Published ahead of print on March 22, 2007, doi:10.1164/rccm.200609-1342OC Am. J. Respir. Crit. Care Med., Volume 175, Number 11, June 2007, 1134-1138 A more recent version of this article appeared on June 1, 2007
Submitted on September 19, 2006 Leupeptin Inhibits Ventilator-Induced Diaphragm Dysfunction in RatsKaren Maes1*,1 Respiratory Muscle Research Unit, Laboratory of Pneumology, Katholieke Universiteit Leuven, Leuven, Belgium, 2 Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, USA * To whom correspondence should be addressed. E-mail: karen.maes{at}med.kuleuven.be.
Rationale: Controlled mechanical ventilation has been shown to result in elevated diaphragmatic proteolysis and atrophy along with diaphragmatic contractile dysfunction. Objectives: To test whether administration of leupeptin, an inhibitor of lysosomal proteases and calpain, concomitantly with 24 hours of controlled mechanical ventilation would protect the diaphragm from the deleterious effects of mechanical ventilation. Methods: Rats were assigned to either a control group or 24 hours of controlled mechanical ventilation; animals in the ventilation group received either a single intramuscular injection of saline or 15 mg/kg of the protease inhibitor leupeptin. Measurements and main results: Compared with controls, mechanical ventilation resulted in a significant reduction of the in vitro diaphragm specific force production at all stimulation frequencies. Leupeptin completely prevented this reduction in force generation. Atrophy of type IIx/b fibers was present following controlled mechanical ventilation but not after treatment with leupeptin. Cathepsin B and calpain activities were significantly higher following controlled mechanical ventilation compared to the other groups; this was abolished by treatment with leupeptin. Significant inverse correlations were found between diaphragmatic force generation and cathepsin B and calpain activity and illustrate the deleterious role of proteolysis in diminishing diaphragmatic force production following prolonged controlled mechanical ventilation. Conclusion: Administration of the protease inhibitor leupeptin concomitantly with mechanical ventilation completely prevented ventilation-induced diaphragmatic contractile dysfunction and atrophy. Key words: Mechanical ventilation, protein degradation, respiratory muscles
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