目的 從“表型-證候-中藥”關(guān)聯(lián)網(wǎng)絡(luò)，探索哮喘氣道重塑不同證候表型下的藥物表型組學(xué)特征及機(jī)制。方法 收集中醫(yī)藥干預(yù)哮喘氣道重塑的臨床研究文獻(xiàn)（檢索范圍為建庫(kù)至2024年3月24日），提取中醫(yī)藥信息要素及氣道重塑相關(guān)指標(biāo)，進(jìn)行證候表型分類(lèi)，運(yùn)用RStudio執(zhí)行描述性統(tǒng)計(jì)，并通過(guò)Apriori算法、點(diǎn)式互信息法對(duì)各證候表型鏈接的中藥及中藥鏈接的哮喘氣道重塑指標(biāo)進(jìn)行關(guān)聯(lián)規(guī)則探索及hclust函數(shù)挖掘核心中藥組方。利用HERB、GeneCards數(shù)據(jù)庫(kù)聯(lián)合鑒定核心中藥組方治療哮喘氣道重塑的靶標(biāo)譜。馬爾可夫聚類(lèi)算法（Markov cluster algorithm，MCL）挖掘關(guān)鍵功能基因簇，篩選關(guān)鍵靶點(diǎn)，并借助人氣道上皮、鼻拭子、痰液樣本數(shù)據(jù)表征關(guān)鍵靶點(diǎn)對(duì)哮喘氣道重塑的貢獻(xiàn)價(jià)值，最后采用過(guò)表征分析各關(guān)鍵功能基因簇的通路及生物功能。結(jié)果 納入76篇文獻(xiàn)，哮喘分為冷哮、風(fēng)哮、熱哮、虛哮、瘀哮5個(gè)證候表型，篩選得到139味中藥，涉及轉(zhuǎn)化生長(zhǎng)因子-β1（transforming growth factor-β1，TGF-β1）、腫瘤壞死因子-α（tumor necrosis factor-α，TNF-α）、基質(zhì)金屬蛋白酶-9（matrix metalloproteinases-9，MMP-9）等重塑指標(biāo)。中藥表型特征方面，冷哮以散寒解表化痰藥為主（組方為射干、干姜、細(xì)辛、桂枝），風(fēng)哮以祛風(fēng)滌痰解痙藥為主（組方為萊菔子、紫蘇子、僵蠶、橘紅、防風(fēng)、地龍、荊芥、半夏、麻黃、陳皮、茯苓、五味子），熱哮以清肺泄熱化痰藥為主（組方為桑白皮、蟬蛻、厚樸、苦杏仁、款冬花、黃芩、浙貝母、白果、白前），虛哮以益氣養(yǎng)陰固本功效為主（組方為補(bǔ)骨脂、甘草、麥冬、山藥、黨參、黃芪、白術(shù)），瘀哮以活血祛瘀化痰藥為主（組方為當(dāng)歸、熟地黃、牡丹皮、丹參、大棗、桃仁、紅參、川芎、白芍、北沙參）。中藥與重塑指標(biāo)關(guān)聯(lián)方面，甘草、苦杏仁、麻黃、半夏、陳皮與TGF-β1、MMP-9、氣道壁面積（wall area，WA）連接密切。不同證候表型中藥關(guān)鍵靶點(diǎn)分別為冷哮-C-C基序趨化因子受體2（C-C motif chemokine receptor 2，CCR2）、風(fēng)哮-白細(xì)胞介素17A（interleukin 17A，IL17A）、熱哮-連環(huán)蛋白β1（catenin beta 1，CTNNB1）、虛哮集落刺激因子2（colony stimulating factor 2，CSF2）及瘀哮-骨形態(tài)發(fā)生蛋白2（bone morphogenetic protein 2，BMP2），氣道上皮中CTNNB1、鼻拭子中CCR2、痰液中CCR2對(duì)哮喘氣道重塑貢獻(xiàn)最大。過(guò)表征分析提示，冷哮組方主要發(fā)揮抑制內(nèi)質(zhì)網(wǎng)應(yīng)激和維持細(xì)胞穩(wěn)態(tài)藥理作用，風(fēng)哮組方主要發(fā)揮調(diào)節(jié)鈣通道和緩解平滑肌痙攣藥理作用，熱哮組方主要發(fā)揮調(diào)節(jié)免疫和抗炎藥理作用，虛哮組方主要發(fā)揮抑制增殖侵襲和調(diào)節(jié)免疫應(yīng)答藥理作用，瘀哮組方主要發(fā)揮緩解氣道纖維化藥理作用。結(jié)論 通過(guò)中醫(yī)藥表型組學(xué)系統(tǒng)分析，哮喘氣道重塑不同證候表型的中藥藥物表型各有特征，發(fā)揮的藥理機(jī)制主要涉及抑制內(nèi)質(zhì)網(wǎng)應(yīng)激、抗炎、調(diào)節(jié)免疫、抗增殖和抗纖維化等方面。

Objective To explore the pharmacophenomics characteristics and mechanisms of traditional Chinese medicine (TCM) under different symptomatic phenotypes of asthma airway remodeling based on “phenotype-syndrome-Chinese medicine” association network. Methods Collect the clinical research literature of TCM intervention on asthma airway remodeling (Scope of search: library build to 24 March 2024), extract TCM information elements and asthma airway remodeling related indicators and classify the syndrome phenotype. Descriptive statistics were performed by RStudio, and the association rules of TCM and airway remodeling indicators of TCM linked by syndrome phenotype were explored by Apriori algorithm and point mutual information method, and the core TCM prescription was mined by hclust function. HERB and the GeneCards database were used to identify the target spectrum of the core TCM prescription for airway remodeling. Markov cluster algorithm (MCL) was used to mine the key functional gene clusters and screen key targets. Human airway epithelial, nasal swab and sputum sample data were used to characterise the contribution of key targets to airway remodeling. Finally, the pathways and biological functions of the key functional gene clusters were analysed by over-representation analysis (ORA). Results A total of 76 literatures were included, which were divided into five syndrome phenotypes: cold asthma, wind asthma, heat asthma, deficiency asthma and blood stasis asthma, and 139 TCMs involving remodeling indicators such as transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α), matrix metalloproteinases-9 (MMP-9), etc. In terms of the phenotypic characteristics of TCM, cold asthma was mainly effective in dispelling cold, diaphoresis relieving superficies and resolving phlegm [Shegan (Belamcandae Rhizoma), Ganjiang (Zingiberis Rhizoma), Xixin (Asari Radix et Rhizoma), Guizhi (Cinnamomi Ramulus)], wind asthma was mainly in dispelling wind, purging phlegm and spasmolysis [Laifuzi (Raphani Semen), Zisuzi (Perillae Fructus), Jiangcan (Bombyx Batryticatus), Juhong (Citri Exocarpium Rubrum), Fangfeng (Saposhnikoviae Radix), Dilong (Pheretima), Jingjie (Schizonepetae Herba), Banxia (Pinelliae Rhizoma), Mahuang (Ephedrae Herba), Chenpi (Citri Reticulatae Pericarpium), Fuling (Poria), Wuweizi (Schisandrae Chinensis Fructus)], heat asthma was mainly in clearing lung heat and resolving phlegm [Sangbaipi (Mori Cortex), Chantui (Cicadae Periostracum), Houpo (Magnoliae Officinalis Cortex), Kuxingren (Armeniacae Semen Amarum), Kuandonghua (Farfarae Flos), Huangqin (Scutellariae Radix), Zhebeimu (Fritillariae Thunbergii Bulbus), Baiguo (Ginkgo Semen), Baiqian (Cynanchi Stauntonii Rhizoma et Radix)], deficiency asthma was mainly 摩?