中国科技论文统计源期刊　中文核心期刊  
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《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊  
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医药导报
医药导报, 2023, 42(2): 173-177
doi: 10.3870/j.issn.1004-0781.2023.02.006
乌头汤治疗类风湿关节炎的研究进展*
Research Progress of Wutou Decoction in the Treatment of Rheumatoid Arthritis
巴鑫, 陈哲, 涂胜豪
华中科技大学同济医学院附属同济医院中西医结合科,武汉 430030
BA Xin,, CHEN Zhe, TU Shenghao,
Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030,China
通信作者 涂胜豪(1965-),男,教授,博生生导师,研究方向:风湿免疫。电话:027-83664402,E-mail:shtu@tjh.tjmu.edu.cn。

作者简介 巴鑫(1994-),男,湖北武汉人,博士,从事免疫风湿方向的研究。ORCID:0000-0002-9273-839X,E-mail:799641835@qq.com。
基金资助: *国家自然科学基金资助项目(81874383)
中图分类号: R28;R593.22     文献标识码: A     文章编号: 1004-0781(2023)02-0173-05
摘要:

乌头汤作为治疗痹证的经典方剂,治疗类风湿关节炎(RA)已有千年历史。一系列临床研究证实,乌头汤在改善RA关节炎症、肿胀、疼痛等方面有较好的疗效。同时作为一种补充替代疗法,乌头汤与西药联合应用可以减少西药的用量,减轻西药副作用,提高现有RA治疗方案的安全性和有效性。随着对RA病理机制研究及乌头汤的药理学研究的深入,乌头汤在治疗RA方面的研究取得许多进展,尤其在抗炎、镇痛、免疫调节以及抑制血管生成等方面。该文从临床研究和实验研究两个方面对乌头汤治疗RA相关进展进行系统性综述。
关键词: 乌头汤; 类风湿关节炎; 炎症; 免疫调节; 镇痛; 血管生成

Abstract:

As a traditional Chinese medicine compound for the treatment of rheumatoid arthritis, Wutou decoction has been used as a classic remedy for the treatment of paralysis for rheumatoid arthritis (RA) in China for thousands of years. A series of clinical studies have confirmed that Wutou decoction has a good effect on improving RA joint inflammation, swelling and pain. At the same time, as a supplementary alternative therapy, the combined application of Wutou decoction with western medicine can reduce the dosage of western medicine, reduce the side effects of western medicine, and improve the safety and effectiveness of existing RA treatment regimens. With the advancement of pharmacology research of Wutou decoction and the pathological mechanism of rheumatoid arthritis, many advances have been made in the treatment of RA, especially in anti-inflammatory, analgesic, immunomodulatory and angiogenic inhibition. This study systematically reviewed the progress of Wutou decoction in the treatment of rheumatoid arthritis from clinical research and experimental research.
Key words: Wutou decoction; Rheumatoid arthritis; Inflammation; Immunomodulatory; Analgesia; Angiogenesis

开放科学(资源服务)标识码(OSID)

类风湿关节炎(rheumatoid arthritis,RA)是一种全身性慢性自身免疫性疾病,影响全球0.5%~1.0%的人口。RA主要表现为关节对称性、持续性炎症损害,若不及时治疗会导致患者关节变形,关节活动度降低,躯体功能下降,甚至最终生活不能自理。目前,改善病情抗风湿药物(disease modifying antirheumatic drugs,DMARDs)是RA的主要治疗药物。根据作用机制的不同,DMARDs可以分为三类:传统合成DMARDs(如甲氨蝶呤、来氟米特)、生物DMARDs[如肿瘤坏死因子α(TNF-α)拮抗剂]和靶向DMARDs(如Janus激酶的抑制剂)。其中合成DMARDs不良反应较大,副作用较多,患者耐受性差;生物DMARDs虽不良反应少,但仍有三分之一治疗效果不理想[1],且价格昂贵,患者难以负担;此外,靶向DMARDs药物非选择性的JAK抑制剂(Xeljanz)Ⅳ期临床研究失败,未达到心血管事件、恶性肿瘤发生率非劣效终点,因而被美国食品药品管理局(FDA)给予黑框警告[1]。总之,目前针对 RA的治疗,存在部分患者效果不佳、或无法阻止疾病进展等情况。因此,寻找治疗RA安全有效的中医药显得十分有意义。

