Abstract
BackgroundHigh 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.MethodsRats 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.ResultsDiaphragmatic 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.ConclusionsAdministration 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.
Highlights
High dose of corticosteroids has been previously shown to protect against controlled mechanical ventilation (CMV)-induced diaphragmatic dysfunction while inhibiting calpain activation
Our group showed that administration of a single high dose of methylprednisolone (80 mg/kg, corresponding ~13 mg/kg in humans) during controlled mechanical ventilation protected the diaphragm from the deleterious effects of prolonged mechanical ventilation through inhibition of the calpain system [9]
Since the literature supports the fact that the calpaininhibiting effect of corticosteroids depends on the dose administered, the aim of the present study was to determine whether administration of lower doses of corticosteroids would provide protection against ventilator-induced diaphragm dysfunction (VIDD)
Summary
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 provide protection of the diaphragm during CMV. This may be important for patients undergoing mechanical ventilation and receiving corticosteroids. In vitro degradation of neurofilament proteins from rat spinal cord homogenates through calpain activation, was substantially inhibited by corticosteroids in a dose-dependent fashion [7]. Release of myofilaments for subsequent degradadtion by the UPP occurs by the calpain and/or caspase system and may be the rate-limiting step in skeletal muscle proteolysis [18]
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