title: Leupeptin inhibits ventilator-induced diaphragm dysfunction in rats.
abstract: BACKGROUND
  Controlled mechanical ventilation (CMV) has been shown to result in elevated diaphragmatic proteolysis and atrophy together with diaphragmatic contractile dysfunction.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors: Respiratory Muscle Research Unit, Laboratory of Pneumology, Katholieke Universiteit Leuven, Leuven, Belgium.
authors: Karen
authors: K
authors: Maes
authors: Dries
authors: D
authors: Testelmans
authors: Scott
authors: S
authors: Powers
authors: Marc
authors: M
authors: Decramer
authors: Ghislaine
authors: G
authors: Gayan-Ramirez
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism; D003964:Diaphragm / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D004195:Disease Models, Animal; D005470:Fluorometry; D008297:Male; D015122:Mercaptopurine / Q000627:therapeutic use*; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009135:Muscular Diseases / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D019384:Nucleic Acid Synthesis Inhibitors / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012121:Respiration, Artificial / Q000009:adverse effects*; D016896:Treatment Outcome
chemical_list: D019384:Nucleic Acid Synthesis Inhibitors; D015122:Mercaptopurine; D002154:Calpain; D002401:Cathepsin B