右美托咪定对大鼠肺缺血再灌注损伤后诱导型一氧化氮合酶表达的影响

Effect of dexmedetomidine on the expression of inducible nitric oxide synthase after lung ischemiareperfusion injury in rats

目的通过建立在体大鼠肺缺血再灌注损伤(IRI)模型,探讨右美托咪定对肺IRI后诱导型一氧化氮合酶(iNOS)表达的影响及其机制。方法将40只Sprague-Dawley大鼠随机分为4组,每组10只。假手术组大鼠开胸游离左肺门,未行肺门阻断;IRI组大鼠阻断肺门45min后开放再灌注120min;低剂量右美托咪定-IRI组(低剂量-IRI组)大鼠腹腔内注射50μg/kg右美托咪定,30min后行肺门阻断,45min后开放再灌注120min;高剂量右美托咪定-IRI组(高剂量-IRI组)大鼠腹腔内注射100μg/kg右美托咪定,30min后行肺门阻断,45min后开放再灌注120 min。再灌注120 min后处死大鼠,取其左肺组织,检测肺组织湿/干质量比值(W/D值)和TNF-α、丙二醛(MDA)、髓过氧化物酶(MPO)、iNOS的表达水平,并进行病理学检查。结果假手术组、低剂量-IRI组和高剂量-IRI组的W/D值分别为4.15±0.58、4.68±0.51和4.62±0.35,均显著低于IRI组的5.58±0.35(P值均<0.05),低剂量-IRI组与高剂量-IRI组间W/D值的差异无统计学意义(P>0.05)。假手术组、低剂量-IRI组和高剂量-IRI组的TNF-α、MDA、MPO和iNOS表达水平均显著低于IRI组(P值均<0.05);高剂量-IRI组的iNOS表达水平显著低于低剂量-IRI组(P<0.05),低剂量-IRI组与高剂量-IRI组间TNF-α、MDA、MPO表达水平的差异均无统计学意义(P值均>0.05)。假手术组大鼠毛细血管内无充血,炎性细胞浸润不明显;IRI组大鼠毛细血管内充血明显,炎性细胞浸润增多;低剂量-IRI组大鼠毛细血管充血减轻,炎性细胞浸润减少;高剂量-IRI组大鼠毛细血管充血减轻,炎性细胞浸润明显减少。结论右美托咪定可下调肺IRI后iNOS水平,减少过氧化物及其介导的细胞毒性反应发生和细胞因子释放,减轻肺损伤,且此保护效应具有剂量依赖性。

Objective To investigate the effect of dexmedetomidine on the expression of inducible nitric oxide synthase （iNOS） after lung ischemia-reperfusion injury （IRI） in rats. Methods Forty Sprague-Dawley rats were evenly randomized into 4 groups., sham operation group （thoracotomy without pulmonary hilum occlusion）, IRI group （occlusion of the left pulmonary hilum for 45 min, followed by a 2 h reperfusion）, low-dose dexmedetomidine group （intraperiteneal injection of 50 μg/kg dexmedetomidine before ischemia-reperfusion）, and high-dose dexmedetomidine group （intraperiteneal injection of 100μg/kg dexmedetomidine before ischemia-reperfusion）. The ratio of wet to dry lung weight （W/D）, concentration of tumor necrosis factor-α （TNF-α）, malondialdehyde （MDA）, myeloperoxidase （MPO）, and iNOS were detected 120 min after reperfusion. And histopathology of left lung was assessed. Results The W/D ratio was 4. 15 ±0.58, 4.68 ± 0.51 and 4. 62 ± 0.35 in the sham operation group, low-dose dexmedetomidine group and were significantly lower than that in IRI group （5.58±0 high-dose dexmedetomidine group, respectively, which 35, all P〈0. 05）. There was no significant differece in the W/D ratio between high- and low-dose dexmedetomidine group （P〉0.05）. The expression of TNF-α, MDA, MPO and iNOS in the sham operation group, low-dose dexmedetomidine group and high-dose dexmedetomidine group were significantly lower than those in IRI group （all P〈0.05）. The expression of iNOS in the high-dose dexmedetomidine group was significantly lower than that in the low-dose dexmedetomidine group （P〈0.05）, but there was no significant difference in the concentrations of TNF-α, MDA or MPO between high- and low-dose dexmedetomidine groups （all P〉0.05）. Pathological results showed that there was no hyperemia in the sham operation group compared with IRI group, there were less hyperemia and inflammatory cells in high- and low-dose dexmedetomidine groups. Conclusion Dexmedetomidine can downregulate the expression of inducible nitric oxide synthase after lung ischemia-reperfusion injury, reduce cytotoxicity mediated by peroxide and the release of inflammatory factors, and alleviate lung injury in rats in a dose-dependent manner.