川陈皮素通过FOXO3a/SIRT1通路减轻脂多糖诱导的肺损伤

Nobiletin Alleviates LPS-induced Lung Injury via FOXO3a/SIRT1 Pathway

目的 观察川陈皮素在脓毒症肺损伤中的作用,并探究其潜在机制。方法 采用随机数字表法将48只8~10周的雄性C57 BL/6小鼠分为4组,即对照组、肺损伤组、治疗组(5mg/kg)和治疗组(10mg/kg),每组各12只。对照组不做任何处理;肺损伤组小鼠腹腔注射脂多糖(10mg/kg);治疗组(5mg/kg)小鼠接受腹腔注射脂多糖(10mg/kg)的同时予以川陈皮素(5mg/kg)灌胃;治疗组(10mg/kg)小鼠接受腹腔注射脂多糖(10mg/kg),同时予以川陈皮素(10mg/kg)灌胃。脂多糖腹腔注射12h后,检测各组小鼠肺功能及动脉血气,同时留取肺组织,分别从病理学和分子生物学层面评估小鼠肺损伤状况及可能靶点。结果 与对照组比较,肺损伤组小鼠气道压力、PaCO_(2)、肺损伤评分明显增高,PaO_(2)明显降低(P<0.05);与肺损伤组比较,治疗组(5mg/kg)和治疗组(10mg/kg)小鼠气道压力、PaCO_(2)、肺损伤评分明显降低,PaO_(2)明显升高(P<0.05)。Western blot法检测结果显示,与对照组比较,肺损伤组小鼠肺组织中IL-1β、TNF-α、TXNIP和4-HNE的蛋白表达水平明显升高(P<0.05);与肺损伤组比较,治疗组(5mg/kg)和治疗组(10mg/kg)小鼠肺组织上述蛋白表达水平明显降低(P<0.05)。此外,肺损伤组小鼠肺组织中FOXO3a和SIRT1的蛋白表达水平较对照组明显降低(P<0.05);与肺损伤组比较,治疗组(5mg/kg)和治疗组(10mg/kg)小鼠肺组织中FOXO3a和SIRT1蛋白表达水平明显上调(P<0.05)。结论 川陈皮素可抑制小鼠脓毒症肺损伤并减轻氧化应激和炎性反应,其机制可能与川陈皮素对FOXO3a/SIRT1通路激活有关。

Objective To observe the role of nobiletin in sepsis-induced lung injury and explore its potential mechanism.Methods According to random number table,48male C57 BL/6mice aged 8-10 weeks were divided into 4groups,namely control group,lung injury group,treatment group(5mg/kg),and treatment group(10mg/kg),with 10mice in each group.The mice of control group did not receive any treatment;LPS(10mg/kg)was injected intraperitoneally in mice of lung injury group;the mice of treatment group(5mg/kg)received intraperitoneal injection of lipopolysaccharide(10mg/kg)and intragastric administration of nobiletin(5mg/kg);the mice of treatment group(10mg/kg)received intraperitoneal injection of lipopolysaccharide(10mg/kg)and intragastric administration of nobiletin(10mg/kg).After 12hours of intraperitoneal injection of lipopolysaccharide,the lung function and arterial blood gas of mice in each group were detected,and the lung tissue collected to evaluate the lung injury status and possible targets of mice from the pathological and molecular biological levels.Results Compared with the control group,the airway pressure,PaCO_(2) and lung injury score in the lung injury group were significantly increased,while PaO_(2) was significantly decreased(P<0.05);Compared with lung injury group,the airway pressure,PaCO_(2) and lung injury score in the treatment group(5mg/kg)and treatment group(10mg/kg)were significantly decreased,and PaO_(2) was significantly increased(P<0.05).Western blot showed that the protein expression levels of IL-1β,TNF-α,TXNIP and 4-HNE significantly increased in lung injury group(P<0.05);Compared with the lung injury group,the expression levels of the above proteins in the lung tissue of mice in the treatment group(5mg/kg)and the treatment group(10mg/kg)were significantly decreased(P<0.05).In addition,the protein expression levels of FOXO3a and SIRT1 of mice in the lung injury group were significantly lower than those in control group(P<0.05);Compared with the lung injury group,the protein expression levels of FOXO3a and SIRT1 in the treatment group(5mg/kg)and the treatment group(10mg/kg)were significantly up-regulated(P<0.05).Conclusion Nobiletin can inhibit the lung injury in mice with sepsis by reducing oxidative stress and inflammatory reaction,and its mechanism may be related to the activation of FOXO3a/SIRT1 pathway.