抗新型冠状病毒方剂基于花生四烯酸代谢通路防治“细胞因子风暴”的研究

Study on treatment of"cytokine storm"by anti-2019-nCoV prescriptions based on arachidonic acid metabolic pathway

新型冠状病毒(2019-nCoV)肺炎疫情暴发以来,发展迅速,形势严峻,受到国内外广泛关注。发表在《柳叶刀》杂志的研究指出新型冠状病毒的感染与"细胞因子风暴"(cytokine storm)存在密切联系。"细胞因子风暴"是机体对病毒、细菌等外界刺激产生的一种过度免疫反应。当病毒攻击机体时,刺激分泌产生大量的炎症因子,如白细胞介素(interleukin,IL)、干扰素(interferon,IFN)、趋化因子(C-X-C motif chemokine,CXCL)等,进而引发细胞因子级联反应。随着炎症因子渗出,多种细胞因子在组织、器官中异常升高,干扰免疫系统,造成机体过度免疫应答反应,引起肺部细胞的弥漫性损伤,肺部出现纤维化,且导致多器官损伤,严重则可能导致死亡。花生四烯酸(arachidonic acid,AA)代谢通路主要用于合成炎症介质,可介导多种炎症因子的产生,如单核细胞趋化蛋白-1(monocyte chemotactic protein 1,MCP-1)、肿瘤坏死因子(tumor necrosis factor,TNF)、IL、IFN等,与炎症的发生发展及消退均有密切联系。因此抑制花生四烯酸代谢通路,有助于抑制机体炎症因子的释放,缓解"细胞因子风暴"。该研究基于花生四烯酸代谢通路关键靶点抑制剂的药效团模型,筛选中药化学成分数据库(traditional Chinese medicine database,TCMD 2009)。选择匹配值(fit value)大于0.7的成分作为潜在活性成分,对活性成分来源中药进行频数统计,结合《国家新型冠状病毒感染的肺炎诊疗方案(试行第六版)》中的中药方剂进行分析,获取对"细胞因子风暴"具有潜在治疗作用的方剂。结果显示,对花生四烯酸代谢通路具有抑制作用的成分为厚朴木脂体Ⅰ、忍冬苦苷、大黄素甲醚-8-O-β-D-吡喃葡萄糖苷等,中药为厚朴、生姜、金银花、大黄、丹参、黄芩、栀子、人参、牛蒡子、绵马贯众、赤芍、山药。结合新型冠状病毒治疗方剂进行分析,发现藿香正气胶囊、金花清感颗粒、连花清瘟胶囊、清肺排毒汤、血必净注射液、热毒宁注射液、痰热清注射液对花生四烯酸通路具有潜在抑制作用,可能通过缓解"细胞因子风暴"抑制新型冠状病毒引起的肺炎。该研究旨在为新型冠状病毒临床用药提供指导,并为探索治疗新型冠状病毒中药及方剂的治疗机制和临床用药提供参考。

Since the outbreak of 2019-nCoV,the epidemic has developed rapidly and the situation is grim.LANCET figured out that the 2019-nCoV is closely related to"cytokine storm"."Cytokine storm"is an excessive immune response of the body to external stimuli such as viruses and bacteria.As the virus attacking the body,it stimulates the secretion of a large number of inflammatory factors:interleukin(IL),interferon(IFN),C-X-C motif chemokine(CXCL)and so on,which lead to cytokine cascade reaction.With the exudation of inflammatory factors,cytokines increase abnormally in tissues and organs,interfering with the immune system,causing excessive immune response of the body,resulting in diffuse damage of lung cells,pulmonary fibrosis,and multiple organ damage,even death.Arachidonic acid(AA)metabolic pathway is principally used to synthesize inflammatory cytokines,such as monocyte chemotactic protein 1(MCP-1),tumor necrosis factor(TNF),IL,IFN,etc.,which is closely related to the occurrence,development and regression of inflammation.Therefore,the inhibition of AA metabolism pathway is benefit for inhibiting the release of inflammatory factors in the body and alleviating the"cytokine storm".Based on the pharmacophore models of the targets on AA metabolic pathway,the traditional Chinese medicine database 2009(TCMD 2009)was screened.The potential herbs were ranked by the number of hit molecules,which were scored by pharmacophore fit value.In the end,we obtained the potential active prescriptions on"cytokine storm"according to the potential herbs in the"National novel coronavirus pneumonia diagnosis and treatment plan(trial version sixth)".The results showed that the hit components with the inhibitory effect on AA were magnolignanⅠ,lonicerin and physcion-8-O-β-D-glucopy-ranoside,which mostly extracted from Magnoliae Officinalis Cortex,Zingiberis Rhizoma Recens,Lonicerae Japonicae Flos,Rhei Radix et Rhizoma,Salviae Miltiorrhizae Radix et Rhizoma,Scutellariae Radix,Gardeniae Fructus,Ginseng Radix et Rhizoma,Arctii Fructus,Dryopteridis Crassirhizomatis Rhizoma,Paeoniaeradix Rubra,Dioscoreae Rhizoma.Finally the anti-2019-nCoV prescriptions were analyzed to obtain the potential active prescriptions on AA metabolic pathway,Huoxiang Zhengqi Capsules,Jinhua Qinggan Granules,Lianhua Qingwen Capsules,Qingfei Paidu Decoction,Xuebijing Injection,Reduning Injection and Tanreqing Injection were found that may prevent 2019-nCoV via regulate cytokines.This study intends to provide reference for clinical use of traditional Chinese medicine to resist new coronavirus.