Department of Applied Physiology and Kinesiology, Center for Exercise Science, University of Florida, Gainesville, FL, USA.
Crit Care Med. 2012 Mar;40(3):927-34. doi: 10.1097/CCM.0b013e3182374a84.
Although mechanical ventilation is a life-saving measure for patients in respiratory failure, prolonged mechanical ventilation results in diaphragmatic weakness attributable to fiber atrophy and contractile dysfunction. Therefore, identifying the signaling pathways responsible for mechanical ventilation-induced diaphragmatic weakness is important. In this context, it is established that oxidative stress is required for mechanical ventilation-induced diaphragmatic weakness to occur. Numerous redox-sensitive signaling pathways exist in muscle including the transcription factor nuclear factor-κB. Although it has been suggested that nuclear factor-κB contributes to proteolytic signaling in inactivity-induced atrophy in locomotor muscles, the role that nuclear factor-κB plays in mechanical ventilation-induced diaphragmatic weakness is unknown. We tested the hypothesis that nuclear factor-κB activation plays a key signaling role in mechanical ventilation-induced diaphragmatic weakness and that oxidative stress is required for nuclear factor-κB activation.
Cause and effect was determined by independently treating mechanically ventilated animals with either a specific nuclear factor-κB inhibitor (SN50) or a clinically relevant antioxidant (curcumin).
Inhibition of nuclear factor-κB activity partially attenuated both mechanical ventilation-induced diaphragmatic atrophy and contractile dysfunction. Further, treatment with the antioxidant curcumin prevented mechanical ventilation-induced activation of nuclear factor-κB in the diaphragm and rescued the diaphragm from both mechanical ventilation-induced atrophy and contractile dysfunction.
Collectively, these findings support the hypothesis that nuclear factor-κB activation plays a significant signaling role in mechanical ventilation-induced diaphragmatic weakness and that oxidative stress is an upstream activator of nuclear factor-κB. Finally, our results suggest that prevention of mechanical ventilation-induced oxidative stress in the diaphragm could be a useful clinical strategy to prevent or delay mechanical ventilation-induced diaphragmatic weakness.
虽然机械通气是呼吸衰竭患者的救命措施，但长时间的机械通气会导致膈肌纤维萎缩和收缩功能障碍，从而导致膈肌无力。因此，确定导致机械通气引起的膈肌无力的信号通路非常重要。在这种情况下，已经确定氧化应激是机械通气引起的膈肌无力发生所必需的。肌肉中存在许多氧化还原敏感的信号通路，包括转录因子核因子-κB。尽管已经表明核因子-κB有助于运动肌肉失用性萎缩中的蛋白水解信号通路，但核因子-κB在机械通气引起的膈肌无力中的作用尚不清楚。我们假设核因子-κB 的激活在机械通气引起的膈肌无力中起着关键的信号作用，并且氧化应激是核因子-κB 激活所必需的。
通过分别用特定的核因子-κB 抑制剂（SN50）或临床相关的抗氧化剂（姜黄素）处理机械通气的动物，确定了因果关系。
核因子-κB 活性的抑制部分减轻了机械通气引起的膈肌萎缩和收缩功能障碍。此外，抗氧化剂姜黄素的治疗预防了机械通气引起的膈肌核因子-κB 的激活，并使膈肌免受机械通气引起的萎缩和收缩功能障碍的影响。
这些发现共同支持了这样的假设，即核因子-κB 的激活在机械通气引起的膈肌无力中起着重要的信号作用，氧化应激是核因子-κB 的上游激活剂。最后，我们的结果表明，预防机械通气引起的膈肌氧化应激可能是预防或延迟机械通气引起的膈肌无力的一种有用的临床策略。
