莪术醇通过SIRT1/FOXO1通路改善重症急性胰腺炎大鼠肺损伤及诱导肺泡巨噬细胞凋亡的机制

Mechanism of curcumol in ameliorating lung injury and inducing apoptosis of alveolar macrophages in rats with severe acute pancreatitis via SIRT1/FOXO1 pathway

目的:探讨莪术醇通过沉默信息调节因子1(SIRT1)/叉头转录因子1(FOXO1)通路对重症急性胰腺炎(severe acute pancreatitis,SAP)大鼠肺损伤的改善作用及其对肺泡巨噬细胞凋亡的影响。方法:按照体重排序法将75只大鼠随机分为对照组、模型组、莪术醇低剂量组(4 mg·kg^(-1))、莪术醇高剂量组(16 mg·kg^(-1))和拮抗剂组(莪术醇16 mg·kg^(-1)+EX5272 mg·kg^(-1)),每组15只。除对照组外均建立急性胰腺炎大鼠模型,然后立即灌胃相应药物或生理盐水,12 h后再次给药1次。72 h后处死大鼠,比较各组血清淀粉酶(AMS)、内毒素水平,肺组织病理评分,肺泡巨噬细胞凋亡率,肺泡巨噬细胞中肿瘤坏死因子-α(TNF-α)、一氧化氮(NO)水平,以及肺泡巨噬细胞中SIRT1、FOXO1、乙酰化FOXO1(Ac-FOXO1)、核因子-κB p65(NF-κB p65)蛋白表达量。结果:与对照组比较,模型组血清AMS、内毒素水平,肺组织病理学评分和肺泡巨噬细胞TNF-α、NO水平、NF-κB p65蛋白相对表达量均显著升高(P<0.05);与模型组比较,莪术醇低剂量组、莪术醇高剂量组、拮抗剂组上述指标均显著降低(P<0.05),且莪术醇高剂量组低于莪术醇低剂量组和拮抗剂组(P<0.05)。与对照组比较,模型组肺泡巨噬细胞凋亡率及肺泡巨噬细胞SIRT1、Ac-FOXO1蛋白相对表达量降低(P<0.05);与模型组比较,莪术醇低剂量组、莪术醇高剂量组、拮抗剂组上述指标升高(P<0.05),且莪术醇高剂量组高于莪术醇低剂量组和拮抗剂组(P<0.05)。结论:莪术醇有助于改善SAP大鼠肺损伤,其调控机制可能与激活SIRT1/FOXO1信号通路诱导肺泡巨噬细胞凋亡有关。

OBJECTIVE To investigate the ameliorative effect of curcumol on lung injury of severe acute pancreatitis(SAP)rats via the silent information regulator transcript 1(SIRT1)/forkhead transcription factor 1(FOXO1)pathway and its effect on alveolar macrophage apoptosis.METHODS Seventy-five rats were randomly divided into control group(normal saline),model group(normal saline),low-dose curcumol group(4 mg·kg^(-1) curcumol),high-dose curcumol group(16 mg·kg^(-1) curcumol),and antagonist group(16 mg·kg^(-1) curcumol+2 mg·kg^(-1) EX527)according to weight ranking method,15 rats in each group.The rat model of acute pancreatitis was established except the control group,which was then immediately administrated with the appropriate drug or saline by gavage and given once again after 12 hours.Rats were sacrificed after 72 hours.The serum amylase(AMS),endotoxin levels,lung tissue pathology scores,alveolar macrophage apoptosis rate,tumor necrosis factor-α(TNF-α)and nitric oxide(NO)levels in alveolar macrophages,and the expression of SIRT1,FOXO1,Ac-FOXO1 and nuclear factor-κB(NF-κB)p65 protein in alveolar macrophages were compared in each group.RESULTS Compared with those in the control group,the serum AMS level,endotoxin level,lung histopathological score,alveolar macrophage TNF-α and NO levels and NF-κB p65 protein relative expression level in the model group were significantly increased(P<0.05).Compared with those in the model group,the above indexes in the low-dose curcumol group,high-dose curcumol group and antagonist group were significantly reduced(P<0.05),and those in the high-dose curcumol group were lower than those in the low-dose curcumol group and antagonist group(P<0.05).Compared with those in the control group,the apoptosis rate of alveolar macrophages and the relative expression of SIRT1 and Ac-FOXO1 protein in the alveolar macrophages in the model group decreased(P<0.05).Compared with those in the model group,the above indexes of the low-dose curcumol group,high-dose curcumol group and antagonist group increased(P<0.05),and those in the high-dose curcumol group were higher than those in the low-dose curcumol group and antagonist group(P<0.05).CONCLUSION Curcumol can help improve lung injury in SAP rats,and its regulatory mechanism may be related to activating the SIRT1/FOXO1 signaling pathway to induce the apoptosis of alveolar macrophages.