乌头汤源自《金匮要略》“病历节不可屈伸,疼痛,乌头汤主之”,其主要组成为:麻黄、芍药、黄芪三两,炙甘草,川乌五枚(㕮咀,以蜜二升,煎取一升,即出乌头)。乌头汤为温经散寒、除湿止痛之良剂,主治寒湿历节之证,凡寒湿凝滞、经脉闭阻之痹证、诸痛、脚气等病,皆可运用。现今乌头汤主要用于治疗风湿性疾病、坐骨神经痛、膝骨关节炎等疾病,特别是在治疗RA上,开展一系列临床研究和实验研究,并取得一些进展。

1 乌头汤治疗RA的临床研究

乌头汤作为治疗痹症的经方,在临床上被广泛应于治疗RA。一系列临床试验证明乌头汤可以明显改善病情,联合西药使用时可以减少西药用量,从而减少副作用的发生。

临床研究证实,单用乌头汤治疗RA 8周后,患者临床症状得到明显改善,尤其是缓解疼痛、肿胀等效果显著;病情活动度也得到明显改善,C-反应蛋白(CRP)水平、红细胞沉降率(ESR)和DAS28评分都明显降低;血清中炎症因子,如白细胞介素(IL)-6、TNF-α的水平也明显降低[3,4]。此外,在降低抗环瓜氨酸肽抗体(cycliccitrullinated peptide,CCP)、类风湿因子(RF)上,与对照组甲氨蝶呤比较乌头汤组有一定优势[3];在降低CRP水平上,比雷公藤效果更明显[5]。更多的研究是将乌头汤加味和DMARDs(如甲氨蝶呤、来氟米特、艾拉莫德)、非甾体抗炎药(NSAIDs)等西药联合应用[6,7,8,9]。研究发现,乌头汤联合西药治疗寒湿痹阻型RA,在怕冷关节数、关节肿胀数、关节压痛数、视觉模拟评分、晨僵等指标方面改善作用均优于单用常规西药,并且在降低血沉、CRP、RF、IL-1β和 TNF-α等炎症相关指标水平方面也均优于对照组。此外,乌头汤配合西药能显著降低西药的不良反应,特别是消化道反应[10,11,12,13]。总之,不论单用乌头汤治疗还是中西医结合治疗,乌头汤都可以明显改善RA患者临床症状,控制病情活动,提高关节活动能力,降低致残率,提高药物使用安全性,使患者获益。

2 乌头汤治疗RA的实验研究

乌头汤治疗RA不仅在临床研究方面被证实确有疗效,在实验机制研究方面也取得一些进展。目前,关于乌头汤治疗RA的机制研究主要集中在抗炎、镇痛、免疫调节以及抑制血管生成等方面。

