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

血管-免疫相互作用在缺血性卒中病理的发生和传播中起着关键作用 在缺血开始时和再灌注后。除了导致潜在的中风风险外，全身性 炎症放大了缺血-再灌注损伤（IRI）的病理效应。虽然抗血小板药物 他汀类药物对减少中风后炎症有适度的作用，靶向治疗是绝望的， needed.我们已经发现了一种新的机制，肺脑耦合诱导后，急性缺血 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， 急性缺血性卒中（AIS）后出现。我们发现急性脑缺血可引起一系列肺损伤， 病理学，包括1）肺泡结构和气道炎症的简化，2）内皮细胞 渗透性和脂质过氧化，3）呼吸力学的变化，和4）选择性损失的 内源性肺抗氧化剂细胞外超氧化物歧化酶（SOD 3）。值得注意的是，靶向表达 远端气道内的SOD 3消除中风诱导的肺病理，抑制全身性炎症， 减少累积的中风负担。综合这些数据，我们推测中风引起的变化 在肺中，SOD 3活性是通过影响全身免疫而导致中风结果关键决定因素 启动和脑血管弹性。在这个建议中，我们调查了参与的机制， 中风依赖性的SOD 3表达丧失（SA 1），证明了SOD 3耗竭对全身性 免疫启动（SA 2），并探讨脑卒中风险调节剂对SOD 3调节和脑卒中的影响 结果。这些研究提供了一个新的视角，探讨减少脑损伤的潜在方法， 恢复，并减轻与AIS相关的并发症。除了扩大我们对 关于肺脑耦合的基本基础，这项工作最终可能导致 开发用于中风和其他急性神经系统疾病的基于免疫的吸入疗法， 全身性炎症是一个核心组成部分。

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.