Oxidative stress is required for mechanical ventilation‐induced protease activation in the diaphragm

Abstract

Prolonged mechanical ventilation (MV) results in diaphragmatic weakness due to both fiber atrophy and contractile dysfunction. Recent work reveals that activation of the proteases calpain and caspase‐3 are required for MV‐induced diaphragmatic atrophy and contractile dysfunction. However, the mechanism to trigger activation of these proteases remains unknown. To address this issue, we tested the hypothesis that oxidative stress is essential for the activation of calpain and caspase‐3 in the diaphragm during MV. We tested this postulate by preventing MV‐induced diaphragmatic oxidative stress using the antioxidant trolox. Treatment of animals with trolox was successful in the prevention of MV‐induced protein oxidation and lipid peroxidation in the diaphragm. Importantly, this avoidance of MV‐induced oxidative stress inhibited the activation of both calpain and caspase‐3 in the diaphragm during MV. Further, the prevention of MV‐induced oxidative stress not only averted the activation of these proteases but also rescued the diaphragm from MV‐induced diaphragmatic atrophy and contractile dysfunction. Collectively, these findings support the hypothesis that oxidative stress is required for MV‐induced activation of calpain and caspase‐3 in the diaphragm and suggest that antioxidant therapy could be beneficial in the prevention of diaphragmatic weakness during prolonged MV.