Title: Leupeptin inhibits ventilator-induced diaphragm dysfunction in rats
Authors: Maes, Karen
Testelmans, Dries
Powers, Scott
Decramer, Marc
Gayan-Ramirez, Ghislaine # ×
Issue Date: Jun-2007
Series Title: American Journal of Respiratory and Critical Care Medicine vol:175 issue:11 pages:1134-8
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.
ISSN: 1073-449X
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Pneumology
× corresponding author
# (joint) last author

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