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 ischemia-reperfusion. 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.

• Authors: Nguyen Mai, Kathleen Miller-Rhodes, Viollandi Prifti, Minsoo Kim, Michael A O'Reilly, Marc W Halterman
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 8 Issue 9 Pg. e011801 (05 07 2019) ISSN: 2047-9980 [Electronic] England
• PMID: 31030600 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• SOD3 protein, human
• Superoxide Dismutase

Topics

• Animals
• Blood-Brain Barrier (enzymology, immunology, pathology)
• Brain (enzymology, immunology, pathology)
• Brain Edema (enzymology, pathology, prevention & control)
• Brain Ischemia (enzymology, immunology, pathology)
• Capillary Permeability
• Disease Models, Animal
• Humans
• Immunity, Innate
• Lung (enzymology, immunology)
• Male
• Mice, Inbred C57BL
• Mice, Transgenic
• Neurovascular Coupling
• Neutrophil Infiltration
• Pneumonia (enzymology, immunology, pathology, prevention & control)
• Pulmonary Edema (enzymology, pathology, prevention & control)
• Reperfusion Injury (enzymology, immunology, pathology, prevention & control)
• Superoxide Dismutase (genetics, metabolism)