阿托伐他汀对急性肺栓塞大鼠SIRT2/NF-κB通路及动脉血气指标的影响

Effects of atorvastatin on SIRT2/NF-κB pathway and arterial blood gas indexes in rats with acute pulmonary embolism

目的探讨阿托伐他汀对急性肺栓塞大鼠SIRT2/NF-κB通路及动脉血气指标的影响。方法采用自体血栓回输法构建急性肺栓塞(APE)大鼠模型,随机分为假手术组、阿托伐他汀低剂量组(1 mg/kg)、阿托伐他汀中剂量组(2 mg/kg)、阿托伐他汀高剂量组(4 mg/kg)、速碧林组(0.01 ml/kg),每组12只,另取12只SD大鼠设为假手术组,分组处理后,测定大鼠肺动脉平均压(mPAP)和右心室压力(RVP);检测大鼠动脉血气指标氧分压(PaO_(2))和二氧化碳分压(PaCO_(2));HE染色检测大鼠肺组织病理形态;酶联免疫吸附实验(ELISA)检测大鼠肺泡灌洗液(BALF)中IL-18、IL-6水平;蛋白免疫印迹实验检测大鼠肺组织SIRT2/NF-κB通路相关蛋白表达。结果与假手术组相比,模型组大鼠肺组织呈现肺泡结构损环,间隔充血水肿,炎性细胞浸润明显,肺血管管腔变窄,动脉内膜明显增生等病理损伤,mPAP、RVP、动脉血PaCO_(2)、BALF中IL-18及IL-6水平、肺组织核内NF-κB蛋白表达明显升高(P<0.05),动脉血PaO_(2)及肺组织SIRT2蛋白表达明显降低(P<0.05);与模型组相比,阿托伐他汀低、中、高剂量组及速碧林组大鼠肺组织病理损伤减轻,mPAP、RVP、动脉血PaCO_(2)、BALF中IL-18及IL-6水平、肺组织核内NF-κB蛋白表达降低,动脉血PaO_(2)及肺组织SIRT2蛋白表达升高,且阿托伐他汀各组之间呈剂量依赖性,差异有统计学意义(P<0.05);阿托伐他汀高剂量组与速碧林组相比,各指标差异无统计学意义(P>0.05)。结论阿托伐他汀可上调SIRT2表达,抑制NF-κB蛋白核转移,缓解APE大鼠肺组织炎性反应及病理损伤,降低肺动脉压力,改善肺动脉血气指标,修复肺功能。

Objective To investigate the effects of atorvastatin on SIRT2/NF-κB pathway and arterial blood gas indexes in rats with acute pulmonary embolism(APE).Methods The rat models with APE were established by auto-thrombotic reinfusion.The rats were randomly divided into sham operation group,low-dose(1mg/kg)atorvastatin group,medium-dose(2mg/kg)atorvastatin group,high-dose(4mg/kg)atorvastatin group and Fraxiparine group(0.01ml/kg),with 12 rats n each group.And the other 12 SD rats were taken as sham operation group.The mean pulmonary artery pressure(mPAP),right ventricular pressure(RVP),the arterial blood gas indexes,PaO_(2) and PaCO_(2),were measured.Moreover,HE staining was used to detect the pathological morphology of lung tissue.ELISA was used to detect the levels of IL-18 and IL-6 in bronchoalveolar lavage fluid(BALF).Western blot was used to detect the expressions of proteins related with SIRT2/NF-κB pathway.Results Compared with those in sham operation group,the pathological damage including alveolar structure damage,septal hyperemia and edema,obvious inflammatory cell infiltration,narrowing of pulmonary vascular lumen,obvious hyperplasia of arterial intima,were found in the lung tissue in model group.The mPAP,RVP,the PaCO_(2) in arterial blood,the levels of IL-18 and IL-6 in BALF and the expression levels of nuclear NF-κB protein in lung tissues were significantly increased(P>0.05),however,the PaO_(2) levels in arterial blood and expression levels of SIRT2 in lung tissue were significantly decreased(P>0.05).Compared with those in model group,the pathological damage of lung tissues in low-dose atorvastatin group,medium-dose atorvastatin group,high-dose atorvastatin group and Fraxiparine group was obviously relieved,and the levels of mPAP,RVP,PaCO_(2),IL-18 and IL-6 in BALF and the expression levels of nuclear NF-κB protein in lung tissue were significantly decreased,however,the PaO_(2) levels in arterial blood and expression levels of SIRT2 in lung tissue were significantly increased(P<0.05),with a dose-dependent manner in atorvastatin groups(P>0.05).In addition,there were no significant differences in the above indexes between high-dose atorvastatin group and Fraxiparine group(P>0.05).Conclusion Atorvastatin can up-regulate the expression of SIRT2,inhibit the nuclear transfer of NF-κB protein,alleviate the inflammatory reaction and pathological damage of pulmonary tissue in rats with APE,reduce the pressure of pulmonary artery,improve the blood gas index of pulmonary artery and repair the pulmonary function.