目标。鉴于其在调节对缺血再灌注损伤的炎症反应中的显着作用，肺是一个易于获得的靶标，可以测试假定的神经保护策略。