Neutrophils (PMNs) are the first cells to respond to an inflammatory stimulus and can cause direct neurotoxicity by producing reactive oxygen species, degradative enzymes, and chemokines that recruit more cells to the site of injury. PMN priming is a two-stage activation process that results in maximal degranulation and NADPH oxidase activity at the terminal site of migration. Our lab explores PMN priming and trafficking in models of focal stroke and cardiac arrest. We find that cerebral ischemia-reperfusion injury is exacerbated by systemic inflammation, consistent with observations from the clinical literature.
Despite many small molecules and biologic-based clinical studies, attempts to target the immune component of CNS ischemia-reperfusion injury have failed. We have found that the lung plays a central role in moderating of systemic inflammation and post-ischemic reperfusion injury via effects on the innate immune system. Specifically, targeted expression of extracellular superoxide dismutase reduces acute lung injury, neutrophil priming, and neurovascular injury in models of cardiac arrest and focal stroke. We are currently pursuing interventions designed to short-circuit lung-dependent immune priming that will improve patient outcomes after cardiac arrest, acute ischemic stroke, among other acquired injuries.
Mai N, Prifti L, Rininger E, Bazarian H, and MW Halterman. (2017) Endotoxemia induces lung-brain coupling and multi-organ injury following cerebral ischemia-reperfusion. Experimental Neurology; 297:82-91. PMID: 28757259.
Buczynski B, Mai N, Min Y, Allen J, Prifti L, Halterman M, Cory-Slechta D, and M O’Reilly. (2018) Neonatal hyperoxia alters neurodevelopment in adult mice through a pathway that is protected by lung-specific overexpression of EC-SOD. Frontiers in Medicine; 5:334. PMID 30619855.
Mai N, Miller-Rhodes K, Knowlden S, and MW Halterman. (2019) The post-cardiac arrest syndrome: A case for lung-brain coupling and opportunities for neuroprotection. J Cereb Blood Flow Metab [Epub ahead of print]. PMID: 30866740.
Mai N, Miller-Rhodes K, Prifti V, Kim M, O’Reilly MA, and MW Halterman. (2019) Lung-Derived SOD3 Attenuates Neurovascular Injury After Transient Global Cerebral Ischemia. J Am Heart Assoc; 8(9): e011801. PMID: 31030600.