黄芪注射液通过调控mTOR/p70S6K信号通路对急性出血坏死型胰腺炎肺损伤炎症反应的影响

Astragalus injection improves inflammatory response in lung injury in acute hemorrhagic necrotizing pancreatitis by regulating the mTOR/p70S6K signal pathway

背景急性出血坏死型胰腺炎是临床常见的消化系统急症,肺损伤是其常见并发症和致死原因.黄芪注射液具有调节内分泌、增强免疫力、抑制病毒、抗炎、抗氧化应激等作用,但目前尚未见关于黄芪注射液在重症急性胰腺炎肺损伤中的相关研究.目的分析黄芪注射液通过调控雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)/核糖体70S小亚基S6蛋白激酶(ribosome 70S small subunit S6 protein kinase,p70S6K)信号通路对急性出血坏死型胰腺炎(acute hemorrhagic necrotic pancreatitis,AHNP)肺损伤炎症反应的影响.方法48只成年SD大鼠简单随机化分为对照组、模型组、低、中、高黄芪注射液组、阳性对照组,各8只,记录各组胰腺与肺组织组织病理学变化,比较各组Schmidt评分、血清淀粉酶(amylase,AMS)Hofouaer评分、动脉血二氧化碳分压(PaCO_(2))、动脉血氧分压(PaO_(2))、炎症因子[肿瘤坏死因子-α(tumor necrosis factor-alpha,TNF-α)、白介素-6(interleukin-6,IL-6)]、mTOR/p70S6K信号通路蛋白[mTOR、p70S6K、p-p70S6K、p-mTOR、真核启动因子4E结合蛋白1(p-4E binding protein 1,4EBP1)]水平.结果对照组胰腺、肺组织无异常变化;模型组胰腺实质呈片状坏死、充血水肿,胰腺腺泡细胞与间质细胞大量破坏,小叶结构紊乱,大量炎症细胞浸润与红细胞溢出,肺泡结构排卵紊乱、间质水肿、炎性细胞浸润、肺泡间隔增宽、灶性或片状肺不张、出血;低、中、高黄芪注射液组胰腺与模型组相比,呈现出不同程度改善,且随黄芪注射液剂量增加,改善程度依次增加,其中高黄芪注射液组与阳性对照组组织病理呈现出相似特征;模型组Schmidt评分、AMS、Hofouaer评分PaCO_(2)均高于对照组,PaO_(2)均低于对照组(P<0.05);低、中、高黄芪注射液组Schmidt评分、AMS、Hofouaer评分PaCO_(2)依次降低,PaO_(2)依次升高(P<0.05);模型组TNF-α、IL-6高于对照组(P<0.05);低、中、高黄芪注射液组TNF-α、IL-6依次降低(P<0.05);模型组mTOR、p70S6K、p-p70S6K、p-mTOR、4EBP1高于对照组(P<0.05);低、中、高黄芪注射液组mTOR、p70S6K、p-p70S6K、p-mTOR、4EBP1依次降低(P<0.05).结论黄芪注射液可呈剂量依赖性改善AHNP血气指标、炎症反应、胰腺与肺组织病理状态,其机制可能是通过调控mTOR/p70S6K信号通路实现的,抑制mTOR/p70S6K信号通路可能为AHNP肺损伤的治疗提供了一个新思路.

BACKGROUND Acute hemorrhagic necrotic pancreatitis is a clinically common digestive system emergency.Lung injury is a common complication and cause of death.Astragalus injection can regulate endocrine balance,enhance immunity,inhibit virus,and exert anti-inflammatory and antioxidant effects.However,there has been no relevant study on Astragalus injection in lung injury caused by severe acute pancreatitis.AIM To analyze the effect of Astragalus injection on the inflammatory response in lung injury secondary to acute hemorrhagic necrotic pancreatitis(AHNP)with regard to regulating the target protein of rapamycin/ribosomal 70S small subunit S6 protein kinase(mTOR/p70S6K).METHODS Forty-eight adult SD rats were randomly divided into a control group,a model group,low,medium,and high dosage Astragalus injection groups,and a positive control group,with 8 rats in each group.The histopathological changes of pancreas and lung tissues were recorded.Schmidt score,serum amylase(AMS),Hofouaer score,arterial blood carbon dioxide partial pressure(PaCO_(2)),arterial oxygen partial pressure(PaO_(2)),inflammatory factors[tumor necrosis factor-α(TNF-α)and interleukin-6(IL-6)],and mTOR/p70S6K signaling pathway protein(mTOR,p70S6K,p-p70S6K,p-mTOR,and 4EBP1)levels were assessed.RESULTS There were no abnormal changes in the pancreas and lung tissues in the control group.The pancreatic parenchyma of mice in the model group showed flaky necrosis,congestion,and edema,massive destruction of pancreatic acinar cells and interstitial cells,disordered lobular structure,infiltration of inflammatory cells and red blood cell overflow,and disordered alveolar structure,interstitial edema,inflammatory cell infiltration,alveolar septum widening,focal or flaky atelectasis,and hemorrhage.Compared with the model group,the low,medium,and high dosage Astragalus injection groups showed different degrees of improvement in a dose dependent manner.The histopathology of the high dosage Astragalus injection group and the positive control group showed similar characteristics.The Schmidt score,AMS,Hofouaer score,and PaCO_(2) in the model group were higher than those in the control group,and PaO_(2) was lower than that of the control group(P<0.05).Schmidt score,AMS,Hofouaer score,and PaCO_(2) decreased,and PaO_(2) increased in the low,medium,and high dosage Astragalus injection groups compared with the model group(P<0.05).TNF-αand IL-6 in the model group were higher than those of the control group(P<0.05);TNF-αand IL-6 decreased in the low,medium,and high dosage Astragalus injection groups compared with the model group(P<0.05).mTOR,p70S6K,p-p70S6K,p-mTOR,and 4EBP1 were higher in the model group than in the control group(P<0.05),while the low,medium,high dosage Astragalus injection groups had lower mTOR,p70S6K,p-p70S6K,p-mTOR,and 4EBP1 than the model group(P<0.05).CONCLUSION Astragalus injection can improve blood gas indexes,inflammatory response,pancreas and lung pathological state in AHNP in a dose dependent manner.Such effects may be achieved by regulating the mTOR/p70S6K signaling pathway,and inhibiting the mTOR/p70S6K signaling pathway may provides a new idea for the treatment of lung injury in AHNP.