阿托伐他汀对脂多糖致肺损伤的保护作用研究

Atorvastatin attenuates lipopolysaccharide-induced lung injury by inhibiting ERK signaling pathway

目的探讨阿托伐他汀对脂多糖(LPS)诱导肺损伤大鼠的保护作用及机制。方法 30只Wistar大鼠随机分为对照组、模型组(LPS组)、阿托伐他汀组,每组10只。采用腹腔注射LPS(5 mg/kg)的方法制备大鼠肺损伤模型,对照组注射同等剂量的生理盐水,阿托伐他汀组将阿托伐他汀灌胃(20 mg/kg),8 h后留取各组大鼠肺组织及血标本。光镜下观察肺组织病理改变;计算肺组织湿/干质量(W/D)比值;用ELISA法检测各组血浆中白细胞介素18(IL-18)、肿瘤坏死因子α(TNF-α)含量,并检测各组肺匀浆中一氧化氮(NO)、丙二醛(MDA)、超氧化物歧化酶(SOD)含量;免疫组化法检测ERK蛋白表达情况。结果光镜下观察对照组肺组织结构完整,肺泡腔结构清晰;LPS组肺泡壁增厚,渗出增多,肺组织呈损伤性变化;阿托伐他汀组病理改变较LPS组明显减轻。与对照组比较,LPS组肺组织W/D比值,血浆IL-18、TNF-α含量,肺匀浆NO、MDA含量均明显升高(P<0.05),而血浆SOD含量则降低;与LPS组比较,阿托伐他汀组肺组织W/D比值,血浆IL-18、TNF-α含量,肺匀浆MDA、NO含量均明显降低,而血浆SOD含量则增高。免疫组化结果显示:与对照组比较,LPS组ERK蛋白在胞浆和胞核表达均明显增加,而阿托伐他汀组较LPS组表达减轻。结论阿托伐他汀通过抗氧化、减轻炎症及抑制ERK信号通路发挥对LPS诱导大鼠肺损伤的保护作用。

Objective To investigate whether atorvastatin has a beneficial effect on lipopolysaccharide(LPS) induced acute lung injury in rats,and to explore the possible underlying mechanisms.Methods Thirty Wistar rats were randomly assigned into control group,model group(LPS group),atorvastatin group,with 10 in each group.Lung injury rat model was reproduced by intraperitoneal injection of LPS(5 mg/kg).The rats in the control group received an equal volume of normal saline at the same time.The rats in atorvastatin group were gavaged by atorvastatin(20 mg/kg),Animals were sacrificed 8 hours after LPS challenge.Plasma and lung tissue samples were collected,Histopathological evaluation,lung wet/dry(W/D) ratio.Tumor necrosis factor-α(TNF-α),Interleukin-18(IL-18),malondialdehyde(MDA),nitric oxide(NO)and superoxide dismutase(SOD) were analyzed.Immunohistochemical method was used to detect the protein expression of ERK.Results In the control groups,lung tissue showed a normal structure and clear pulmonary alveoli under a light microscope.In the model group,lung injury characters such as extensive thickening of the alveolar wall,significant infiltration of inflammatory cells,demolished structure of pulmonary alveoli,and hemorrhage were found.In the atorvastatin group,these pathological changes in lung is markedly alleviated compare LPS-induced lung injury group with the control group.Compared with control groups,lung W/D ratio,TNF-α and IL-18 in plasma,and lung MDA,NO levels in lung homogenates in the LPS group were increased significantly,while the lung SOD levels in the LPS group were decreased.Compared with the LPS group,lung W/D ratio,TNF-α and IL-18 in plasma,and lung MDA,NO levels in lung homogenates in the atorvastatin group were decreased significantly,while the lung SOD levels in the atorvastatin groups were increased.Immunohistochemistry showed that positive expressions of ERK in cytoplasm and nucleus in the atorvastatin treatment group were significantly lower than those in the model group.Conclusion Atorvastatin significantly ameliorated the lung injury induced by LPS in rats via the inhibition of ERK signaling pathway and reducing inflammation and antioxidant effect.