Muscle-derived extracellular superoxide dismutase inhibits endothelial activation and protects against multiple organ dysfunction syndrome in mice
Autor: | Jarrod A. Call, Borna Mehrad, Victor E. Laubach, Kyle S. Martin, Russell P. Bowler, Carolina A. Galarreta, Jean A. Donet, Zhongmin Du, Ashish Sharma, Zhen Yan, Alexander L. Klibanov, Vitor A. Lira, Mei Zhang, Mitsuharu Okutsu, Shayn M. Peirce, Brian H. Annex, Jiuzhi Zhang, Xiaobin Chen, Jie Cai |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Genetically modified mouse Endothelium Lipopolysaccharide Multiple Organ Failure Muscle Proteins Mice Transgenic 030204 cardiovascular system & hematology Biology Biochemistry Article Endothelial activation Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Physiology (medical) medicine Animals Humans VCAM-1 Muscle Skeletal Superoxide Dismutase Cell adhesion molecule Skeletal muscle medicine.disease Endotoxemia Disease Models Animal 030104 developmental biology medicine.anatomical_structure chemistry Immunology Cancer research Multiple organ dysfunction syndrome |
Zdroj: | Free Radical Biology and Medicine. 113:212-223 |
ISSN: | 0891-5849 |
Popis: | Multiple organ dysfunction syndrome (MODS) is a detrimental clinical complication in critically ill patients with high mortality. Emerging evidence suggests that oxidative stress and endothelial activation (induced expression of adhesion molecules) of vital organ vasculatures are key, early steps in the pathogenesis. We aimed to ascertain the role and mechanism(s) of enhanced extracellular superoxide dismutase (EcSOD) expression in skeletal muscle in protection against MODS induced by endotoxemia. We showed that EcSOD overexpressed in skeletal muscle-specific transgenic mice (TG) redistributes to other peripheral organs through the circulation and enriches at the endothelium of the vasculatures. TG mice are resistant to endotoxemia (induced by lipopolysaccharide [LPS] injection) in developing MODS with significantly reduced mortality and organ damages compared with the wild type littermates (WT). Heterogenic parabiosis between TG and WT mice conferred a significant protection to WT mice, whereas mice with R213G knock-in mutation, a human single nucleotide polymorphism leading to reduced binding EcSOD in peripheral organs, exacerbated the organ damages. Mechanistically, EcSOD inhibits vascular cell adhesion molecule 1 expression and inflammatory leukocyte adhesion to the vascular wall of vital organs, blocking an early step of the pathology in organ damage under endotoxemia. Therefore, enhanced expression of EcSOD in skeletal muscle profoundly protects against MODS by inhibiting endothelial activation and inflammatory cell adhesion, which could be a promising therapy for MODS. |
Databáze: | OpenAIRE |
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