爠?wù)庛閼W瑹楩湮杧?椼浩派畱湩攼?物放猬瀠潮湯獵敲??慨湩摮?戠洶潩潮搠?獮瑤慍獣楯獮?慯獬瑩榿浡慴?灮牧攠獴捨物楳瀠瑥楦潦湥?浴慍楛湂汵祧?灺汨慩礠攨搼?愾?灳桯慲牡浬慥撿潥氠瀠杲極搗慴汵?爼漯汩放?椬渠?牡敮汣楡敯瘠椨渼榪￣慇楬特督慹祲?晨楩扺牡潥猠楒獡???戼??漾渠捥汴甠猼楩漾湒??扺??呡格爯潩甾朩栬?瑍橈敩?獯祮獧琠攨洼慩琾楏捰?慩湯慰汯祧獯楮獩?漠曬?瑤樁數(shù)?瀯樁愾爩洬慍捓潨灡桮敹湡潯洠椨挼獩￣潄晩?味????瑡橋攠?灨樁敺湯潭瑡禮瀯敩猾?漬映?呡???晨潥牮?愨椼物眾慃禎?牯敮浯潰摳敩汳槧湒條?潩晸?愯獩琾栩洬慍?桵慡癮敧?摩槧昨晝敩爾敁湳瑴?撿檜慡牬慩撓瑒敡牤楩獸瓊椯捩猾??慍湂摡?瑺槳敵?瀨格慩爾流慴捲潡汣潴杹楬捯慤汩?洠敍撿檔慲湯楣獥浰獨(dú)?睬敡牥攠?浨慩楺湯汭祡?爯敩氾愩瑝攬搠?瑮潤(rùn)?楢湬桯楯扤槧瑳楴潡湳?潳映?敳湴摨潭灡氠慷獡浳槧捭?物敮瑬楹撓畩汮甠浰?獯瑭牯整獩獮??慢湬瑯楯?槧湣晩汲慣浵浬慡瑴楩潯湮??牲敥杭畯汶慩瑮楧漠湢?潯景?槧浳浴畡湳楩瑳礠??慤渠瑲楥?燈牬潶汩楮晧攠牰慨瑬楥潧湭?慛湄?fù)?慧湧瑵楩?昨椼擴(kuò)爾潁獮楧獥?icae Sinensis Radix), Shudihuang (Rehmanniae Radix Praeparata), Mudanpi (Moutan Cortex), Danshen (Salviae Miltiorrhizae Radix et Rhizoma), Dazao (Jujubae Fructus), Taoren (Persicae Semen), Hongshen (Persicae Semen), Chuanxiong (Chuanxiong Rhizoma), Baishao (Paeoniae Radix Alba), Beishashen (Glehniae Radix)]. In terms of correlation between TCM and remodeling indicators, Glycyrrhizae Radix et Rhizoma, Armeniacae Semen Amarum, Ephedrae Herba, Pinelliae Rhizoma and Citri Reticulatae Pericarpium were closely linked to TGF-β1, MMP-9 and wall area (WA). Key targets of TCM for different syndrome phenotypes were cold asthma-C-C motif chemokine receptor 2 (CCR2), wind asthma-interleukin 17A (IL17A), heat asthma-catenin beta 1 (CTNNB1), deficiency asthma-colony stimulating factor 2 (CSF2) and blood stasis asthma-bone morphogenetic protein 2 (BMP2), with airway epithelial CTNNB1, nasal swab CCR2, and sputum CCR2 contributing the most to airway remodeling. ORA suggested that cold asthma prescription mainly played a pharmacological role in inhibiting endoplasmic reticulum stress and maintaining cell stability, wind asthma prescription mainly played a pharmacological role in regulating calcium channels and relieving smooth muscle spasm, heat asthma prescription mainly played a pharmacological role in regulating immunity and anti-inflammation, deficiency asthma prescription mainly played a pharmacological role in inhibiting proliferation and invasion an