2.1 乌头汤的抗炎作用

乌头汤抗炎作用主要体现在它能抑制炎症细胞因子的产生,并且作用强度与其剂量、配伍和配比密切相关。研究发现乌头汤能够有效降低胶原诱导关节炎(collagen induced arthritis,CIA)大鼠血清中促炎细胞因子,如IL-6、IL-15、干扰素(IFN)和粒细胞-巨噬细胞集落刺激因子(GM-CFS)的含量,且与乌头汤浓度呈负相关[14]。同样,对于佐剂性关节炎(adjuvant induced arthritis,AIA)模型大鼠,乌头汤不同配伍组均能不同程度下调血清中IL-1β、TNF-α水平。在配伍研究方面,全方组与其他各组比较较,差异有统计学意义,在调节IL-18、TNF-α水平上,全方组的效果最好[15]。乌头汤也可通过影响趋化因子的表达来调节RA的炎症网络达到治疗效果。MCP-1属于趋化因子CC亚家族,能趋化单核/巨噬细胞的迁移,参与RA等自身免疫性疾病的发病。MCP-1与其受体CCR2结合后能将ERK1/2磷酸化,进而激活NF-κB转录因子,最终调节炎症细胞因子的生成。研究发现乌头汤能降低CIA大鼠血清及踝关节局部MCP-1的含量,降低踝关节中CCR2和磷酸化ERK1/2的表达水平,提示乌头汤通过下调CIA大鼠体内MCP-l/CCR2/ERK1/2信号通路,来调节RA炎症网络。此外,乌头汤对巨噬细胞趋化因子受体5(CCR5)信号通路的调节作用被证实在抑制RA炎症反应中发挥重要作用。巨噬细胞中CCR5信号通路是与细胞免疫应答和细胞因子信号传导相关的最重要信号通路,而CCR5敲除能改善AIA大鼠的关节炎症[16]。该途径中蛋白激酶C(PKC)和p38被视为RA中乌头汤的靶蛋白,而PKC、p38可以促进巨噬细胞中的趋化因子[如巨噬细胞炎性蛋白(MIP-1α)、受激活调节正常T细胞表达和分泌因子(RANTES)、单核细胞趋化蛋白1(MCP-1)、干扰素诱导蛋白10(IP-10)]的表达,从而趋化和募集巨噬细胞、中性粒细胞、T细胞等到关节处,加重关节滑膜的炎症。与CIA模型组大鼠比较,乌头汤治疗组大鼠血清中趋化因子MIP-lα、MIP-2、RANTES、IP-10和MCP-1的蛋白水平及踝关节中趋化因子MIP-lα、RANTES和IP-10的mRNA相对表达水平均明显降低。此外,乌头汤还降低来自CIA大鼠踝关节巨噬细胞中CCR5,PKC和p38的磷酸化水平[17]。以上实验表明乌头汤可以通过MCP-l/CCR2/ERK1/2信号通路和CCR5信号通路来调节CIA大鼠中的炎症因子网络,改善关节滑膜的炎症,而达到治疗RA目的。

2.2 乌头汤的免疫调节作用

研究显示,乌头汤不仅可以调节炎症细胞因子的表达,而且可以降低RA相关自身免疫抗体的水平,并且细胞水平调节T细胞亚群之间的平衡。乌头汤治疗CIA模型大鼠后,可以不同程度降低血清和关节软骨中炎性细胞因子,如IL-1、IL-17、TNF-α、血管内皮生长因子(VEGF)表达水平,降低血清中抗CⅡ型胶原抗体IgG、IgM的水平。与模型组比较,乌头汤治疗组可以降低AIA模型大鼠外周血的 CD 4 + 细胞百分比,升高 CD 8 + 细胞的百分比,进而使得 CD 4 + / CD 8 + 比值呈现不同程度的下调,但没有显著的量效关系[18]。进一步研究发现,AIA模型大鼠脾脏Toll样受体2(TLR2)、TNF受体相关因子6(TRAF6)、凋亡因子相关配体(FasL)等基因显著高表达,而乌头汤可以显著抑制TLR2、TRAF6、FasL等基因的异常高表达。由于TLR的活化不仅可以启动炎症性细胞因子、趋化因子、组织破坏性酶和I型干扰素的产生,也可以通过上调抗原提呈细胞的共刺激分子B7,激活下游细胞内信号分子TRAF家族成员而发挥细胞活化或凋亡等多种效应功能。一方面通过活化转录因子NF-κB或凋亡蛋白1(AP-1)以促进细胞因子、趋化因子等基因转录;另一方面也通过下游的TRAF分子经不同途径介导抗凋亡或凋亡作用。CD95(FasL)分子在参与诱导T细胞凋亡过程中起关键作用,决定着T、B细胞在数量上的平衡。这些结果提示乌头汤抗炎及调节外周血T细胞亚群可能是通过TLR2/TRAF6/FasL信号通路[19]。

