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Administration of 80 mg/kg methylprednisolone has been shown to prevent controlled mechanical ventilation (CMV) diaphragm dysfunction in rats, partly by inhibiting the calpain system . The current experiments determined whether lower doses of corticosteroids will also provide protection against ventilator-induced diaphragm dysfunction.
Rats were assigned to a control group or to 24 hours of CMV receiving a single injection of saline or 5 mg/kg (low MP) or 30 mg/kg (high MP) of methylprednisolone.
Diaphragm force production was decreased after CMV but significantly more in the low MP group while similar to controls in the high MP group. Atrophy of the type IIa fibers was only present in the low MP group. Atrophy of the type IIx/b fibers was more severe in the low MP group than in the CMV group while no atrophy was observed in the high MP group. Diaphragm calpain activity was increased after CMV (+93%, P < 0.05 vs C) and in the low MP group (+83%, P < 0.05 vs C), while it was similar to controls in the high MP group. Expression of calpastatin was decreased in the CMV and the low MP group (-18%, P < 0.05 vs C) but its level was preserved to control levels in the high MP group. Analysis of the caspase-3 mediated cleavage of αII-spectrin revealed that CMV induced a significant rise in caspase-3 activity when compared with C (+194%, P < 0.001). Caspase-3 activity was similarly increased in the MP-5 and the MP-30 groups (+96% and +78% respectively, P < 0.05 vs C) but this increase was significantly less compared with that of CMV. Significant negative correlations were found between calpain activity and diaphragm force (-0.50 <r <-0.41, P < 0.05) as well as with CSA of the type IIx/b fibers (r = -0.57, P < 0.02). Significant positive correlations were observed between calpastatin and diaphragm force (0.43 <r < 0.54, P < 0.05) and calpastatin and CSA of the type IIx/b fibers (r = 0.57, P < 0.02).
The ability of corticosteroids to protect against CMV-induced diaphragmatic contractile dysfunction and atrophy are dose dependent with only high doses of corticosteroids providing protection.
Supported by Astra Zeneca Pharmaceuticals and FWO Vlaanderen.