Lung‐Derived SOD3 Attenuates Neurovascular Injury After Transient Global Cerebral Ischemia

Abstract

Background-Systemic innate immune priming is a recognized sequela of post-ischemic neuroinflammation and contributor to delayed neurodegeneration. Given mounting evidence linking acute stroke with reactive lung inflammation, we asked whether enhanced expression of the endogenous antioxidant extracellular superoxide dismutase 3 (SOD3) produced by alveolar type II pneumocytes would protect the lung from transient global cerebral ischemia and the brain from the delayed effects of ischemiareperfusion. Methods and Results-Following 15 minutes of global cerebral ischemia or sham conditions, transgenic SOD3 and wild-type mice were followed daily for changes in weight, core temperature, and neurological function. Three days after reperfusion, arterial and venous samples were collected for complete blood counts, flow cytometry, and SOD3 protein blotting, and immunohistochemistry was performed on lung and brain tissue to assess tissue injury, blood-brain barrier permeability, and neutrophil transmigration. Relative to ischemic controls, transgenic SOD3 mice performed better on functional testing and exhibited reduced peripheral neutrophil activation, lung inflammation, and blood-brain barrier leak. Once released from the lung, SOD3 was predominantly not cell associated and depleted in the venous phase of circulation. Conclusions-In addition to reducing the local inflammatory response to cerebral ischemia, targeted enrichment of SOD3 within the lung confers distal neuroprotection against ischemia-reperfusion injury. These data suggest that therapies geared toward enhancing adaptive lung-neurovascular coupling may improve outcomes following acute stroke and cardiac arrest.

Lung SOD3 limits neurovascular reperfusion injury and systemic immune activation following transient global cerebral ischemia

“…We have previously shown that hSOD3 limits PMN activation in response to 3VO-induced ischemia alone. 44 Consistent with these results, flow analyses confirmed that focal SOD3 expression within the lung in TgSOD3 mice reduced expression of the activation marker CD11b relative to WT controls (TgSOD3 MFI: 25,906 vs. WT MFI: 45,064 for 10,000 events) in response to combined 3VO/LPS treatment (Fig. 1D).…”

Evaluation of electroacupuncture as a non-pharmacological therapy for astrocytic structural aberrations and behavioral deficits in a post-ischemic depression model in mice

“…A score of two is considered normal for each domain, with a maximum total score of 12. Assessments were performed 1 day before and/or 2 days after the BCCAO operation ( Mai et al, 2019 ; Supplementary Figure 2 ).…”

Adaptive Immune Cells Link Microbial Metabolites to Stroke Recovery

“…Ischemic stroke has pervasive effects outside the CNS, leading to a cascade of inflammatory events that drives multiorgan dysfunction and hampers long-term stroke recovery. Peripheral organs, such as the lung (Mai et al, 2017(Mai et al, , 2019, heart (Bieber et al, 2017), and intestine (Singh et al, 2016;Stanley et al, 2016), are particularly susceptible to stroke-induced injury and inflammation. For example, stroke increases the permeability of intestinal barriers (Singh et al, 2016;Stanley et al, 2016), alters bacterial composition of the gut, causing gut dysbiosis (Houlden et al, 2016;Singh et al, 2016), and promotes seeding of gut bacteria within the lung, spleen, and liver (Stanley et al, 2016).…”