传统中药治疗新型冠状病毒肺炎的疗效及机制研究进展

李霖 ,  吴昱铮 ,  王佳宝 ,  闫慧敏 ,  卢佳 ,  王彧 ,  张伯礼 ,  张俊华 ,  杨剑 ,  王小莹 ,  张敏 ,  李越 ,  苗琳 ,  张晗

工程（英文） ›› 2022, Vol. 19 ›› Issue (12) : 139 -152.

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工程（英文） ›› 2022, Vol. 19 ›› Issue (12) : 139 -152. DOI: 10.1016/j.eng.2021.08.020

传统中药治疗新型冠状病毒肺炎的疗效及机制研究进展

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Potential Treatment of COVID-19 with Traditional Chinese Medicine: What Herbs Can Help Win the Battle with SARS-CoV-2?

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摘要

在世界范围内，中药已成功用于治疗由SARS-CoV-2 病毒引起的新型冠状病毒肺炎（COVID-19）。然而，中药治疗COVID-19 的药理机制仍不明确。因此，本文结合基于中医理论的药理检测方法，梳理了具有抗病毒感染、调节免疫、改善肺损伤和肺纤维化作用的中药活性化合物以及中药方剂，并对其可能的作用靶点和信号通路进行了总结。这些研究结果表明，COVID-19 的发生发展涉及病毒与受体互作以及炎症免疫激活等错综复杂的调节机制。因此，亟需对中药方剂或中药活性化合物治疗COVID-19 的药效及机制进行更多、更深层次的研究，以确定中药与COVID-19 之间的联系，用现代科技手段阐明中药治疗COVID-19 的药理机制。

Abstract

Traditional Chinese medicine (TCM) has been successfully applied worldwide in the treatment of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the pharmacological mechanisms underlying this success remain unclear. Hence, the aim of this review is to combine pharmacological assays based on the theory of TCM in order to elucidate the potential signaling pathways, targets, active compounds, and formulas of herbs that are involved in the TCM treatment of COVID-19, which exhibits combatting viral infections, immune regulation, and amelioration of lung injury and fibrosis. Extensive reports on target screening are elucidated using virtual prediction via docking analysis or network pharmacology based on existing data. The results of these reports indicate that an intricate regulatory mechanism is involved in the pathogenesis of COVID-19. Therefore, more pharmacological research on the natural herbs used in TCM should be conducted in order to determine the association between TCM and COVID-19 and account for the observed therapeutic effects of TCM against COVID-19.

关键词

中药 / SARS-CoV-2 / COVID-19 / 抗病毒 / 抗炎症 / 免疫调节

Key words

Traditional Chinese medicine / SARS-CoV-2 / COVID-19 / Antivirus / Anti-inflammation / Immune regulation

引用本文

引用格式 ▾
李霖,吴昱铮,王佳宝,闫慧敏,卢佳,王彧,张伯礼,张俊华,杨剑,王小莹,张敏,李越,苗琳,张晗. 传统中药治疗新型冠状病毒肺炎的疗效及机制研究进展[J]. 工程（英文）, 2022, 19(12): 139-152 DOI:10.1016/j.eng.2021.08.020

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1、 引言

截至2021年4月25日，全球已有超过1.47亿人被诊断为新型冠状病毒肺炎（COVID-19）[1]，对人类的健康、经济发展以及社会稳定产生了极大的负面影响[2]。然而，目前临床上仍然缺乏针对COVID-19的有效治疗药物。

中药在治疗严重急性呼吸综合征（SARS）和COVID-19等由病毒引起的传染性肺炎方面具有显著疗效。在2020年2月7日，中华人民共和国国家卫生健康委员会和国家中医药管理局联合推荐金花清感颗粒、连花清瘟胶囊、血必净注射液及清肺排毒汤、化湿败毒方、宣肺败毒方用于治疗COVID-19（http://yzs.satcm.gov.cn/zhengcewenjian/），因为这些药物是治疗流感样症状、哮喘、炎症、扁桃体炎和咽喉肿痛的经典处方，且此“三药三方”在治疗新型冠状病毒肺炎的实战中发挥了重要的作用，显示出良好的临床疗效[3‒8]。然而，关于这些药物抑制SARS-CoV-2病毒的具体药理学机制还未被阐明。因此，在本文中，通过筛选现有的研究，讨论了中医理论在治疗COVID-19中的应用，并全面总结了中药抗病毒感染、调节免疫、抗炎、缓解肺损伤和肺纤维化的可能机制。

