Lung-brain coupling and the immune response to acute ischemic stroke

肺脑耦合和对急性缺血性中风的免疫反应

基本信息

批准号：
10447799
负责人：
MARC W HALTERMAN
金额：
$ 57.04万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
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 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10447799
关键词：
Acute Alveolar Antioxidants Antiplatelet Drugs Blood - brain barrier anatomy Blood Vessels Brain Brain Injuries Cerebral Ischemia Cessation of life Chronic Coupling Data Development Diagnosis Distal Endothelium Estrogens Evolution Gatekeeping Genetic Polymorphism Glycocalyx Goals Heparin Binding Immune Immune response Immunotherapy Impairment Inflammation Inflammatory Inhalation Intervention Ischemia Ischemic Brain Injury Ischemic Stroke Kinetics Lead Ligands Lipid Peroxidation Lung Mechanics Mediating Molecular Mus Neurologic Organ Pathologic Pathology Patients Peripheral Permeability Play Predisposition Pulmonary Pathology Recombinants Recovery Regulation Reperfusion Injury Reperfusion Therapy Respiratory Mechanics Role Stroke Structure Superoxide Dismutase Testing Therapeutic Work acute stroke airway inflammation body system cell type cellular targeting cerebrovascular cytokine disability exhaustion extracellular improved outcome innovation insight lung injury mimetics mouse model neuroprotection neurovascular neurovascular injury novel post stroke receptor resilience response severe injury sexual dimorphism stroke outcome stroke risk stroke therapy systemic inflammatory response targeted treatment

项目摘要

Vascular-immune interactions play a pivotal role in the initiation and propagation of ischemic stroke pathology at the onset of ischemia and after reperfusion. In addition to contributing to underlying stroke risk, systemic inflammation amplifies pathological effects of ischemia-reperfusion injury (IRI). And while antiplatelet agents and statins have modest effects on reducing post-stroke inflammation, targeted therapies are desperately needed. We have discovered a novel mechanism of lung-brain coupling induced following an acute ischemic stroke that regulates systemic inflammation, innate immune priming, neurovascular compromise, and secondary ischemic brain damage. Our long-term goal is to identify the mechanistic basis for this response and test whether approaches targeting post-stroke lung pathology could improve outcomes in patients presenting after acute ischemic stroke (AIS). We find that acute cerebral ischemia induces a range of lung pathologies, including 1) simplification of alveolar structures and airway inflammation, 2) increased endothelial permeability and lipid peroxidation, 3) changes in respiratory mechanics, and 4) selective loss of the endogenous lung antioxidant extracellular superoxide dismutase (SOD3). Notably, targeted expression of SOD3 within the distal airways abrogates stroke-induced lung pathology, inhibits systemic inflammation, and reduce cumulative stroke burden. Collectively these data lead us to hypothesize that stroke-induced changes in pulmonary SOD3 activity are a critical determinant of stroke outcomes via effects on systemic immune priming and cerebrovascular resilience. In this proposal, we investigate the mechanism(s) involved in the stroke-dependent loss of SOD3 expression (SA1), demonstrate the effects of SOD3 exhaustion on systemic immune priming (SA2), and explore the influence of stroke risk modifiers on SOD3 regulation and stroke outcomes. These studies provide a new perspective on potential approaches to reduce brain injury, hasten recovery, and mitigate complications associated with AIS. In addition to expanding our understanding regarding the fundamental underpinnings of lung-brain coupling, this work could ultimately lead to the development of inhaled, immune-based therapies for stroke and other acute neurological conditions in which systemic inflammation is a central component.

血管-免疫相互作用在缺血性中风病理的发生和传播中发挥关键作用在缺血开始时和再灌注后。除了增加潜在的中风风险外，系统性炎症会放大缺血再灌注损伤（IRI）的病理效应。而抗血小板药物他汀类药物对减少中风后炎症的效果有限，但靶向治疗迫切需要需要。我们发现了急性缺血后诱导肺脑耦合的新机制调节全身炎症、先天免疫启动、神经血管损害和继发性缺血性脑损伤。我们的长期目标是确定这种反应的机制基础并测试针对中风后肺部病理学的方法是否可以改善患者的预后急性缺血性中风（AIS）后出现。我们发现急性脑缺血可诱发一系列肺损伤病理学，包括 1) 肺泡结构和气道炎症的简化，2) 内皮细胞的增加通透性和脂质过氧化，3) 呼吸力学的变化，以及 4) 选择性丧失内源性肺抗氧化剂细胞外超氧化物歧化酶（SOD3）。值得注意的是，有针对性的表达远端气道内的 SOD3 消除中风引起的肺部病理，抑制全身炎症，并减少累积的中风负担。总的来说，这些数据使我们推测中风引起的变化肺部 SOD3 活性通过影响全身免疫而成为中风结果的关键决定因素启动和脑血管弹性。在本提案中，我们研究了涉及的机制中风依赖性 SOD3 表达缺失 (SA1)，证明 SOD3 耗竭对全身系统的影响免疫启动（SA2），并探讨中风风险调节因子对 SOD3 调节和中风的影响结果。这些研究为减少脑损伤、加速脑损伤的潜在方法提供了新的视角。恢复并减轻与 AIS 相关的并发症。除了扩大我们的了解关于肺-脑耦合的基本基础，这项工作最终可能导致开发基于免疫的吸入疗法来治疗中风和其他急性神经系统疾病，其中全身性炎症是一个核心组成部分。