目的 在“聚于胃，關(guān)于肺”視角下探索胃食管反流?。╣astroesophageal reflux，GERD）與特發(fā)性肺纖維化（idiopathic pulmonary fibrosis，IPF）共病“中虛氣逆”病機(jī)的生物學(xué)內(nèi)涵，并探索麥門冬湯干預(yù)共病的機(jī)制。方法 從基因表達(dá)綜合數(shù)據(jù)庫(kù)獲取GERD和IPF基因表達(dá)譜以篩選共享差異表達(dá)基因（differentially expressed genes，DEGs），免疫細(xì)胞浸潤(rùn)與基因集富集分析（gene set enrichment analysis，GSEA）鑒定共病核心生物通路以揭示GERD與IPF共病的生物學(xué)機(jī)制。綜合網(wǎng)絡(luò)藥理學(xué)、分子對(duì)接、受試者操作特征（receiver operating characteristic，ROC）曲線、外部數(shù)據(jù)集驗(yàn)證和功能富集分析探索麥門冬湯干預(yù)共病的核心靶點(diǎn)及機(jī)制。從Decode獲取血漿順式蛋白質(zhì)數(shù)量性狀位點(diǎn)數(shù)據(jù)，從IEU OpenGWAS獲取GERD和IPF的全基因組關(guān)聯(lián)研究數(shù)據(jù)，利用孟德爾隨機(jī)化（mendelian randomization，MR）驗(yàn)證麥門冬湯干預(yù)共病的核心靶點(diǎn)。結(jié)果 共得到1 303個(gè)共享DEGs；靜息樹突狀細(xì)胞、M0期巨噬細(xì)胞、漿細(xì)胞和調(diào)節(jié)性T細(xì)胞在GERD與IPF中表達(dá)趨勢(shì)相同；共病核心生物通路包括凝固、上皮間質(zhì)轉(zhuǎn)化、鼠類肉瘤病毒癌基因（kirsten rat sarcoma viral oncogene，KRAS）通路下調(diào)和血管生成等。209個(gè)麥門冬湯有效成分作用于16個(gè)共病靶點(diǎn)，這些靶點(diǎn)主要富集在晚期糖基化終末產(chǎn)物及其受體、細(xì)胞周期、血小板活化等通路。分子對(duì)接、ROC曲線、外部數(shù)據(jù)集和MR明確了3個(gè)共病核心靶點(diǎn)：III型膠原蛋白的α1鏈［collagen alpha-1 (III) chain，COL3A1］、組織蛋白酶K（cathepsin K，CTSK）和半乳糖凝集素（galectin-7，LGALS7）。其中COL3A1與GERD和IPF發(fā)病呈負(fù)相關(guān)，LGALS7與GERD和IPF發(fā)病呈正相關(guān)，CTSK與IPF發(fā)病呈負(fù)相關(guān)、與GERD發(fā)病呈正相關(guān)。結(jié)論 促炎與抗炎免疫細(xì)胞失衡是GERD與IPF共病“中虛氣逆”病機(jī)的生物學(xué)內(nèi)涵，麥門冬湯可以通過調(diào)控免疫炎癥等途徑干預(yù)共病，豐富了“聚于胃，關(guān)于肺”理論的內(nèi)涵，為共病機(jī)制及干預(yù)研究提供了參考。

Objective To explore the biological connotation of “Zhongqi deficiency inverse” in gastroesophageal reflux disease (GERD) and idiopathic pulmonary fibrosis (IPF) comorbidity from the perspective of “gathering in the stomach, focusing on the lung”. Moreover, it explores the mechanism of Maimendong Decoction (麥門冬湯) in the multimorbidity intervention. Methods GERD and IPF gene expression profiles were obtained from the Gene Expression Omnibus database to screen shared differentially expressed genes (DEGs). Gene set enrichment analysis (GSEA) and immune cell infiltration identified core biological pathways to reveal the biological mechanism of GERD and IPF comorbidity. Network pharmacology, molecular docking, receiver operating characteristic (ROC) curve, external dataset validation and functional enrichment analysis were used to explore the core targets and mechanisms of Maimendong Decoction in the intervention of multimorbidity. The quantitative trait loci of plasma cis proteins were obtained from Decode, and the genome-wide association study data of GERD and IPF were obtained from IEU OpenGWAS. Mendelian randomization (MR) was used to verify the core targets of Maimendong Decoction in the intervention of comorbidities. Results A total of 1 303 shared DEGs were obtained. The expressions of resting dendritic cells, M0 phase macrophages, plasma cells, and regulatory T cells in GERD and IPF were similar. The core biological pathways of comorbidity include coagulation, epithelial-mesenchymal transition, downregulation of the kirsten rat sarcoma viral oncogene (KRAS) pathway, and angiogenesis. A total of 209 active components of Maimendong Decoction acted on 16 comorbidity targets, which were mainly enriched in advanced glycation end products and their receptors, cell cycle, platelet activation, and other pathways. Molecular docking, ROC curves, external datasets, and MR identified three core targets for comorbidity: collagen alpha-1 (III) chain was negatively correlated with GERD and IPF, galectin-7 was positively correlated with GERD and IPF, and cathepsin K was negatively correlated with IPF and positively correlated with GERD. Conclusion The imbalance of pro-inflammatory and anti-inflammatory immune cells is the biological connotation of the comorbidity of “Zhongqi deficiency inverse” in GERD and IPF. Maimendong Decoction can intervene with the comorbidity by regulating immune inflammation and other mechanisms, which enriches the connotation of the theory of “gathering in the stomach, focusing on the lung” and provides a reference for the study of the mechanism and intervention of the comorbidity.

Q811.4;TP18;R285

國(guó)家自然科學(xué)基金面上項(xiàng)目（82174347，82374403）；四川省中醫(yī)藥管理局面上項(xiàng)目（2023MS363）；成都中醫(yī)藥大學(xué)2023年度“杏林學(xué)者”學(xué)科人才青基進(jìn)階人才專項(xiàng)（QJJJ2023006）