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

• 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
• 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

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卒中病理学的启动和传播中起关键作用 在缺血开始和再灌注后。除了促进潜在的中风风险外， 炎症扩大了缺血 - 再灌注损伤（IRI）的病理影响。而抗血小板剂 他汀类药物对减少冲程后炎症有适度的影响，靶向疗法拼命为 需要。我们发现了急性缺血后引起的肺脑耦合的一种新型机制 调节系统性炎症，先天免疫启动，神经血管妥协和 次要缺血性脑损伤。我们的长期目标是确定此反应的机械基础 并测试针对势力后肺病理学的方法是否可以改善患者的预后 在急性缺血性中风（AIS）之后出现。我们发现急性脑缺血会诱导一系列肺 病理，包括1）简化牙槽结构和气道炎症，2）内皮增加 渗透性和脂质过氧化，3）呼吸力学的变化，4）选择性丧失 内源性肺抗氧化细胞外超氧化物歧化酶（SOD3）。值得注意的是，针对性的表达 远端气道中的SOD3消除了中风引起的肺病理学，抑制全身性炎症，并 减轻累积中风负担。这些数据共同使我们假设中风引起的变化 在肺SOD3中，通过对全身免疫的影响，SOD3活性是中风结果的关键决定因素 启动和脑血管弹性。在此提案中，我们研究了涉及的机制 SOD3表达（SA1）的中风依赖性丧失，证明了SOD3耗尽对系统性的影响 免疫启动（SA2），并探索中风风险修饰符对SOD3调节和中风的影响 结果。这些研究为减少脑损伤的潜在方法提供了新的观点 恢复，并减轻与AIS相关的并发症。除了扩大我们的理解 关于肺脑耦合的基本基础，这项工作最终可能导致 开发中风和其他急性神经系统疾病的吸入，基于免疫的疗法 系统性炎症是中心部分。