Lowes Damon A, Thottakam Bensita M V, Webster Nigel R, Murphy Michael P, Galley Helen F
Academic Unit of Anaesthesia and Intensive Care, School of Medicine, Institute of Medical Sciences, Foresterhill, Aberdeen, UK.
Free Radic Biol Med. 2008 Dec 1;45(11):1559-65. doi: 10.1016/j.freeradbiomed.2008.09.003. Epub 2008 Sep 17.
Sepsis is characterised by a systemic dysregulated inflammatory response and oxidative stress, often leading to organ failure and death. Development of organ dysfunction associated with sepsis is now accepted to be due at least in part to oxidative damage to mitochondria. MitoQ is an antioxidant selectively targeted to mitochondria that protects mitochondria from oxidative damage and which has been shown to decrease mitochondrial damage in animal models of oxidative stress. We hypothesised that if oxidative damage to mitochondria does play a significant role in sepsis-induced organ failure, then MitoQ should modulate inflammatory responses, reduce mitochondrial oxidative damage, and thereby ameliorate organ damage. To assess this, we investigated the effects of MitoQ in vitro in an endothelial cell model of sepsis and in vivo in a rat model of sepsis. In vitro MitoQ decreased oxidative stress and protected mitochondria from damage as indicated by a lower rate of reactive oxygen species formation (P=0.01) and by maintenance of the mitochondrial membrane potential (P<0.005). MitoQ also suppressed proinflammatory cytokine release from the cells (P<0.05) while the production of the anti-inflammatory cytokine interleukin-10 was increased by MitoQ (P<0.001). In a lipopolysaccharide-peptidoglycan rat model of the organ dysfunction that occurs during sepsis, MitoQ treatment resulted in lower levels of biochemical markers of acute liver and renal dysfunction (P<0.05), and mitochondrial membrane potential was augmented (P<0.01) in most organs. These findings suggest that the use of mitochondria-targeted antioxidants such as MitoQ may be beneficial in sepsis.
脓毒症的特征是全身炎症反应失调和氧化应激，常导致器官衰竭和死亡。目前认为，与脓毒症相关的器官功能障碍的发生至少部分归因于线粒体的氧化损伤。MitoQ是一种选择性靶向线粒体的抗氧化剂，可保护线粒体免受氧化损伤，并且已证实在氧化应激动物模型中可减少线粒体损伤。我们推测，如果线粒体的氧化损伤在脓毒症诱导的器官衰竭中确实起重要作用，那么MitoQ应该能够调节炎症反应，减少线粒体氧化损伤，从而减轻器官损伤。为了评估这一点，我们在体外脓毒症内皮细胞模型和体内脓毒症大鼠模型中研究了MitoQ的作用。在体外，MitoQ降低了氧化应激并保护线粒体免受损伤，表现为活性氧生成速率降低（P = 0.01）以及线粒体膜电位得以维持（P < 0.005）。MitoQ还抑制了细胞促炎细胞因子的释放（P < 0.05），而抗炎细胞因子白细胞介素-10的产生则因MitoQ而增加（P < 0.001）。在脓毒症期间发生的器官功能障碍的脂多糖-肽聚糖大鼠模型中，MitoQ治疗导致急性肝肾功能障碍的生化标志物水平降低（P < 0.05），并且大多数器官中的线粒体膜电位增强（P < 0.01）。这些发现表明，使用诸如MitoQ之类的线粒体靶向抗氧化剂可能对脓毒症有益。