2、 COVID-19的病理机制

2.1 SARS-CoV-2病毒的复制和感染机制

SARS-CoV-2是一种有包膜的单链RNA病毒，属于冠状病毒家族[9]。该病毒由四个主要的结构蛋白组成，即膜蛋白（M蛋白）、穗状蛋白（S蛋白）、包膜蛋白（E蛋白）和核壳蛋白（N蛋白）[10]。不同的结构蛋白具有不同的功能。M蛋白在决定病毒包膜的形状方面起着关键的作用。S蛋白是病毒与宿主细胞结合的关键媒介，是病毒进入宿主细胞的关键[11]。E蛋白参与病毒包膜的形成以及病毒的出芽和组装[12]。N蛋白与病毒的RNA基因组结合，与E蛋白类似，N蛋白也参与了病毒的出芽和组装[11]。除了这些结构蛋白外，非结构蛋白RNA依赖性RNA聚合酶（RdRP）和3CL蛋白酶（3CLpro）在SARS-CoV-2的生命周期中也起着重要作用。RdRP是病毒复制和转录复合体的核心成分[13]，3CLpro负责病毒多聚物的翻译后修饰。因此，RdRP和3CLpro对于病毒的复制和感染都是不可缺少的[14]。

在人体内，血管紧张素转换酶2（ACE2）负责调节血压。ACE2在鼻黏膜、支气管、肺、心脏、食道、肾脏、胃、膀胱和回肠中广泛表达，这些器官都容易受到SARS-CoV-2的影响[15]。此外，已有研究表明ACE2是SARS-CoV-2与人类细胞膜结合的受体，ACE2通过与病毒S蛋白的相互作用介导SARS-CoV-2进入宿主细胞。因此，ACE2在病毒感染中起着关键作用[16]。

2.2 感染SARS-CoV-2病毒后的病理损害

SARS-CoV-2主要通过飞沫或直接接触传播。在病毒感染初期，其复制主要发生在上呼吸道的黏膜上皮细胞中，随后，病毒会进一步侵害下呼吸道[17]。成年人感染SARS-CoV-2的早期临床表现包括发烧、咳嗽、气短和疲劳。随着疾病的进展，患者将出现肺泡损伤，大量巨噬细胞和淋巴细胞浸润以及间质性肺炎和肺纤维化[18]。在重症病例中，患者表现出极其复杂的症状，包括急性呼吸窘迫综合征（ARDS）、急性肝脏和心脏损伤、肾衰竭、继发感染和脓毒性休克等多器官受累表现[19]。

SARS-CoV-2感染后，巨噬细胞和树突状细胞首先触发免疫反应，表现为淋巴细胞增多和细胞因子释放。然而，随着病毒的不断复制，炎症反应被过度激活并损伤了对SARS-CoV-2具有清除能力的淋巴细胞[20]。同时，细胞因子的分泌迅速失调，最终导致细胞因子风暴[21]。炎症及细胞因子风暴损害了肺部上皮屏障，从而进一步导致了肺部炎症。随着疾病的进展，这种炎症损害逐步扩散到肾脏、心脏、血管和大脑等其他器官，导致多器官受累[22]（图1）。

图1 COVID-19的致病机制。SARS-CoV-2进入人体后，通过与细胞膜表面的ACE2结合侵入细胞，并开始在宿主细胞的细胞质中复制。该病毒由巨噬细胞和树突状细胞识别并递呈给B细胞和T细胞，激活宿主的免疫系统。B细胞和T细胞在感染信号的刺激下分化为效应性免疫细胞，诱发促炎细胞因子和趋化因子的产生。然而，免疫系统的持续激活和细胞因子的积累会导致细胞因子风暴，使肺和其他器官受到严重损害。MODS：多器官功能障碍综合征；TMPRSS2：跨膜蛋白酶丝氨酸2；Th：T辅助细胞；CTL：细胞毒性T淋巴细胞；DC：树突状细胞；NK：自然杀伤细胞；Tn：幼稚T细胞；Mφ：巨噬细胞；sgRNA：单向导RNA。

