Leupeptin inhibits ventilator-induced diaphragm dysfunction in rats.
| Autor: | Maes K; Respiratory Muscle Research Unit, Laboratory of Pneumology, Katholieke Universiteit Leuven, Leuven, Belgium., Testelmans D, Powers S, Decramer M, Gayan-Ramirez G |
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| Jazyk: | angličtina |
| Zdroj: | American journal of respiratory and critical care medicine [Am J Respir Crit Care Med] 2007 Jun 01; Vol. 175 (11), pp. 1134-8. Date of Electronic Publication: 2007 Mar 22. |
| DOI: | 10.1164/rccm.200609-1342OC |
| Abstrakt: | 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. |
| Databáze: | MEDLINE |
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