Nuclear factor-κB signaling contributes to mechanical ventilation-induced diaphragm weakness

Objectives: 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-kappa B. Although it has been suggested that nuclear factor-kappa B contributes to proteolytic signaling in inactivity-induced atrophy in locomotor muscles, the role that nuclear factor-kappa B plays in mechanical ventilation-induced diaphragmatic weakness is unknown. We tested the hypothesis that nuclear factor-kappa B activation plays a key signaling role in mechanical ventilation-induced diaphragmatic weakness and that oxidative stress is required for nuclear factor-kappa B activation. Design: Cause and effect was determined by independently treating mechanically ventilated animals with either a specific nuclear factor-kappa B inhibitor (SN50) or a clinically relevant antioxidant (curcumin). Measurements and Main Results: Inhibition of nuclear factor-kappa B 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-kappa B in the diaphragm and rescued the diaphragm from both mechanical ventilation-induced atrophy and contractile dysfunction. Conclusions: Collectively, these findings support the hypothesis that nuclear factor-kappa B activation plays a significant signaling role in mechanical ventilation-induced diaphragmatic weakness and that oxidative stress is an upstream activator of nuclear factor-kappa B. 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. (Crit Care Med 2012; 40:927-934)