Laboratory of Drug Safety Management, Department of Clinical Dietetics and Human Nutrition, Josai University, Saitama, Japan.
J Trauma Acute Care Surg. 2013 Aug;75(2):241-9. doi: 10.1097/TA.0b013e3182905f11.
Crush syndrome (CS) is characterized by ischemia/reperfusion-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 that treatment of lethal CS rat model with dexamethasone (DEX) have therapeutic effects on the laboratory findings and clinical course and outcome.
To create a CS model, anesthetized rats were subjected to bilateral hind limb compression with rubber tourniquets for 5 hours and randomly divided into three groups as follows: saline-treated CS group, CS groups treated with low (0.1 mg/kg) and high doses (5.0 mg/kg) of DEX. 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 histologic and biochemical analysis at designated 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 immediately before reperfusion activated endothelial nitric oxide synthase (eNOS) by sequential phosphorylation through the nongenomic phosphoinositide 3-kinase (PI3K)-Akt-eNOS signaling pathway. DEX also exhibited anti-inflammatory effects by modulating proinflammatory and anti-inflammatory mediators, consequently suppressing myeloperoxidase activities and subsequent systemic inflammation, showing a complete recovery of the rats from lethal CS.
These results indicate that high-dose DEX reduces systemic inflammation and contributes to the improved survival rate in a rat CS model.
挤压综合征（CS）的特征是缺血/再灌注引起的横纹肌溶解，随后发生全身炎症。即使患者接受常规治疗，CS 也与高死亡率相关。我们假设用地塞米松（DEX）治疗致死性 CS 大鼠模型对实验室发现和临床过程及结果有治疗作用。
为了创建 CS 模型，麻醉大鼠双侧后肢用橡皮止血带压迫 5 小时，并随机分为三组：盐水处理的 CS 组、接受低（0.1mg/kg）和高剂量（5.0mg/kg）DEX 的 CS 组。CS 组给予生理盐水，DEX 处理的 CS 组在再灌注前立即给予 DEX。在连续监测和记录动脉血压的情况下，在再灌注前后指定时间采集血液和组织样本，进行组织学和生化分析。
大鼠后肢缺血性压迫降低了挤压肌肉中的亚硝酸盐含量，随后的再灌注诱导活性氧介导的循环崩溃和全身炎症，最终导致再灌注后 48 小时死亡率达到 76%。再灌注前单次注射高剂量 DEX 通过非基因组磷酸肌醇 3-激酶（PI3K）-Akt-eNOS 信号通路顺序磷酸化激活内皮型一氧化氮合酶（eNOS）。DEX 还通过调节促炎和抗炎介质发挥抗炎作用，从而抑制髓过氧化物酶活性和随后的全身炎症，使大鼠从致死性 CS 中完全恢复。
这些结果表明，高剂量 DEX 可减少全身炎症，并有助于提高大鼠 CS 模型的生存率。
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