Bortezomib partially protects the rat diaphragm from ventilator‐induced diaphragm dysfunction

Abstract

Controlled mechanical ventilation leads to diaphragmatic contractile dysfunction and atrophy. Since proteolysis is enhanced in the diaphragm during controlled mechanical ventilation, we examined whether the administration of a proteasome inhibitor, Bortezomib, would have a protective effect against ventilator‐induced diaphragm dysfunction.Anesthetized rats were submitted for 24h to CMV while receiving 0.05mg/kg Bortezomib (MVB) or saline (CMV). Control rats were acutely anesthetized (C). After 24 hours, diaphragm forces were significantly decreased in the CMV group compared to C (−36%, p<0.001). Administration of Bortezomib improved the forces compared to CMV (+15%, p<0.01), but did not return to control levels. Compared to C, diaphragm cross sectional area (CSA) of the type IIx/b fibers was significantly decreased with 22% after CMV (p<0.05), while the CSA of the different fiber types in MVB remained similar to that of C. Diaphragmatic calpain activity was significantly increased (+63%, p<0.05) in CMV, but not in MVB. No differences were found in the activity of caspase‐3. These data show that the administration of Bortezomib partially protects the diaphragm from CMV‐induced diaphragm dysfunction.