Center for Skeletal Muscle Research at Robert Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA; Departments of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
Departments of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA.
Free Radic Biol Med. 2017 Dec;113:212-223. doi: 10.1016/j.freeradbiomed.2017.09.029. Epub 2017 Oct 2.
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.
多器官功能障碍综合征 (MODS) 是危重病患者的一种有害临床并发症，死亡率很高。新出现的证据表明，重要器官血管的氧化应激和内皮激活（诱导黏附分子表达）是发病机制的关键早期步骤。我们旨在确定增强的细胞外超氧化物歧化酶 (EcSOD) 在骨骼肌中的表达在防止内毒素血症引起的 MODS 中的作用和机制。我们表明，在骨骼肌特异性转基因小鼠 (TG) 中过表达的 EcSOD 通过循环重新分布到其他外周器官，并在血管内皮中富集。与野生型同窝仔 (WT) 相比，TG 小鼠对内毒素血症（通过脂多糖 [LPS] 注射诱导）具有抗性，在发展为 MODS 时死亡率和器官损伤明显降低。TG 和 WT 小鼠之间的异基因联体赋予 WT 小鼠显著保护作用，而具有 R213G 插入突变的小鼠，一种导致外周器官中 EcSOD 结合减少的人类单核苷酸多态性，使器官损伤恶化。从机制上讲，EcSOD 抑制血管细胞黏附分子 1 的表达和炎症性白细胞在内皮细胞黏附到重要器官的血管壁上，阻断了内毒素血症下器官损伤的病理早期步骤。因此，骨骼肌中 EcSOD 的增强表达通过抑制内皮激活和炎症细胞黏附，可显著预防 MODS，这可能是 MODS 的一种有前途的治疗方法。