2.3 SARS-CoV-2病毒与其他病毒的比较

作为冠状病毒家族的一员，SARS-CoV-2与SARS-CoV和中东呼吸综合征冠状病毒（MERS-CoV）分别有大约80.0%和50.0%的遗传相似性[23]。同时，SARS-CoV-2与上述两种病毒具有相似的流行病学和生物学特征。这些冠状病毒都可引起严重的呼吸道感染，且伴有细胞因子风暴，导致病毒性肺炎和ARDS [24]。然而，这三种病毒之间也存在差异，特别是它们对宿主受体的亲和力以及它们的致病性。冠状病毒通过其S蛋白与宿主受体结合进入宿主细胞，随后S蛋白被蛋白酶裂解，暴露出S2融合结构与宿主细胞进行膜融合[25‒26]。二肽基肽酶4是MERS-CoV的受体，是一种多功能的细胞表面蛋白，不仅在肾脏、小肠、肝脏、前列腺上皮细胞和活化的白细胞中广泛表达，同时也在人类的上呼吸道上皮中广泛表达[27‒28]。ACE2是SARS-CoV和SARS-CoV-2在宿主细胞上的受体，在呼吸道的肺泡上皮细胞、气管、支气管、支气管浆液腺、肺泡单核细胞和巨噬细胞中广泛表达[29]。然而，SARS-CoV-2与宿主细胞ACE2的亲和力高于SARS-CoV与宿主细胞ACE2的亲和力[30]，因此SARS-CoV-2相比SARS-CoV具有更高的传播率。此外，针对SARS-CoV受体结合域（RBD）的单克隆抗体（mAb）不能与SARS-CoV-2的S蛋白RBD有效结合[30]，表明针对SARS-CoV的mAb与SARS-CoV-2的交叉反应性有限。

SARS-CoV-2和SARS-CoV的宿主受体及激活蛋白酶的组织表达存在差异，导致它们具有各自独特的病理生理学特征。除了呼吸道症状外，MERS-CoV感染的患者可能会出现肌肉酸痛和胃肠道表现。主要的临床并发症包括肾衰竭和伴有休克的严重呼吸窘迫综合征[31]。在肺部病理变化方面，SARS-CoV能够引起严重的肺纤维化，而SARS-CoV-2则较易导致严重的渗出反应[32]。此外，SARS-CoV-2主要损害支气管和肺泡，导致大量黏液和痰液的分泌并堵塞气道，从而引起继发感染、ARDS和呼吸衰竭[9,33]。

3、 中医药治疗COVID-19的理论基础

据史料记载，中国在过去3000年中经历了500多次瘟疫[34]。因此，我国人民在预防和治疗流行性疾病方面有着丰富的经验，并据此形成了系统的治疗瘟疫的理论体系。基于这一理论体系，中医专家判定COVID-19属于“瘟疫”的范畴[1]。大多数COVID-19患者在发病时表现为低热、咳嗽、乏力、食欲不振以及舌苔厚腻[19]，并出现肺部和胃肠道功能损伤等“湿毒症”特征[35]。湿气黏滞，阻碍气机，导致病程延长和多个器官功能损害。此外，随着疾病的发展，COVID-19的症状转化为“燥”“热”“虚”“冷”等不同亚型。因此，COVID-19属于典型的“湿毒疫”（dampness-toxicity plague），其发病特点包括“湿、热、毒、瘀、虚、闭”[36]。根据这一理论，对COVID-19患者的治疗应采用能缓解湿毒病发病机理的中药处方，并注重清热、理气、祛痰、解毒。

4、 中医药治疗COVID-19的科学基础

研究并开发针对COVID-19病毒感染特征的特效药物对于疾病的控制和治疗具有十分重要的意义[37]。中药凭借其“多成分、多靶点、协同作用”的独特优势，在治疗COVID-19的实践中发挥了抗病毒感染、调节免疫、抑制炎症，以及预防肺部损伤和纤维化的综合作用。在科学解读中药治疗COVID-19的机制、探索各类中药的主要成分和有效靶点，并分析中药靶点与COVID-19的相关性方面，网络药理学发挥了不可小觑的作用[38‒44]。网络药理学方法通过全面收集药材的化合物成分以及COVID-19的靶点基因，建立靶点网络模型，并进一步采用京都基因和基因组数据库（KEGG）、基因本体（GO）和蛋白质-蛋白质相互作用（PPI）分析来评估中药调控COVID-19的主要生物靶点和途径，为后续的实验验证提供依据。本文根据治疗COVID-19的三个主要过程，即抗病毒感染、调节免疫和抑制肺损伤和肺纤维化，基于网络药理学及现代化实验手段的研究结果，筛选和鉴定了能够有效治疗COVID-19的中药方剂、药材及其活性化合物，总结了中医药治疗COVID-19的科学基础。

4.1 中药防治SARS-CoV-2病毒感染

SARS-CoV-2的S蛋白、RdRP和3CLpro是病毒侵入人体的三个主要功能蛋白[45]。因此，阻断细胞表面受体ACE2与S蛋白的结合或抑制RdRP和3CLpro的酶活性是中药治疗COVID-19的潜在作用机制（图2）。

图2 中药的抗病毒作用。中药可通过多种机制抑制SARS-CoV-2的感染，包括直接与ACE2和S蛋白结合并阻止其活性，下调宿主细胞中S蛋白受体的表达[如ACE2和血管紧张素Ⅱ受体（AGTR2）]，以及抑制RdRP和3CLpro的表达从而抑制病毒的复制。绿色方框中列出了与每种机制相关的代表性中药。Mpro：主蛋白酶。

4.1.1. 防治SARS-CoV-2病毒感染的中药活性化合物

研究者通过分子对接的手段，筛选出一些与S蛋白、RdRP和3CLpro具有相对较低结合能和抑制常数的化合物，这些化合物可以对SARS-CoV-2产生潜在的抑制作用[2,46]。Tahir ul Qamar等[14]分析了3CLpro的蛋白序列，构建了三维同源模型，并将该模型与药用植物库中32 297种具有潜在抗病毒能力的化合物进行了分子对接筛选。结果表明，5,7,3′,4′-tetrahydroxy-2′-(3,3-dimethylallyl) isoflavone、myricitrin、methyl rosmarinate、3,5,7,3′,4′,5′-hexahydroxy flavanone-3-O-β-D-glucopyranoside、(2S)-eriodictyol 7-O-(6″-O-galloyl)-β-D-glucopyranoside、calceolarioside B、myricetin 3-O-β-D-glucopyranoside、 licoleafol和amaranthin是潜在的抗SARS-CoV-2的活性化合物，具备被开发成用于防治COVID-19的药物的潜力[14]。此外，穿心莲内酯、姜黄素和表没食子素-3-棓酸盐也是SARS-CoV-2的主要蛋白酶（Mpro）和3CLpro的潜在抑制剂[47‒49]。金银花中的主要黄酮类成分，即木犀草素能够与SARS-CoV-2的Mpro结合，从而阻止病毒进入宿主细胞[50]。基于分子对接实验的分析，三种天然来源的成分，即crocin、digitoxigenin和β‍-eudesmol具备抑制SARS-CoV-2的S蛋白的能力[51]。此外，分子对接结果预测，地高辛（digitoxin）也能够与S蛋白结合，从而抑制病毒与人体细胞的相互作用[52]。黄芪广泛用于治疗咳嗽、腹泻、发热和炎症。最近的一项研究表明，黄芪可以通过抑制SARS-CoV-2感染人体的关键蛋白（即eIF4A和PHB1/2的水平）来抑制病毒的感染[53]。

由于SARS-CoV-2是冠状病毒家族的成员，因此具有抗冠状病毒活性的中药化合物有可能成为治疗COVID-19的候选化合物[20]。姜黄素是一种著名的具有抗病毒作用的天然化合物。该化合物通过抑制病毒复制周期中的关键步骤[48]、改变病毒的表面蛋白结构、与病毒竞争性结合细胞受体，以及抑制ACE2受体的表达等途径发挥抗病毒感染的作用[54‒55]。体外细胞感染实验表明，姜黄素可有效抑制SARS-CoV-2的S蛋白水平[55]，并减少病毒感染细胞的斑块数量[54]。此外，柴胡皂苷B2也被证实具有抗冠状病毒活性[56]。生物信息学分析显示，柴胡皂苷能与白细胞介素-6受体（IL-6R）、Janus激酶-3（JAK3）和烟酰胺腺嘌呤二核苷酸磷酸酯（NADPH）-氧化酶5（NOX5）等炎症相关蛋白有效结合，从而抑制病毒感染导致的炎症反应[57]。此外，大黄和蓼科植物中广泛存在的蒽醌类化合物大黄素，能够显著阻断S蛋白和ACE2受体的相互作用，并以剂量依赖的方式降低S蛋白假型逆转录病毒在Vero E6细胞中的致病性[58]。

4.1.2. 草药

许多草药已显示出对病毒性疾病的治疗潜力。例如，桔皮提取物显著降低了感染小鼠肝炎病毒（MHV）-A59的HeLa-CEACAM1a细胞的病毒载量[59]。此外，半数有效浓度（EC50）为2.0~27.5 μg·mL-1的生麻、苦楝、黄连、黄柏、苦参等中药提取物可降低MHV、水泡性口炎病毒（VSV）和猪流行性腹泻病毒（PEDV）等的复制，抑制细胞内RNA和蛋白的表达[60]。此外，半抑制浓度（IC50）为1~10 μg·mL-1的大黄、何首乌和首乌藤可抑制SARS-CoV-2与ACE2的相互作用[58]。

血管紧张素Ⅱ受体2（AGTR2）是一种对SARS-CoV-2的S蛋白具有高亲和力的蛋白，在肺部特异性表达方面，中药接骨木、穿心莲可通过下调AGTR2的表达来阻断病毒入侵细胞[61]。黄麻-苦杏仁是抗COVID-19的处方中常见的对药（couplet medicine），网络药理学分析结果发现这些药物具有抗SARS-CoV-2的活性[62]。通过分子对接分析发现，从麻黄和苦杏仁中分离得到β-谷甾醇、雌酮和豆甾醇与3CLpro和ACE2具有较高的结合亲和力[62]。ACE2/细胞膜色谱分析也显示麻黄的成分可能与ACE2结合[63]。麻黄-甘草在治疗COVID-19中也有潜在作用。网络药理学分析结果显示，甘草通过靶向3CLpro或S蛋白来调控环磷酸腺苷（cAMP）水平和PI3K-Akt、JAK-STAT等信号通路，从而抑制病毒复制[64]。

4.1.3. 复方

Cai等[65]分析发现，化湿败毒方中的223种活性成分可能与ACE2、雌激素受体1、肾上腺素受体α1和组蛋白脱乙酰酶等84个COVID-19相关靶基因相互作用。GO和KEGG分析结果表明，这些靶基因被富集在NF-κB、肾素-血管紧张素相关信号传导和腺苷酸活化蛋白激酶（AMPK）信号通路中，表明化湿败毒方通过调节各种途径在COVID-19的治疗中发挥作用[65]。

Zhou等[66]通过超高效液相色谱和质谱（UHPLC-LTQ-Orbitrap-MS）分析清肺排毒方的主要成分，并表征了87种化合物，包括黄酮类、生物碱、三萜皂苷、倍半萜和酚酸。给小鼠服用清肺排毒方后，血浆中共检测到12种化合物[67]。网络药理学分析结果表明，所涉及机制主要包括调节氧化还原酶活性、脂质代谢、脂质结合、小分子代谢和体内平衡[68]。此外，分子对接实验结果表明，清肺排毒方中的化合物通过直接与SARS-CoV-2的关键蛋白和宿主蛋白结合而发挥抗病毒作用[69]。因此，清肺排毒方可以有效抑制SARS-CoV-2的感染和复制。此外，一项研究表明，早期治疗中应用清肺排毒方可使病毒减弱、缩短住院时间[70]。同样，排毒一号方也用于预防和治疗COVID-19。分子对接显示，配方中1071个已知化学成分中的118个成分对SARS-CoV-2中的3CLpro表现出高结合亲和力[71]。

麻杏石甘汤（MXSGD）是治疗肺病的经典方剂，由麻黄、杏仁、石膏、甘草组成。通过液相色谱-电喷雾电离-串联质谱（LC-ESI-MS/MS）[72]从MXSGD 中鉴定出总共97种成分。KEGG分析结果显示，MXSGD治疗COVID-19的潜在信号通路主要富集于免疫系统和病毒感染。体外研究还发现，MXSGD通过增加大鼠肺上皮II型细胞（RLE-6TN）中B淋巴细胞瘤-2基因（Bcl-2）的表达，有效抑制IL-6刺激的JAK-STAT活化并抑制肺上皮损伤[73]。

连花清瘟胶囊是一种广泛用于治疗流感的中成药，具有广谱抗病毒作用[74]。网络药理学分析表明，连花清瘟胶囊可调节ACE2的表达[75]。此外，药代动力学表明，大黄酸、连翘苷A、连翘苷I和新绿原酸等活性化合物可抑制ACE2的活性[76]，抑制Vero E6细胞中SARS-CoV-2病毒的活性[77]。

六神胶囊（LS）显著抑制了SARS-CoV-2的复制，减少Vero E6细胞中病毒颗粒的数量[78]。参附汤（Shenfu decoction）主要用于治疗重症COVID-19患者，从参附汤中筛选的43种活性成分，主要通过抑制病毒Mpro、RdRP和S蛋白水平发挥抗病毒作用[79‒80]。

蒲地蓝（PDL）具有清热解毒的作用。研究发现蒲地蓝能有效抑制Vero E6细胞中SARS-CoV-2的病毒复制，显著减少了感染SARS-CoV-2的人血管紧张素转换酶2（hACE2）转基因小鼠肺部的病毒RNA的复制[81]。

血必净主要用于治疗败血症、全身炎症反应综合征、多器官衰竭和严重的SARS-CoV-2感染[77]。网络药理学分析表明，血必净的22种成分与54个SARS-CoV-2感染相关靶点，包括IL-6、肿瘤坏死因子（TNF）、丝裂原活化蛋白激酶1（MAPK1）、甘油醛-3-磷酸脱氢酶和肿瘤蛋白p53等相互作用。此外，分子对接分析结果显示，血必净的成分与SARS-CoV-2的3CLpro水解酶和宿主细胞的ACE2受体具有高亲和力[82]。

4.2 免疫调节和抗炎作用

调节免疫系统功能有助于抵抗病毒感染。激活先天免疫反应是降低SARS-CoV-2致死率的关键环节之一[83‒87]。中药及其活性物质在调节免疫功能方面具有优势（图3）。

图3 中药免疫调节和抗炎作用。中药通过调节宿主免疫系统来治疗SARS-CoV-2感染，包括在疾病发作时增加干扰素（IFN）的产生、抑制Toll样受体（TLR）介导的炎症反应、抑制促炎的产生细胞因子，并诱导T细胞和B细胞分化为效应免疫细胞。绿色方框中列出了作用于每个途径的代表性中药。

姜黄素可以在不同的病毒性疾病中诱导IFN的产生[88‒90]，研究表明姜黄素的阳离子碳点通过刺激干扰素基因的表达和降低Vero细胞中的IL-6和IL-8细胞因子水平，发挥抑制冠状病毒复质的作用[66]。

网络药理学研究发现，MXSGD中的97种有效成分可通过调节急性炎症反应、趋化因子产生、血管通透性、氧自由基反应、氧化应激诱导的凋亡、T细胞分化、免疫球蛋白分泌、细胞外基质分解治疗作用[91]。MXSGD通过抑制巨噬细胞和脂多糖（LPS）诱导的大鼠肺炎模型Toll样受体（TLR）水平发挥抗炎作用[79]。

中成药连花清瘟胶囊可显著减少TNF-α、IL-6、CCL-2/MCP-1、CXCL-10/IP-10的产生[77]。六神丸通过调节NF-κB/MAPK信号通路，显著抑制TNF-α、IL-6、IL-1β、IL-8、CCL-2/MCP-1和CXCL-10/IP-10的表达，发挥抗病毒作用[78]。中成药蒲地蓝可缓解SARS-CoV-2诱导的hACE2小鼠肺炎，减少肺部组织中炎症细胞的浸润[81]。此外，宣肺败毒方是根据中医理论针对COVID-19研制的方剂。临床试验表明，宣肺败毒方与常规药物联合使用时，可显著抑制COVID-19患者炎症因子的表达，缓解临床症状[4]。另一个中药方剂为清毒益肺汤，是专门为治疗COVID-19而设计的。据报道，清毒益肺汤抗炎作用显著。此外，清毒益肺汤联合西药治疗可使患者血清中IL-6和TNF-a的表达水平明显降低

4.3 抑制肺损伤和纤维化

急性肺损伤（ALI）是COVID-19的表现之一，其最严重的表现是ARDS；由于免疫系统过度激活ARDS会导致炎症级联反应，最终造成高死亡率[93‒95]。近来研究发现中药和天然产物可通过多种信号通路抑制ALI和ARDS相关的多种炎症反应（图4）。

图4 中药抑制肺损伤和纤维化。中药通过抑制炎症和氧化相关途径，如通过下调细胞因子、炎性小体和活性氧的表达来减少肺损伤和肺纤维化；抑制肺泡中性粒细胞浸润；调节NF-κB、Nrf2/HO-1和TLR介导的途径，减少氧化应激。绿色方框中列出了作用于每个途径的代表性中药。

厚朴酚（Honokiol）通过抑制小鼠的氧化应激减轻脓毒症相关的ALI [96]。几种天然化合物，包括isoforskolin、ruscogenin和 caffeic acid phenethyl ester等天然化合物，可减轻LPS诱导的小鼠和大鼠ALI [97‒101]。雪灵芝（Xue Ling Zhi）通过激活Nrf2通路和抑制 NF-κB/TGF-β1/Sma2/3轴，减轻肺纤维化[102]。甘草通过抑制NF-κB、辣椒素受体（TRPV1）和瞬时受体电位通道（TRPC）信号通路预防肺损伤和抑制炎症反应[103]。大黄素是大黄主要活性成分之一，通过调节mTOR/HIF-1α/VEGF信号通路，改善LPS诱导的ALI的病理损伤，减少浸润炎症细胞的数量[104]。大黄素通过Nrf2/HO-1信号传导抑制含有pyrin结构域的NLRP3炎症小体激活，从而有效保护大鼠免受急性胰腺炎相关肺损伤[105]。大黄素还通过抑制p38 MAPK通路与减少脓毒症期间的氧化应激和炎症反应，对患脓毒症大鼠的肺损伤发挥保护作用[106]。黄芩素抑制NF-κB介导的炎症反应和上调Nrf2/HO-1通路对LPS诱导的大鼠ALI具有保护作用[107]。姜黄素通过激活调节性T（Treg）细胞的分化来调节IL-35水平，从而控制CLP诱导的ALI炎症反应[108]。香叶木素通过激活Nrf2和抑制NLRP3炎症小体的激活，对LPS诱导的ALI模型具有抑制作用[109]。紫杉醇是一种从红豆杉树皮中分离出来的经典抗癌药物，通过激活黏蛋白1（MUC1）和抑制TLR-4/NF-κB通路，减轻CLP诱导的脓毒症小鼠的ALI [110]。β-谷甾醇是一种中国药用植物中常见的植物甾醇，通过调节IFN/STAT等信号通路，改善甲型流感病毒（IVA）诱导的小鼠炎症反应[111]。丹参酮IIA是丹参的主要活性成分之一，通过抑制NF-κB水平，对LPS诱导的小鼠肺损伤具有保护作用[112]。

冬虫夏草（DCXC）提取物降低了实验性ALI小鼠的组织病理学损伤程度、湿/干重比和髓过氧化物酶（MPO）活性[113]，抑制了支气管肺泡灌洗液（BALF）中总细胞、中性粒细胞、巨噬细胞的数量和BALF中TNF-α、IL-1β、IL-6和一氧化氮（NO）的水平。冬虫夏草通过抑制NF-κB p65磷酸化以及环氧化酶-2（COX-2）和一氧化氮合成酶（iNOS）的表达，对LPS诱导的ALI发挥抗炎和抗氧化作用。

多糖是中药的活性成分之一。多项研究表明，多糖具有免疫调节、抗肿瘤、抗病毒和抗肺纤维化作用[114‒115]。从中药、藻类和真菌中提取的16种多糖具有显著的抗肺纤维化活性，改善了博来霉素（BLM）诱导的动物模型中的肺组织病理学变化和胶原蛋白沉积。这些多糖的抗肺纤维化作用，主要通过TGF-β1/Smad2/3等通路发挥作用[115]，表明多糖是预防和治疗 COVID-19患者肺纤维化的潜在有效物质。

5、 讨论

本文结合已报道的网络药理学和分子对接结果，总结了中药天然化合物、中草药和中药复方治疗COVID-19感染的潜在靶点。实验研究发现，中药的抗病毒作用主要表现为直接抑制病毒复制。中药复方及其活性成分可通过调节免疫系统、减轻炎症细胞因子风暴和肺损伤，发挥对COVID-19的治疗作用。

但目前中医药治疗COVID-19的研究进展还存在一定局限性。首先，发表的数据大多来自虚拟筛选或网络药理学预测，因此迫切需要提供中医药治疗COVID-19的靶点或机制的直接实验证据。其次，虽然有一些实验证据表明中药具有免疫系统调节、抗炎和抑制肺损伤的作用，但基于SARS-CoV-2感染的体内外实验模型尚不充分，尽管所研究的疾病模型可能与COVID-19具有相似的病理阶段或过程，但仍需要进行更多与COVID-19感染直接相关的实验验证。

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