Mitochondria-targeted antioxidants protect against mechanical ventilation-induced diaphragm weakness.
Mitochondria-targeted antioxidants protect against mechanical ventilation-induced diaphragm weakness.
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DOI：
10.1097/ccm.0b013e3182190b62
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发表时间：
2011-07
影响因子：
8.8
通讯作者：
Smuder AJ
中科院分区：
文献类型：
--
作者：
Powers SK;Hudson MB;Nelson WB;Talbert EE;Min K;Szeto HH;Kavazis AN;Smuder AJ
机械通气（MV）是一种挽救生命的干预措施，用于为呼吸衰竭患者提供充足的肺通气。然而，MV延长与肌纤维萎缩和收缩功能障碍引起的显著肌无力相关。虽然几个信号通路有助于隔膜无力在MV期间，它是建立，氧化应激是必要的隔膜无力发生。因此，鉴定隔膜中MV诱导的活性氧（ROS）产生的位点是重要的。这些实验测试了线粒体ROS排放升高是MV诱导的膈肌氧化应激、萎缩和收缩功能障碍所需的假设。通过使用一种新的靶向抗氧化剂（SS-31）防止MV诱导的大鼠膈肌线粒体ROS释放来确定因果关系。与用盐水处理的机械通气动物相比，用SS-31处理的动物可防止MV诱导的线粒体功能障碍、氧化应激和隔膜中的蛋白酶活化。重要的是，用线粒体抗氧化剂治疗动物也保护隔膜免受MV诱导的肌纤维萎缩和收缩功能障碍。这些结果表明，预防MV诱导的线粒体ROS排放增加保护隔膜MV诱导的线粒体衰弱。这一重要的新发现表明，线粒体是延长MV期间隔膜中ROS产生的主要来源。这些结果可能会导致治疗干预的发展，以阻止MV诱导的神经衰弱。
Mechanical ventilation (MV) is a life-saving intervention used to provide adequate pulmonary ventilation in patients suffering from respiratory failure. However, prolonged MV is associated with significant diaphragmatic weakness resulting from both myofiber atrophy and contractile dysfunction. Although several signaling pathways contribute to diaphragm weakness during MV, it is established that oxidative stress is required for diaphragmatic weakness to occur. Therefore, identifying the site(s) of MV-induced reactive oxygen species (ROS) production in the diaphragm is important. These experiments tested the hypothesis that elevated mitochondrial ROS emission is required for MV-induced oxidative stress, atrophy, and contractile dysfunction in the diaphragm. Cause and effect was determined by preventing MV-induced mitochondrial ROS emission in the diaphragm of rats using a novel mitochondrial-targeted antioxidant (SS-31). Compared to mechanically ventilated animals treated with saline, animals treated with SS-31 were protected against MV-induced mitochondrial dysfunction, oxidative stress, and protease activation in the diaphragm. Importantly, treatment of animals with the mitochondrial antioxidant also protected the diaphragm against MV-induced myofiber atrophy and contractile dysfunction. These results reveal that prevention of MV-induced increases in diaphragmatic mitochondrial ROS emission protects the diaphragm MV-induced diaphragmatic weakness. This important new finding indicates that mitochondria are a primary source of ROS production in the diaphragm during prolonged MV. These results could lead to the development of a therapeutic intervention to impede MV-induced diaphragmatic weakness.