Nuclear factor-?B signaling contributes to mechanical ventilation-induced diaphragm weakness*.

ABSTRACT: 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-?B. Although it has been suggested that nuclear factor-?B contributes to proteolytic signaling in inactivity-induced atrophy in locomotor muscles, the role that nuclear factor-?B plays in mechanical ventilation-induced diaphragmatic weakness is unknown. We tested the hypothesis that nuclear factor-?B activation plays a key signaling role in mechanical ventilation-induced diaphragmatic weakness and that oxidative stress is required for nuclear factor-?B activation.Cause and effect was determined by independently treating mechanically ventilated animals with either a specific nuclear factor-?B inhibitor (SN50) or a clinically relevant antioxidant (curcumin).Inhibition of nuclear factor-?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-?B 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-?B activation plays a significant signaling role in mechanical ventilation-induced diaphragmatic weakness and that oxidative stress is an upstream activator of nuclear factor-?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.

SUBMITTER: Smuder AJ 

PROVIDER: S-EPMC3786346 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature