Research Development and Strategies of "Wind Elimination" Method in the Treatment of Childhood Asthma in Three Stages
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摘要: 哮喘患儿先天禀赋有异, 形成“伏风”内潜的体质, 加之贼风外邪侵犯, 两风相合引起哮喘发病。提出在传统哮喘发作期、缓解期的分期方法之外增加迁延期, “消风法”三期分证论治小儿哮喘: 发作期疏外风消伏风, 降气平喘; 迁延期扶正气抑伏风, 缓解发作; 缓解期补脏气御外风, 调补肺脾肾。论述如何从消风论治小儿哮喘三期证候, 明确哮喘“伏风”证候演变特点及辨证治疗规律, 结合现代机制研究, 为小儿哮喘的中医临床诊疗提供理论支持及实施策略。Abstract: This paper points out that the congenital endowment of children with asthma is different, forming the latent constitution of "latent-wind", combined with the invasion of external evil by harmful wind, leads to the pathogenesis of asthma. It is proposed that, the middle and later stage should be increased in addition to the traditional asthma attack and remission staging methods. The "wind elimination method" in the treatment of three-stage pediatric asthma: during the attack stage, expel external wind and "latent-wind" elimination, downregulate qi, and relieve asthma; treatment methods for the middle and later stages are promoting healthy qi and suppressing "latent-wind"; during the remission period, restores organ qi and resists external wind, tonifying the lung, spleen, and kidney. This paper focuses on how to treat the three-stage asthma syndrome in children using the theory of eliminating wind; to clarify the evolution characteristics and syndrome differentiation law of the "latent-wind" in asthma syndrome. This paper provides theoretical support and implementation strategies for TCM clinical diagnosis and treatment of pediatric asthma, combining modern clinical and mechanism research progress.
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Key words:
- Asthma /
- wind elimination /
- latent-wind /
- treatment in three stages
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表 1 发作期消风代表方剂及药物
Table 1. The representative prescriptions and plants of the method of eliminate wind in the stage of an asthma attack
代表方剂 复方
消风机制君药麻黄
消风机制单味药 单味药
消风机制小青龙汤 抑制胸腺基质淋巴细胞生成素(TSLP)和NF-κB的表达, 通过调节TSLP信号通路, 降低IL-1β、TNF-α、NF-κB等炎症因子水平, 发挥消风、抗炎、平喘的作用[17] 抑制过敏介质释放[9]; 减轻气道及肺部炎症、下调炎性因子的释放, 减轻炎性细胞浸润; 缓解氧化应激、减少气道黏液高分泌; 抑制蛋白酶/抗蛋白酶失衡, 增强免疫功能调节等[10]
抑制Th2细胞分化及IL-5等细胞因子的分泌和炎性细胞的浸润与活化, 阻止IgE的合成及嗜酸性粒细胞在气道积聚, 促进嗜酸性粒细胞凋亡[18]细辛 改善MMP-9/TIMP-1比例失调, 减轻气道重塑[19] 干姜 抑制嗜酸性粒细胞、单核细胞和中性粒细胞数量, 降低IgE、IL-4水平, 增加IFN-γ水平, 回调能量代谢和氧化应激相关通路的部分代谢产物[20] 半夏 降低嗜酸性粒细胞、巨噬细胞和淋巴细胞数量, 降低IL-4、IL-13、IgE水平, 并抑制iNOS表达和NF-kB活性[21] 芍药 抑制白细胞、嗜酸性粒细胞和嗜中性粒细胞分泌, 抑制IL-4、IL-17水平和巨噬细胞炎性蛋白-1α含量, 通过调节脂肪酸代谢、炎症反应和黏附途径实现治疗哮喘的作用[22]；抑制IgE水平, 降低IL-5、IL-13、IL-17和嗜酸性粒细胞趋化因子的水平, 抑制p-ERK和p-JNK蛋白表达, 通过抑制MAPK通路的激活来发挥抗炎作用[23] 三子养亲汤 下调miR-155表达, 调节Th17/Treg平衡[24] 葶苈子 调控TLR4/NF-κB信号通路改善气道炎症、介导MLCK和连接蛋白调节上皮损伤改善过敏性哮喘大鼠的肺通透性[25] 紫苏子 降低总白细胞、淋巴细胞、单核细胞、嗜中性粒细胞和嗜酸性粒细胞的数量, 减少IL-6、TNF-α、IL-4的产生, 降低IgE、IgG1、IgG2a和IgG2b的水平, 通过抑制Syk及其下游介质减轻体内过敏性气道炎症[26] 麻黄杏仁甘草
石膏汤降低IL-4、TNF-α水平, 提高IL-2水平, 对Th1/Th2有调节作用, 修复气道生理结构, 抗气管组织上皮纤维化, 减少AECs凋亡[27] 杏仁 抑制TNF-α、IL-6、IL-8和MUC5AC的增加, 抑制TLR4/NF-κb信号的激活[28] 甘草 抑制ERK1/2的磷酸化, 抑制炎性细胞因子IL-4、IL-6、TNF-α的水平[29] 大青龙汤 降低IgE、IL-4、TNF-α水平, 提升动脉血氧交换能力[30] 桂枝 抑制IL-4释放, 促进IFN-γ、IL-18释放, 纠正失衡的Th1/Th2细胞比例, 抑制肥大细胞脱颗粒从而减少过敏介质的释放, 抑制IgE的生成及减轻嗜酸性粒细胞的浸润[31] 生姜 降低IL-4、IL-5、IL-13的水平, 增加IFN-γ水平, 减弱气道高反应性, 通过上调AMPK/Nrf2/HO-1信号通路来减轻氧化损伤和炎症[32] 荆防败毒散 抑制p38MAPK的磷酸化和NF-κB p65的活化, 缓解哮喘气道炎症[33] 荆芥 上调Treg的数量, 下调Th17型细胞因子, 降低Th17/Tregs的比例, 抑制Th17型免疫水平, 降低TGF-β细胞内信号转导分子Smad2/3的蛋白水平[34] 防风 通过Lyn/Syk/PLCγ、PI3K/AKT/NF-κB以及MAPK信号转导通路来调控I型变态反应[35] 白芷 抑制嗜酸性粒细胞分泌, 降低ROS水平, 降低IL-4、IL-5、TNF-α、总IgE水平, 通过部分上调HO-1改善气道炎症和氧化应激[36] 银翘散 降低IFN-γ及IFN-γ/IL-4比值, 逆转Thl/Th2的失衡, 减少机体的免疫炎症损伤, 增加slgA分泌, 减轻气道炎症[37] 金银花 提高NK细胞活性, 提升T淋巴细胞活力, 恢复T淋巴细胞亚群之间的平衡, 抑制脾细胞凋亡来提高免疫功能[38] 连翘 抑制IgE、IL-4、IL-5和IL-13的产生, 抑制NF-κB活化, 通过激活Nrf2/HO-1信号通路抑制哮喘炎症反应[39] 薄荷 抑制IgE和Th2型细胞因子如IL-4、IL-5的增加, 减少ROS的产生[40] 
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表 2 迁延期抑风代表方剂及药物
Table 2. The representative prescriptions and plants of the method of suppress latent-wind in the middle and later stage of asthma
代表方剂 复方抑风机制 单味药 单味药抑风机制 射干麻黄汤 减少血浆内血栓素及其代谢产物水平, 诱发嗜酸性粒细胞凋亡, 调节体内环磷酸腺苷、环磷酸鸟苷的平衡, 提升IL-2水平, 从而缓解患者气道痉挛及炎症反应, 减少咳嗽、气喘等症状[44]
