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- W3201059411 abstract "Systemic inflammation and multi-organ failurerepresent two hallmarks of the Post Cardiac Arrest Syndrome(PCAS), and when present, are associated with severe neurologicalinjury and often mortality. With the return of spontaneouscirculation, ‘primed,’ neurotoxic neutrophils (PMNs) releasedegradative enzymes, cytokines, and reactive oxygen species thatcause blood-brain-barrier dysfunction, tissue injury, and furtherPMN activation. In our pilot studies, we noted that remote cerebralischemiareperfusion triggered the activation and accumulation PMNsin the lung. Evidence from the critical care literature alsosuggests that interactions with the pulmonary endothelium, amongothers, may regulate systemic PMN de-priming. These observationsled us to propose the existence of immunological coupling betweenthe lung and brain and to investigate whether systemicinflammation impairs this protective influence in the setting ofischemia-reperfusion. To test this, we developed a model ofPCAS in mice by pairing transient global cerebral ischemia(achieved by three-vessel occlusion, 3VO) with the exposure to theprototypical endotoxin lipopolysaccharide (LPS) upon reperfusion.After establishing an intraperitoneal dose of LPS sufficient toproduce serum levels observed in post-arrest patients, we foundthat combined 3VO/LPS treatment induced PMN activation, bloodbrainbarrier compromise, microglial activation, and a doubling of PMNaccumulation and injury in the cerebral cortex. The 3VO/LPSprocedure also promoted PMN accumulation and edema in the lung, aswell as the trafficking of PMNs to the non-ischemic kidney andliver. Studies have shown that targeted expression of theantioxidant extracellular superoxide dismutase (SOD3) from type IIpneumocytes is sufficient to reduce oxidantinduce lung injury andinflammation in mice. To test whether focal manipulation of lungredox biology could exert similar effects in our model, we examinedthe effects of 3VO/LPS treatment in the Tg(SOD3) model. Ourresults indicate that increased SOD3 expression in the lung wasprotective against 3VO/LPS-induced lung edema, pulmonary PMNaccumulation, microglial activation, cortical damage, andhippocampal apoptosis. SOD3 expression reduced the expression ofCD11b on the surface of PMNs but had little effect on traffickingto the brain following 3VO/LPS. The protective effects of SOD3were, however, limited in mice exposed to transient global ischemiaalone. Our work highlights the importance of lung-braincoupling in ischemia-reperfusion injury and suggests thatinterventions targeting both PMN priming and redox changes thatoccur in the lung after ischemia-reperfusion may be valuable. Thesefindings are particularly salient given the increased risk ofstroke in patients with underlying lung disease and endothelialdamage caused by smoking and other cardiovascular risk factors.Given its accessibility to pharmacological manipulation, our worksuggests that targeting the lung with inhaled pharmacological…" @default.
- W3201059411 created "2021-09-27" @default.
- W3201059411 creator A5006650796 @default.
- W3201059411 date "2017-01-01" @default.
- W3201059411 modified "2023-09-27" @default.
- W3201059411 title "Lung-Brain Immunological Coupling Mediates NeutrophilDe-Priming and Neuroprotection following CerebralIschemia-Reperfusion" @default.
- W3201059411 hasPublicationYear "2017" @default.
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