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  • Title: Leupeptin inhibits ventilator-induced diaphragm dysfunction in rats.
    Author: Maes K, Testelmans D, Powers S, Decramer M, Gayan-Ramirez G.
    Journal: Am J Respir Crit Care Med; 2007 Jun 01; 175(11):1134-8. PubMed ID: 17379854.
    Abstract:
    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.
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