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

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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.