摘要
目的:研究黄连解毒汤对脓毒症急性肺损伤(ALI)的改善作用及其机制。方法:通过网络药理学平台挖掘黄连解毒汤改善脓毒症ALI作用的药效物质基础及潜在的作用机制;将60只SD大鼠随机分为6组:假手术组,模型组,地塞米松组(10 mL·kg^(-1)),黄连解毒汤低、高剂量组(3.6、14.4 g·kg^(-1)),黄连解毒汤高剂量+核因子E_(2)相关因子2(Nrf2)抑制剂组(14.4 g·kg^(-1)+30 mg·kg^(-1)),采用盲肠结扎穿孔术制作脓毒症ALI模型12 h后进行灌胃给药,建模7 d后处死并分离肺组织,观察组织病理学改变和相关键靶点的表达。结果:通过网络药理学平台挖掘分析,黄连解毒汤治疗ALI的高频活性成分为β-谷甾醇、槲皮素、豆甾醇、黄连碱、表小檗碱;通过作用于谷胱甘肽过氧化物酶4(GPX4)、检测Nrf2、血红素加氧酶-1(HO-1)、TP53基因(TP53)、丝裂原活化蛋白激酶3(MAPK3)、肿瘤坏死因子(TNF)、信号传导及转录激活蛋白3(STAT3)、白细胞介素(IL)-1β、原癌基因(MYC)9个核心靶点,调控铁死亡等信号通路等来调控脓毒症ALI的作用。黄连解毒汤可改善脓毒症ALI大鼠肺泡间质水肿、肺泡壁增厚等病理损伤;使丙二醛(MDA)、Fe^(2+)、活性氧(ROS)水平均明显降低(P<0.05),超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH)水平明显升高(P<0.05);电镜和普鲁士蓝染色显示可显著改善线粒体微结构和铁沉积;使Nrf2、溶质载体家族7成员11(SLC7A11)、GPX4和HO-1蛋白表达均明显升高(P<0.05)。Nrf2抑制剂能够显著逆转黄连解毒汤对脓毒症ALI肺组织的保护作用。结论:黄连解毒汤可通过多途径多靶点改善脓毒症ALI,其代表性机制可能为激活Nrf2/SLC7A11/GPX4信号通路来发挥作用。
Objective:To study the improvement effect and mechanism of Huanglian Jiedutang on acute lung injury(ALI)in sepsis.Methods:Exploring the pharmacological substance basis and potential mechanisms of Huanglian Jiedutang in improving ALI in sepsis through online pharmacology platforms;sixty SD rats were randomly divided into 6 groups:sham group,model group,positive group(10 mL·kg^(-1)),Huanglian Jiedutang low-dose group,Huanglian Jiedutang high-dose group(3.6、14.4 g·kg^(-1)),and Huanglian Jiedutang high-dose+nuclear factor-erythroid 2-related factor 2(Nrf2)inhibitor group(Huanglian Jiedutang+ML385)(14.4 g·kg^(-1)+30 mg·kg^(-1)).A sepsis induced ALI model was created by cecal ligation and perforation surgery for 12 hours,followed by gavage administration.After 7 days of modeling,lung tissue was euthanized and isolated,and histopathological changes and expression of related key targets were observed.Results:The results showed that the high-frequency active ingredients of Huanglian Jiedutang in treating ALI wereβ-sitosterol,quercetin,stigmasterol,berberine,and berberine;By acting on 9 core targets including(GPX4),Nrf2,Heme Oxygenase-1(HO-1),TP53,mitogen-activated protein kinase 3(MAPK3),tumor necrosis factor(TNF),signal transducer and activator of transcription(STAT3),interleukin(IL)-1β,MYC,and regulating signaling pathways such as ferroptosis,the effect of sepsis induced ALI is regulated.Huanglian Jiedutang can improve pathological damage such as alveolar interstitial edema and alveolar wall thickening in ALI rats with sepsis.The levels of malondialdehyde(MDA),Fe2+,and reactive oxygen species(ROS)were significantly reduced(P<0.05),while the levels of superoxide dismutase(SOD)and glutathione peroxidase(GSH)were significantly increased(P<0.05).Electron microscopy and Prussian blue staining showed significant improvement in mitochondrial microstructure and iron deposition.Significantly increase the expression of Nrf2,solute carrier family 7 member 11(SLC7A11),GPX4,and HO-1 proteins(P<0.05).ML385 can significantly reverse the protective effect of Huanglian Jiedutang on sepsis induced ALI lung tissue.Conclusion:Huanglian Jiedutang can improve ALI in sepsis through multiple pathways and targets,and its representative mechanism may be the activation of the Nrf2/SLC7A11/GPX4 signaling pathway.
作者
龙敏
刘克琴
岳煜
费立博
邵龙刚
童佳佳
秦慧玲
张潇月
李探
陈慧敏
赵谦
辛恒
LONG Min;LIU Keqin;YUE Yu;FEI Libo;SHAO Longgang;TONG Jiajia;QIN Huiling;ZHANG Xiaoyue;LI Tan;CHEN Huimin;ZHAO Qian;XIN Heng(The Second Affiliated Hospital of Nanjing University of Chinese Medicine,Nanjing 210017,China;Nanjing First Hospital,Nanjing 210006 China)
出处
《中国实验方剂学杂志》
北大核心
2025年第23期12-20,共9页
Chinese Journal of Experimental Traditional Medical Formulae
基金
江苏省卫生健康委科研项目(H2023054)
江苏省第二中医院院内课题(SEZYB2023008)。
