瓜蒌薤白汤预防低氧性肺动脉高压作用及其机制研究  

Effect and Mechanism of Gualou Xiebai(瓜蒌薤白)Decoction in Preventing Hypoxic Pulmonary Hypertension

作　　者：王建美 王冉冉 袁天翊[2] 秦雪梅[1] 杜冠华[2] WANG Jianmei;WANG Ranran;YUAN Tianyi;QIN Xuemei;DU Guanhua(Modern Research Center for Traditional Chinese Medicine,Shanxi University,Taiyuan 030006;Beijing Key Lab of Drug Target Identification and Drug Screening,Institute of Materia Medica,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050)

机构地区：[1]山西大学中医药现代研究中心,太原030006 [2]中国医学科学院北京协和医学院药物研究所,北京市药物靶点研究与新药筛选重点实验室,北京100050

出　　处：《中药药理与临床》2023年第5期8-15,共8页Pharmacology and Clinics of Chinese Materia Medica

基　　金：国家自然科学基金(编号:82073853、82141204);中国医学科学院医学与健康科技创新工程-重大协同创新项目(编号:2021-I2M-1-005)。

摘　　要：目的:明确瓜蒌薤白汤对低氧性肺动脉高压(Hypoxic Pulmonary Hypertension, HPH)小鼠的预防作用,初步探讨其作用机制。方法:使用TCMSP数据库对瓜蒌和薤白的活性成分及作用靶点进行预测,利用DrugBank、Genecard、OMIM等数据库寻找疾病靶点,构建“中药-化合物-靶点”网络。利用Metascape平台对瓜蒌薤白汤抗HPH的靶点进行基因功能(GO)和京都基因与基因组百科全书(KEGG)通路富集分析。采用UPLC-MS/MS对瓜蒌薤白汤的化学成分进行分析。将C57雄性小鼠随机分为:正常对照组、模型对照组、西地那非0.1 g/kg组和瓜蒌薤白汤1.8 g/kg组,提前3 d预防给药并制备低氧2 w肺动脉高压模型。实验终点时检测小鼠的血流动力学指数,脏器指数和病理学指标,利用Western blot法检测小鼠肺组织中内皮型一氧化氮合酶(eNOS)、骨形成蛋白2型受体(BMPR2)、过氧化物酶体增殖物激活受体γ(PPARγ)、肿瘤蛋白P53的蛋白表达。通过上述指标对瓜蒌薤白汤抗低氧性肺动脉高压的作用进行评价和机制研究。结果:TCMSP数据库收集活性成分22种包含:前列腺素、槲皮素、葫芦二烯醇、香叶木素、等,预测靶点172种,其中130种靶点与HPH相关。富集分析结果显示瓜蒌薤白汤抗HPH与细胞增殖、细胞迁移等生物学过程,与转录调节因子和过氧化物酶体等细胞成分,还与氧化还原酶激活和抗氧化活性等分子功能紧密相关,此外,还与肿瘤坏死因子(TNF)信号通路、Relaxin信号通路和PPAR信号通路等密切相关。与正常对照组比较,模型对照组小鼠的右心室收缩压显著升高(P<0.01),右心室肥厚指数、肺脏指数及肺血管壁厚均明显升高(P<0.05或P<0.01),肺组织中eNOS、BMPR2、PPARγ、P53蛋白表达均明显下调(P<0.05或P<0.01);与模型对照组比较,瓜蒌薤白汤1.8 g/kg组能显著降低右心室收缩压(P<0.01),明显降低右心室肥厚指数、肺脏指数及肺血管壁厚(P<0.05或P<0.01)Objective:To evaluate the efficacy and reveal the mechanism of Gualou Xiebai(瓜蒌薤白)Decoction in preventing hypoxic pulmonary hypertension(HPH)in mice.Methods:The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP)was employed to predict the active ingredients and targets of Gualou Xiebai Decoction.DrugBank,Genecard,and Online Mendelian Inheritance in Man(OMIM)were used to predict the targets of HPH,and the Chinese Medicine-Compound-Target network was built.Metascape was for the Gene Ontology(GO)annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment of the targets of Gualou Xiebai Decoction against HPH.Ultra-performance liquid chromatography coupled with tandem mass spectrometry(UPLC-MS/MS)was employed to determine the chemical components in this decoction.In the animal experiments,C57 male mice were randomly assigned into a normal control group,a model control group,a sildenafil(0.1 g/kg)group,and a Gualou Xiebai Decoction(1.8 g/kg)group.After three days of prophylactic administration,the HPH model was established.At the end of the experiment,hemodynamic indexes,organ indexes,and pathological indexes of the mice were determined.Western blotting was employed to determine the protein levels of endothelial nitric oxide synthase(eNOS),bone morphogenetic protein receptor type 2(BMPR2),peroxisome proliferator-activated receptorγ(PPARγ),and p53 in the lung tissue.The effect and mechanism of Gualou Xiebai Decoction against HPH were studied based on the above indexes.Results:Gualou Xiebai Decoction contained 22 active ingredients including prostaglandins,quercetin,cucurbitadienol,and diosmetin.These ingredients corresponded to 172 targets,130 of which were associated with HPH.The effect of Gualou Xiebai Decoction on HPH was mainly associated with the biological processes such as cell proliferation and migration,the cellular components such as transcriptional regulators and peroxisomes,and the molecular functions such as oxidoreductase activation and anti

关 键 词：瓜蒌薤白汤 低氧性肺动脉高压 肺血管收缩 肺血管重塑 过氧化物酶体增殖物激活受体信号通路 

分 类 号：R285[医药卫生—中药学]