Kathleen Miller-Rhodes - Ph.D. Candidate
Advisor: Marc Halterman, M.D., Ph.D.
Acute ischemic stroke is a leading cause of death and disability in the aging population. Although available interventions improve recanalization rates, there remain no therapies to treat delayed ischemia-reperfusion injury (IRI). The discrete signals responsible for IRI involve a complex cascade of innate immune priming, neuroinflammation, and delayed post-ischemic neurodegeneration. Emerging evidence implicates organ crosstalk in the pathology of delayed central nervous system (CNS) damage following global cerebral ischemia. In this project, we tested the hypothesis that the prevailing inflammatory milieu within the lung is an essential determinant of post-stroke CNS injury. To test this, we investigated the relationship between acute brain ischemia, lung inflammation, and CNS reperfusion injury in the middle cerebral artery occlusion (MCAO) model of stroke. In male C57Bl6J mice, ischemia-reperfusion was associated with pulmonary function changes, vascular inflammation, and airway immune infiltration. In post-stroke lung tissue, the loss of endogenous SOD3 correlated with increases in 4-HNE modified proteins indicative of elevated oxidant stress. Conversely, mice that express human SOD3 within type II pneumocytes (TgSOD3) exhibited lower post-stroke levels of 4-HNE protein modification and vessel inflammation versus wildtype controls. TgSOD3 mice exhibited reduced blood-brain barrier (BBB) damage and developed smaller infarct volumes 72 hours post-stroke. We also observed sex-related differences in the SOD3-dependent regulation of post-ischemic IRI. Higher basal expression of lung SOD3 observed in female mice was associated with smaller infarcts, a reduced burden of post-stroke hemorrhage, and lower myeloperoxidase levels, ICAM-1, and fibrinogen. These results collectively implicate lung-derived SOD3 as a modulator of neurovascular injury in acute ischemic stroke. Future work defining SOD3 regulation in the lung, lung-dependent immune priming, and the remote effects of SOD3 on the cerebrovasculature could open up a new field of lung-targeted therapies for stroke and other acute neuroglial disorders.
Dec 08, 2020 @ 1:00 p.m.
Host: Neuroscience Graduate Program