Oral administration of BGP‐15 significantly increases HSP72 expression and attenuates ventilator‐induced diaphragm dysfunction

Abstract

Mechanical ventilation (MV) is a life‐saving intervention for patients unable to sustain adequate pulmonary gas exchange on their own. Unfortunately, prolonged MV results in rapid atrophy and contractile dysfunction of the diaphragm, collectively termed ventilator‐induced diaphragm dysfunction (VIDD). Although the mechanisms responsible for VIDD remain elusive, it is established that increased mitochondrial production of reactive oxygen species (ROS) is required for the development of VIDD. Notably, recent evidence reveals that endurance exercise training performed prior to MV is sufficient to protect the diaphragm against VIDD. While the mechanisms responsible for exercise‐induced prevention of VIDD remain unknown, evidence suggests that endurance exercise training may reduce diaphragm oxidative damage by elevating heat shock protein 72 (HSP72) expression. Therefore, these experiments tested the hypothesis that oral administration of a pharmacological inducer of HSP72 expression (BGP‐15) would increase HSP72 expression and attenuate VIDD. Our data reveal that 5 days of oral administration of BGP‐15 prior to prolonged MV results in increased HSP72 expression in the diaphragm and protection against VIDD. Specifically, BGP‐15 administration resulted in the prevention of the MV‐induced decrease in diaphragm muscle cross sectional area. Further, treatment with BGP‐15 protected against both MV‐induced diaphragm contractile dysfunction and attenuated the increase in mitochondrial ROS production in the diaphragm. Collectively, these results reveal that oral administration of BGP‐15 provides protection against VIDD presumably through an increase in HSP72.Support or Funding InformationSupported by NIH R01 AR064189 awarded to SKP