2.3 乌头汤的镇痛作用

研究观察乌头汤对小鼠热板法和醋酸扭体法两种疼痛模型的镇痛作用结果表明,乌头汤能显著提高小鼠热刺激所致疼痛的痛阈值,亦能明显延长醋酸刺激所致扭体反应的潜伏期,并减少其发生的次数,这些证明乌头汤有很好的镇痛作用[20]。与AIA大鼠模型组比较,大、中剂量乌头汤能降低大鼠关节肿胀度,乌头汤各剂量能升高冷板痛阈值,大、中剂量能提高机械痛阈值,大剂量对热辐射痛阈值也有一定的增高作用。同时,乌头汤能降低血浆前列腺素E(prostaglandin E,PGE)、5-羟色胺(5-hydroxytryptamine,5-HT)和背根神经节瞬时感受器电位香草酸受体1(transient receptor potential vanilloid 1,TRPV1)表达水平,提高瞬时感受器电位M8(transient receptor potential melastatin 8,TRPM8)表达水平。这些提示乌头汤具有镇痛作用,其机制可能与降低血浆中PGE和5-HT水平以及调节背根神经节中TRPV1、TRPM8的表达有关[21,22]。另外,通过网络药理学方法,根据乌头汤主要化学成分,找出乌头汤中化合物可能作用于诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)、p38、c-Jun 氨基末端激酶 1、TNF-α、磷酸二酯酶4A(phosphodiesterase 4A,PDE-4A)和 Kappa 阿片受体等靶标,提示其可能调控p38MAPK等信号通路,抑制NO释放;调控JNK信号通路,减弱机械痛敏;作用于Kappa 阿片受体,最终导致突触后膜超极化,阻止痛觉冲动的传导和传递等,达到多靶点、多途径治疗疼痛的效果[23]。

2.4 乌头汤的抑制血管生成作用

乌头汤显著降低CIA大鼠炎症关节滑膜组织中的未成熟血管,还抑制鸡胚中体内血管生成和体外血管内皮生长因子165(vascular endothelial growth factor165,VEGF165)诱导的微血管芽形成。同时,乌头汤抑制MH7A诱导的人脐静脉内皮细胞(human umbilical vein endothelial cells,HUVEC)的迁移、侵袭、粘附和血管形成。此外,乌头汤显著降低CIA大鼠滑膜中和HUVEC中促血管生成细胞因子的表达,包括VEGF、血管内皮生长因子受体2(vascular endothelial growth factor receptor 2,VEGFR2)、白细胞介素1β(IL-1β)、IL-17、转化生长因子β(transforming growth factor β,TGFβ)、血小板衍生生长因子、胎盘生长因子、血管生成素(AngⅠ/Ⅱ)等[24]。进一步研究发现,WTD改善滑膜血管生成的潜在机制可能与PI3K-AKT-mTOR和HIF-1α途径有关[25]。

2.5 其他

此外,乌头汤在抗氧化、减轻关节损伤,表观遗传学及网络药理学方面也取得一些研究进展。乌头汤可以通过升高超氧化物歧化酶(superoxide dismutase,SOD)、谷胱甘肽过氧化物酶(GSH-Px),降低AIA大鼠血清中丙二醛(malondialdehyde,MDA)含量而起到抗氧化作用;抑制基质金属蛋白酶(消化基质蛋白多糖、糖蛋白的基质酶MMP-3、能特异性降解Ⅰ、Ⅱ、Ⅲ型胶原的胶原酶MMPs-1,13和水解蛋白聚糖的金属蛋白酶ADAMTs)的产生,减轻CIA大鼠的软骨损伤[26]。

在表观遗传方面,乌头汤可以通过调节DNA甲基化、组蛋白修饰和miRNA,来改善RA的症状。已有研究显示,与健康者比较,RA患者免疫细胞内甲基化异常及甲基转移酶表达异常,与细胞迁移、细胞黏附、细胞外基质代谢相关的一些基因DNA甲基化出现紊乱,外周血单个核细胞组蛋白去乙酰化酶(histone decetylases,HDAC)的活性显著增加[27]。改善组蛋白乙酰化水平,RA症状也得到缓解[28]。研究发现,与CIA模型组比较,乌头汤组DNA甲基转移酶1(DNMT1)的mRNA表达显著降低、DNA甲基化水平显著降低,而PBMC的组蛋白3(H3)乙酰化过表达。这表明乌头汤可通过DNA甲基化和组蛋白修饰,达到改善RA病情的作用[29]。此外,WTD还可以通过激动芳香烃受体 (AhR),促进长链非编码RNA LOC101928120的转录,进而降低SHC1,最终抑制了IL-1β引起的软骨细胞凋亡和ROS产生[30]。

通过将药物靶标预测,网络分析和实验验证相结合的方法,分析出乌头汤可能通过调节产热PPAR-γ共激活因子发挥缓解寒性RA症状的作用。通过实验验证与PPAR-γ共激活因子产热通路相关蛋白,包括PPAR-γ、核受体辅助活化因子1(nuclear receptor coactivator 1,NC0A1)、核受体辅助活化因子2(NC0A2)、转录中介体复合物1(mediator comple 1,MED1)、类视黄醇X受体α(retinoid X receptor α,RXR-α)和转录因子环磷酸腺苷反应元件结合蛋白(cAMP-response element binding binding protein,CREBBP)等6个分子在大鼠踝关节组织及体外培养的RA-FLS细胞中的蛋白表达水平均显著降低。乌头汤治疗后,CIA寒证模型组的PPAR-γ,RXR-α,MED1和NC0A2蛋白表达水平呈浓度依赖性增加,且作用效果与CIA寒热证型相关。乌头汤在CIA热证模型组中对六种蛋白的调节作用较对CIA寒性组的作用弱[31,32]。乌头汤可能是通过调节PTGS2、ESR1、ESR2、NOS2、AR等靶点,调控TNF信号通路、人巨细胞病毒感染、IL-17信号通路、Th17细胞分化、NOD样受体信号通路、Th1和Th2细胞分化、T细胞受体信号通路、FOXO信号通路、Toll样受体信号通路等通路,从而抑制炎症,调节免疫功能达到治疗RA的目的[33]。

3 结论

乌头汤具有抗炎镇痛、免疫调节、抑制血管生成等作用,可以抑制炎症细胞因子的产生,调节细胞因子网络失衡,抑制细胞因子对滑膜和软骨细胞的刺激作用,阻止滑膜炎症细胞浸润,抑制关节炎性递质和蛋白水解酶的释放,从而减少关节软骨、骨质的吸收,阻止骨的破坏,减少血管翳的形成,减轻病情,这可能是乌头汤治疗RA主要机制之一。随着网络药理学和表观遗传学的发展,对乌头汤治疗RA临床研究和实验研究进一步的深入,有利于探索传统方剂乌头汤治疗RA多靶点、多途径的具体机制,为乌头汤的临床应用提供科学依据,有利于揭示RA的发病机制,为新药的开发提供基础。

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Wutou decoction (WTD) is a Chinese herbal formula alleviating rheumatoid arthritis (RA). SHC adaptor protein 1 (SHC1) regulates apoptosis, inflammation, and the production of reactive oxygen species (ROS). The gene is located near the gene. Bioinformatics analysis showed that the long non-coding RNA LOC101928120 binds to histone deacetylase HDAC1 that might regulate SHC1 expression. The gene might be targeted by the transcriptional factor Aryl hydrocarbon receptor (Ahr). This study determines the involvement of the Ahr/LOC101928120/SHC1 pathway in WTD alleviation of RA. Wistar rats were injected with complete Freund's adjuvant in the hind footpad to construe the RA model. WTD (9.8 g/kg/day) was administered intragastrically for 15 days. The CHON-001 chondrocyte cells were treated with IL-1β (10 ng/mL) alone or in combination with WTD (1 μg/mL). A RNA pull-down assay was performed to determine the interaction between LOC101928120 and HDAC1. Ahr targeting the gene was detected using luciferase reporter and chromatin immunoprecipitation assays. WTD alleviated the swelling of the hind paw in rats with RA and suppressed the chondrocyte apoptosis and ROS production caused by IL-1β. WTD decreased SHC1 but increased LOC101928120 in IL-1β-treated chondrocytes. SHC1 knockdown and LOC101928120 overexpression also showed the protection. However, LOC101928120 knockdown attenuated the protective effects of WTD. WTD stimulated Ahr, which promoted LOC101928120 transcription. LOC101928120 recruited HDAC1 to the promoter region of the gene, thereby decreasing SHC1. This study revealed a new mechanism by which WTD alleviates RA by modulating the Ahr/LOC101928120/SHC1 pathway.
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关键词（key words）
乌头汤
类风湿关节炎
炎症
免疫调节
镇痛
血管生成
Wutou decoction
Rheumatoid arthritis
Inflammation
Immunomodulatory
Analgesia
Angiogenesis
作者
巴鑫
陈哲
涂胜豪
BA Xin
CHEN Zhe
TU Shenghao