Acute lethal crush-injured rats can be successfully rescued by a single injection of high-dose dexamethasone through a pathway involving PI3K-Akt-eNOS signaling

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Crush syndrome (CS) is characterized by ischemia/reperfusion (I/R)-induced rhabdomyolysis and the subsequent onset of systemic inflammation. CS is associated with a high mortality, even when patients are treated with conventional therapy. We hypothesized treatment of lethal CS rat model with dexamethasone (DEX) have therapeutic effects on the laboratory findings and clinical course and outcome. Methods: To create a CS model, anesthetized rats were subjected to bilateral hind limb compression with rubber tourniquets for 5 hours, and randomly divided into 3 groups: saline-treated CS, and low (0.1 mg/kg) and high doses (5.0 mg/kg) of DEX-treated CS groups. Saline for the CS group or DEX for the DEX-treated CS groups was intravenously administered immediately before reperfusion. Under continuous monitoring and recording of arterial blood pressures, blood and tissue samples were collected for histological and biochemical analysis at designated time period before and after reperfusion. Results: Under continuous monitoring and recording of arterial blood pressures, blood and tissue samples were collected for histological and biochemical analysis at designated time period before and after reperfusion. Ischemic compression of rat hind limbs reduced the nitrite content in the crushed muscle, and the subsequent reperfusion induced reactive oxygen species-mediated circulatory collapse and systemic inflammation, finally resulting in a mortality rate of 76% by 48 hours after reperfusion. A single injection of high-dose DEX *Abstract immediately before reperfusion activated endothelial nitric oxide synthase (eNOS) by sequential phosphorylation through the non-genomic phosphoinositide 3-kinase (PI3K)-Akt-eNOS signaling pathway. DEX also exhibited anti-inflammatory effects by modulating pro- and anti-inflammatory mediators, consequently suppressing myeloperoxidase activities and subsequent systemic inflammation, showing a complete recovery of the rats from lethal CS. Conclusion: These results indicate that high-dose DEX reduces systemic inflammation and contributes to the improved survival rate in a rat CS model.

identifier:JOS-TA.0b013e3182905f11