title: Corticosteroid effects on ventilator-induced diaphragm dysfunction in anesthetized rats depend on the dose administered.
abstract: BACKGROUND
  High dose of corticosteroids has been previously shown to protect against controlled mechanical ventilation (CMV)-induced diaphragmatic dysfunction while inhibiting calpain activation. Because literature suggests that the calpain inhibiting effect of corticosteroid depends on the dose administered, we determined whether lower doses of corticosteroids would also provide protection of the diaphragm during CMV. This may be important for patients undergoing mechanical ventilation and receiving corticosteroids.
  
  
  METHODS
  Rats were assigned to controls or to 24 hours of CMV while being treated at the start of mechanical ventilation with a single intramuscular administration of either saline, or 5 mg/kg (low MP) or 30 mg/kg (high MP) of methylprednisolone.
  
  
  RESULTS
  Diaphragmatic force was decreased after CMV and this was exacerbated in the low MP group while high MP rescued this diaphragmatic dysfunction. Atrophy was more severe in the low MP group than after CMV while no atrophy was observed in the high MP group. A significant and similar increase in calpain activity was observed in both the low MP and CMV groups whereas the high dose prevented calpain activation. Expression of calpastatin, the endogenous inhibitor of calpain, was decreased in the CMV and low MP groups but its level was preserved to controls in the high MP group. Caspase-3 activity increased in all CMV groups but to a lesser extent in the low and high MP groups. The 20S proteasome activity was increased in CMV only.
  
  
  CONCLUSIONS
  Administration of 30 mg/kg methylprednisolone during CMV protected against CMV-induced diaphragm dysfunction while 5 mg/kg was more deleterious. The protective effect is due mainly to an inhibition of the calpain system through preservation of calpastatin levels and to a lesser extent to a caspase-3 inhibition.
authors.affiliation: Respiratory Muscle Research Unit, Laboratory of Pneumology and Respiratory Division, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
authors.forename: Karen
authors.initials: K
authors.lastname: Maes
authors.forename: Anouk
authors.initials: A
authors.lastname: Agten
authors.forename: Ashley
authors.initials: A
authors.lastname: Smuder
authors.forename: Scott K
authors.initials: SK
authors.lastname: Powers
authors.forename: Marc
authors.initials: M
authors.lastname: Decramer
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Gayan-Ramirez
mesh_terms: D000305:Adrenal Cortex Hormones / Q000008:administration & dosage; D000818:Animals; D003964:Diaphragm / Q000187:drug effects* / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D007273:Injections, Intramuscular; D008297:Male; D008775:Methylprednisolone / Q000008:administration & dosage*; D009119:Muscle Contraction / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012120:Respiration Disorders / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control*; D012121:Respiration, Artificial / Q000009:adverse effects*; D015656:Respiratory Mechanics / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D000305:Adrenal Cortex Hormones; D008775:Methylprednisolone