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启动和传播中起关键作用 在缺血开始时和再灌流后。除了导致潜在的中风风险外，系统性中风 炎症可放大缺血再灌注损伤(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的作用不大，靶向治疗迫在眉睫 需要的。我们发现了一种新的急性脑缺血后肺-脑耦合的机制 中风，调节全身炎症，先天免疫启动，神经血管损害，以及 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的方法是否可以改善患者的预后 出现在急性缺血性中风(AIS)后。我们发现急性脑缺血可引起一系列的肺损伤。 病理，包括1)肺泡结构简化和呼吸道炎症，2)内皮细胞增加 通透性和脂质过氧化，3)呼吸力学的变化，以及4)选择性的 肺组织内源性抗氧化剂细胞外超氧化物歧化酶(SOD3)。值得注意的是，有针对性地表达 远端呼吸道内的SOD3消除了中风引起的肺部病理，抑制了全身炎症，并 减少累积中风负担。总而言之，这些数据让我们假设中风引起的变化 在肺中，SOD3活性通过对系统免疫的影响是中风预后的关键决定因素 启动和脑血管弹性。在这项建议中，我们调查了(S)参与 卒中相关SOD3表达缺失(SA1)，表明SOD3耗竭对全身的影响 免疫启动(SA2)，并探讨卒中风险调节剂对SOD3调节和卒中的影响 结果。这些研究为减少脑损伤的潜在方法提供了一个新的视角 恢复，并减少与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 治疗中风和其他急性神经系统疾病的吸入性、基于免疫的疗法的发展 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.