调控细胞免疫, 维持Th1/Th2和Th17/Treg细胞平衡, 维持MMP-2/TIMP-1平衡, 下调IL-4、IL-5、IL-6、IL-13、IL-17等炎症因子水平, 上调IL-10等抗炎因子水平[44]
调控VEGF、HIF-1α、TGF-β1、PPAR-γ来延缓气道重塑进程, 从而抑制哮喘发作[45], 减轻气道炎症[44]射干 降低小鼠BALF及巨噬细胞中中炎性细胞数量和LTC4水平; 干预花生四烯酸COX-2、CYP450信号通路及COX和5-LOX相关靶点; 平衡Th1/Th2/Th17, 减轻气道炎症[46] 炙款冬花 抗血小板活化因子、抗炎[47]; GSTP1、IL-2、MAPK14、COX-2等是其细胞过程中潜在靶点基因群[48] 炙紫菀 减少BALF中Th2型细胞因子和嗜酸性粒细胞, 降低血清中IgE, 降低气道高反应性[49] 五味子 降低IgE、IL-4和IL-5水平, 下调iNOS、COX-2和NF-κB信号通路, 舒张气管平滑肌[50] 苏子降气汤 调节细胞因子失衡，降低BALF中白细胞、中性粒细胞和淋巴细胞的百分比、IL-6、TGF-β水平, 上调IL-4水平[51] 紫苏子 抑制Th2反应和气道炎症[52] 肉桂 降低血清中IL-2、IL-5含量, 减少炎症细胞部位嗜酸粒细胞、淋巴细胞浸润; 减缓气道慢性炎症[53] 厚朴 抑制毛细血管通透性的增加从而达到抗炎的作用[54]
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表 3 缓解期御风代表方剂及药物
Table 3. The representative prescriptions and plants of the method of resist external wind during the remission period of asthma
代表方剂 复方御风机制 单味药 单味药御风机制 人参
五味子汤
玉屏风散提高CD4+/CD8+比值, 上调IFN-γ和IL-2;调节异常活化巨噬细胞的TNF-α、IL-1和IL-10的水平影响其功能[55], p38MAPK和NF-κB可能是其发挥作用的途径之一[57]; 提高肺通气功能; 同时降低IL-8、IL-17、瘦素水平[58] 白术 提高Th/Ts比值, 纠正T细胞亚群分布紊乱状态, 提高IL-2水平, 并能增加T细胞表面IL-2的表达; 增强腹腔巨噬细胞吞噬功能, 并促进T淋巴细胞转化和溶血素生成[59] 黄芪 增强细胞、体液免疫及巨噬细胞功能: 促进巨噬细胞NO生成, 升高淋巴细胞内游离钙离子水平, 引起细胞蛋白激酶C活性升高, 主要通过影响机体免疫细胞的信号转导发挥免疫调节作用[60] 防风 促进IL-2对NK细胞的激活, 提高NK细胞活性, 增加IL-2诱导的LAK细胞杀伤活性, 增强脾淋巴细胞的杀伤活性[61] 金匮肾气丸 增强免疫、抗炎: 抑制胸腺活化调节趋化因子和减少嗜酸性粒细胞浸润[62] 附子 诱导抗原呈递细胞分化成熟, 诱导淋巴细胞增殖, 促进细胞因子释放[64] 桂枝 抑制IL-4释放, 促进IFN-γ、IL-18释放, 平衡Th1/Th2细胞亚群, 抑制肥大细胞脱颗粒, 减少过敏介质的释放, 抑制IgE的生成及减轻嗜酸性粒细胞的浸润[31] 地黄 促进小鼠单核巨噬细胞的吞噬能力, 提高脾脏指数和胸腺指数, 刺激脾脏淋巴细胞增殖, 促进Th1型淋巴细胞分泌IL-2和IFN-γ[65] 山药 促进小鼠血清中脾脏淋巴细胞因子(IL-1β、TNF-α)及免疫球蛋白(IgG、IgM)分泌[66] 山茱萸 提高免疫低下小鼠的非特异性免疫功能、体液免疫功能和细胞免疫功能[66] 麦味地黄丸 恢复体液、细胞免疫及防御机能: 血浆cAMP、肝MDA、肝糖原、肾上腺维生素C恢复到正常或接近正常水平[63] 茯苓 诱导巨噬细胞分泌NO、IL-2、IL-6、TNF、IFN-γ和IL-17a, 通过TLR4/TRAF6/NF-κB信号通路调节免疫[67] 牡丹皮 升高IL-4水平, 降低IFN-γ水平, 减轻炎症细胞浸润和胶原沉积, 通过TLR4/NF-κB和MAPK信号通路调节免疫[68] 泽泻 下调NO释放及COX-2、iNOS、IL-1β、IL-6、TNF-α等炎症因子水平[69] 麦冬 提高吞噬指数, 促进淋巴细胞增殖, 增加T淋巴细胞亚群(CD4+/CD8+)比例[70] 五味子 增强单核细胞吞噬作用、溶血素的生成, 提高小鼠胸腺指数和脾指数[71]
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