The Role of Neutrophils in Ischemia/Reperfusion Injury following Acute Stroke

中性粒细胞在急性中风后缺血/再灌注损伤中的作用

基本信息

批准号：
10606952
负责人：
Erika Arias
金额：
$ 4.38万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2026-09-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10606952
关键词：
Acute Address Adhesions Affect Alteplase American Animal Model Anti-Inflammatory Agents Antibodies Area Beds Binding Blocking Antibodies Blood Vessels Blood flow Brain Brain Hypoxia Brain Ischemia Brain Pathology Brain region Cause of Death Cell Adhesion Molecules Cell surface Cells Central Nervous System Cerebral Ischemia Cerebrovascular system Chronic Clinical Clinical Trials Coagulation Process Data Development Effectiveness Endothelial Cells Endothelium Event Excision Extravasation Fellowship Hypoxia Immune Infarction Infiltration Inflammation Inflammatory Inflammatory Response Injury Ischemia Ischemic Stroke Laboratories Leucocytic infiltrate Leukocytes Location Manuscripts Mediator Methods Minor Modeling Motor Mus Myeloid Cells Necrosis Outcome PECAM1 gene Paper Pathologic Pathology Pathway interactions Patients Pattern Physicians Reperfusion Injury Reperfusion Therapy Research Resolution Rodent Model Role Scientist Signal Transduction Stroke Techniques Testing Therapeutic Therapeutic Effect Therapeutic Intervention Time Tissues Training Visit White Blood Cell Count procedure Work acute stroke brain tissue chemokine clinically relevant cytokine disability improved improved outcome in vivo insight intravital imaging intravital microscopy migration mortality nervous system disorder neutrophil novel therapeutic intervention post stroke preclinical study prevent protective effect recruit response restoration spatiotemporal stroke model stroke outcome stroke therapy targeted treatment therapeutic target thrombolysis

项目摘要

PROJECT SUMMARY/ABSTRACT Inflammation is the body's response to tissue damage, including brain tissue after stroke. Stroke is one of the leading causes of death and disability, affecting more that 795,000 Americans per year. A majority of strokes are ischemic strokes, where blood flow to the brain is obstructed. Most therapeutic interventions restore blood flow, but these therapies have a limited time frame in which they are effective. Moreover, some patients do not improve even with blood flow restoration. One likely explanation for the limited therapeutic benefit of blood flow restoration after stroke is the secondary damage caused by the acute inflammatory response. This is the so-called, “ischemia/reperfusion (I/R) injury.” Therefore, further understanding and characterization of the inflammatory response to stroke is critical to the development of new therapeutic interventions. Following an ischemic stroke, brain blood vessels respond to inflammatory signals and recruit leukocytes to the area of damage. Neutrophils (PMN) are the earliest responders to tissue damage in the central nervous system (CNS). Like other leukocytes, PMN interact with adhesion molecules on the endothelial cell surface and undergo transendothelial migration (TEM), squeezing between endothelial cells and migrating into the tissue bed. TEM is important because it is essentially irreversible, committing the cell to extravasation. Our research shows inhibition of TEM significantly reduces stroke infarct size in acute stroke, however the mechanism connecting TEM blockade to a reduction in infarct size is unknown. We show that blocking TEM alters the spatiotemporal distribution of leukocyte infiltration and extravasation across the ischemic core and penumbra but does not change the total number of leukocytes recruited to infarcted region. Analysis of the leukocyte composition showed PMN are the major infiltrating leukocyte type in acute stroke. These findings suggest that modulating PMN infiltration pattern rather than reducing total leukocyte recruitment may have a protective effect in stroke. We seek to understand the mechanisms by which myeloid cell TEM blockade results in reduced stroke infarct size and the effect of specifically interfering with PMN extravasation on stroke outcomes. To understand effect of TEM blockade following I/R, our first aim will identify how inhibition of TEM during I/R injury in acute stroke alters the immune landscape of the stroke microenvironment. Our studies will identify differences between in leukocyte types over time across ischemic brain regions and differences in the cytokine profile due to TEM blockade. Our second aim will determine the therapeutic effect of blocking leukocyte extravasation in comparison to selective PMN depletion following I/R. Our studies will be conducted at different time points after reperfusion, identifying the effect of inhibition on brain pathology, and mouse motor function. PMN extravasation will be inhibited through two methods: use of TEM-blocking antibodies and the selective depletion of PMN. Completion of these studies will provide insight into the mechanisms regulating PMN response to I/R injury and potentially identify a therapeutic intervention that can be used at the relevant time frame.

项目概要/摘要炎症是身体对组织损伤的反应，中风后的脑组织就是其中之一。死亡和残疾的主要原因，每年影响超过 795,000 名美国人。中风是缺血性中风，大多数治疗干预措施可以恢复大脑的血流。血流量，但这些疗法的有效时间有限，而且对一些患者来说。即使血流恢复也没有改善，这是血液治疗效果有限的一种可能解释。脑卒中后血流恢复是急性炎症反应引起的继发性损伤。因此，需要进一步了解和表征“缺血/再灌注（I/R）损伤”。中风的炎症反应对于开发新的治疗干预措施至关重要。缺血性中风后，脑血管对炎症信号做出反应并招募白细胞中性粒细胞（PMN）是中枢神经系统组织损伤的最早反应者。与其他白细胞一样，PMN 与内皮细胞表面的粘附分子相互作用。经历跨内皮迁移（TEM），在内皮细胞之间挤压并迁移到组织床中。 TEM 很重要，因为它本质上是不可逆的，会使细胞外渗。我们的研究表明，抑制 TEM 可显着减少急性中风中的中风梗塞面积，但是阻断 TEM 与减少梗塞面积的机制尚不清楚。改变白细胞浸润和外渗穿过缺血核心的时空分布半影但不改变招募到梗塞区域的白细胞总数。白细胞组成显示 PMN 是急性卒中的主要浸润白细胞类型。表明调节 PMN 浸润模式而不是减少总白细胞募集可能具有我们试图了解骨髓细胞 TEM 阻断的机制。减少中风梗塞面积以及专门干扰 PMN 外渗对中风结果的影响。为了了解 I/R 后 TEM 封锁的效果，我们的首要目标是确定在 I/R 期间 TEM 的抑制如何急性中风中的缺血再灌注损伤会改变中风微环境的免疫景观。缺血脑区的白细胞类型随时间的差异以及细胞因子的差异我们的第二个目标是确定阻断白细胞的治疗效果。与 I/R 后选择性 PMN 消耗相比，我们的研究将在不同的时间进行。再灌注后的时间点，确定抑制对大脑病理学和小鼠运动功能的影响。 PMN 外渗可通过两种方法得到抑制：使用 TEM 阻断抗体和选择性完成这些研究将深入了解调节 PMN 反应的机制。 I/R 损伤并可能确定可在相关时间范围内使用的治疗干预措施。