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

> **NIH NIH R01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2021 · $542,350

## Abstract

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.

## Key facts

- **NIH application ID:** 10294883
- **Project number:** 2R01NS092455-06A1
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** MARC W HALTERMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $542,350
- **Award type:** 2
- **Project period:** 2015-05-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10294883

## Citation

> US National Institutes of Health, RePORTER application 10294883, Lung-brain coupling and the immune response to acute ischemic stroke (2R01NS092455-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10294883. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*