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Leupeptin Inhibits Ventilator-induced Diaphragm Dysfunction in Rats

¹ Respiratory Muscle Research Unit, Laboratory of Pneumology, Katholieke Universiteit Leuven, Leuven, Belgium; and ² Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida

Correspondence and requests for reprints should be addressed to Ghislaine Gayan-Ramirez, Ph.D., Labo Ademspieren, O&N1 bus 706, Herestraat 49, B-3000 Leuven, Belgium. E-mail: ghislaine.gayan-ramirez{at}med.kuleuven.be

Rationale: Controlled mechanical ventilation (CMV) has been shown to result in elevated diaphragmatic proteolysis and atrophy together with diaphragmatic contractile dysfunction.

Objectives: To test whether administration of leupeptin, an inhibitor of lysosomal proteases and calpain, concomitantly with 24 hours of CMV, would protect the diaphragm from the deleterious effects of mechanical ventilation.

Methods: Rats were assigned to either a control group or 24 hours of CMV; 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 control animals, 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 after CMV, but not after treatment with leupeptin. Cathepsin B and calpain activities were significantly higher after CMV compared with 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 after prolonged CMV.

Conclusions: 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

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Controlled mechanical ventilation (CMV) is deleterious for diaphragm function. Animal models of CMV show elevated diaphragmatic proteolysis and atrophy together with diaphragmatic contractile dysfunction. What This Study Adds to the Field Administration of a protease inhibitor protects the diaphragm from proteolysis, atrophy, and contractile dysfunction induced by mechanical ventilation.

 

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