Research ArticleRESPIRATORY DYSFUNCTION

The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction

Science Translational Medicine  03 Aug 2016:
Vol. 8, Issue 350, pp. 350ra103
DOI: 10.1126/scitranslmed.aaf7099

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A little help for the diaphragm

Ventilation-induced diaphragm dysfunction is a common complication of intensive care, where mechanically ventilated patients have to be gradually weaned off ventilator support over an extended period of time until they are finally strong enough to breathe on their own. Salah et al. used a rat model to study the detailed effects of prolonged mechanical ventilation on diaphragm muscles and demonstrate the beneficial effects of a pharmacological intervention with a heat shock protein co-inducer. Through a combination of effects on lipid rafts, mitochondrial efficiency, and other cellular functions, this treatment improved diaphragm muscle force-generating capacity even after multiple days of mechanical ventilation.

Abstract

Ventilation-induced diaphragm dysfunction (VIDD) is a marked decline in diaphragm function in response to mechanical ventilation, which has negative consequences for individual patients’ quality of life and for the health care system, but specific treatment strategies are still lacking. We used an experimental intensive care unit (ICU) model, allowing time-resolved studies of diaphragm structure and function in response to long-term mechanical ventilation and the effects of a pharmacological intervention (the chaperone co-inducer BGP-15). The marked loss of diaphragm muscle fiber function in response to mechanical ventilation was caused by posttranslational modifications (PTMs) of myosin. In a rat model, 10 days of BGP-15 treatment greatly improved diaphragm muscle fiber function (by about 100%), although it did not reverse diaphragm atrophy. The treatment also provided protection from myosin PTMs associated with HSP72 induction and PARP-1 inhibition, resulting in improvement of mitochondrial function and content. Thus, BGP-15 may offer an intervention strategy for reducing VIDD in mechanically ventilated ICU patients.

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