达原饮通过NF-κB信号通路预防低氧性肺动脉高压作用及机制研究

The preventive effect and mechanism of Dayuanyin in hypoxic pulmonary hypertension through NF-κB signaling pathway

达原饮(Dayuanyin,DYY)在新冠肺炎和肺损伤中都有降低肺部炎症的作用。本实验拟探究DYY预防低氧性肺动脉高压(hypoxic pulmonary hypertension,HPH)的药效和作用机制,并对DYY保护肺功能的作用进行评价。动物福利和实验过程均遵循中国医学科学院药物研究所动物伦理委员会的规定并获批准。将雄性C57/BL6J小鼠随机分为正常对照组、模型组、达原饮组(800 mg·kg^(-1))和阳性对照西地那非组(100 mg·kg^(-1)),造模前3天灌胃给予对照溶剂或药物,第4天开始将模型组、达原饮组、西地那非组动物置于含10%±0.5%氧气的低氧舱中饲养,正常对照组动物于正常环境中饲养,继续连续给予对照溶剂或药物14天。实验终点检测小鼠右心室收缩压、右心室肥厚指数、脏器指数等各项指标,同时检测小鼠肺组织中炎症因子的表达水平。利用网络药理学对DYY在肺动脉高压上的潜在作用靶点进行预测,并通过Western blot实验检测细胞核因子κB(nuclear factor kappa B,NF-κB)信号通路相关蛋白的表达。DYY可显著降低HPH小鼠的右心室收缩压,减轻小鼠肺脏损伤,降低炎症因子表达,还可抑制低氧诱导的NF-κB信号通路的激活。DYY具有保护肺功能的作用,表现在DYY对HPH具有良好的药效,预防用药可减缓疾病的发展。作用机制可能与DYY通过降低炎症因子的表达抑制NF-κB及信号转导和转录激活因子3(signal transducer and activator of transcription 3,STAT3)的激活相关。

Dayuanyin(DYY)has been shown to reduce lung inflammation in both coronavirus disease 2019(COVID-19)and lung injury.This experiment was designed to investigate the efficacy and mechanism of action of DYY against hypoxic pulmonary hypertension(HPH)and to evaluate the effect of DYY on the protection of lung function.Animal welfare and experimental procedures are approved and in accordance with the provision of the Animal Ethics Committee of the Institute of Materia Medica,Chinese Academy of Medical Science.Male C57/BL6J mice were randomly divided into 4 groups:control group,model group,DYY group(800 mg·kg^(-1)),and positive control sildenafil group(100 mg·kg^(-1)).The animals were given control solvents or drugs by gavage three days in advance.On day 4,the animals in the model group,DYY group and sildenafil group were kept in a hypoxic chamber containing 10%±0.5%oxygen,and the animals in the control group were kept in a normal environment,and the control solvent or drugs continued to be given continuously for 14 days.The right ventricular systolic pressure,right ventricular hypertrophy index,organ indices and other metrics were measured in the experimental endpoints.Meantime,the expression levels of the inflammatory factors in mice lung tissues were measured.The potential therapeutic targets of DYY on pulmonary hypertension were predicted using network pharmacology,the expression of nuclear factor kappa B(NF-κB)signaling pathway-related proteins were measured by Western blot assay.It was found that DYY significantly reduced the right ventricular systolic pressure,attenuated lung injury and decreased the expression of inflammatory factors in mice.It can also inhibit hypoxia-induced activation of NF-κB signaling pathway.DYY has a protective effect on lung function,as demonstrated by DYY has good efficacy in HPH,and preventive administration can slow down the disease progression,and its mechanism may be related to inhibit the activation of NF-κB and signal transducer and activator of transcription 3(STAT3)by DYY.