重度哮喘中纤毛相关分子候选基因的鉴定与验证
2026/07/31
摘要
背景：哮喘是一种以慢性炎症和气道重塑为特征的疾病。哮喘患者气道上皮的功能发生异常改变，提示气道上皮在疾病发生发展过程中发挥核心作用。既往研究已报道哮喘患者气道上皮存在纤毛相关异常，但其具体机制仍不清楚。本研究旨在探讨重度哮喘患者中纤毛相关异常的分子特征，通过分析多个重度哮喘队列，筛选并鉴定驱动气道上皮重塑的关键分子调控因子。
方法：研究纳入三个大型重度哮喘队列及非哮喘对照队列的支气管刷检上皮细胞转录组数据进行分析：U-BIOPRED队列（GSE76226，n = 105）、SARP队列（GSE63142，n = 81）和IMSA队列（GSE158752，n = 42）。研究重点关注纤毛相关基因，比较重度哮喘组与非哮喘组之间的差异表达情况，并筛选三个队列中共同存在的差异表达基因。随后，在体外实验样本中验证差异最显著的三个候选基因的表达与定位，并分析其与气道上皮重塑特征及临床指标之间的相关性。
结果：在三个数据集中，共发现17个基因在重度哮喘组与非哮喘组之间呈显著差异表达。其中差异最显著的三个候选基因为：PHLDB2（12.7% [4.6–22.4]，p < 0.05）、NEK6（8.4% [5.5–12.8]，p < 0.05）和SCNN1G（6.8% [4.3–9.9]，p < 0.05）。在重度哮喘患者支气管活检组织中：PHLDB2蛋白水平上调1.2倍（p = 0.2844），NEK6上调2.4倍（p < 0.01），SCNN1G上调2.0倍（p < 0.05）。进一步分析发现：上述三个候选基因的表达均与气道上皮重塑特征显著相关，并且这种相关性在重度哮喘组和非哮喘组中均可观察到。体外实验结果显示：在IL-13刺激下，气道上皮细胞中SCNN1G表达明显上调，提示SCNN1G可能在促炎环境下参与调控上皮细胞分化过程。此外，在完全分化的气液界面培养模型中，无论是否给予炎症刺激，PHLDB2、NEK6和SCNN1G蛋白表达均与上皮重塑特征相关。
结论：本研究发现，重度哮喘患者支气管上皮中三种纤毛相关基因：PHLDB2、NEK6、SCNN1G存在明显表达失调。这些基因与气道上皮重塑特征密切相关，并且在炎症环境下参与上皮细胞分化调控过程，提示其可能参与重度哮喘的发病机制。因此，PHLDB2、NEK6和SCNN1G不仅可能成为重度哮喘的重要生物学驱动因子，也有望作为疾病预测生物标志物或潜在治疗靶点。
关键词：气道，哮喘，纤毛，上皮细胞，NEK6，PHLDB2，SCNN1G
（Devilliers MA, Saber Cherif L, Brisebarre A, Chouquet R, Bralet L, Ancel J, Vivien A, Luczka-Majérus E, Bonnomet A, Lalun N, Taillé C, Dubernard X, Mérol JC, Ruaux C, Polette M, Deslée G, Perotin JM, Dormoy V. Identification and validation of cilia-associated molecular candidates deregulated in severe asthma. Respir Res. 2026 Feb 9;27(1):128. doi: 10.1186/s12931-026-03548-y. PMID: 41664127; PMCID: PMC12983791.）
Abstract
Background: Asthma is characterised by a chronic inflammation and airway remodelling. The functionality of the asthma airway epithelium is altered, suggesting a central role in the pathophysiology. Cilia-associated abnormalities have been reported in the airway epithelium of asthmatic patients, but the mechanisms remain elusive. This study investigated cilia-associated dysregulations in cohorts of patients with severe asthma to identify and characterize key molecular drivers of epithelial airway remodelling.
Methods: Transcriptomic data from epithelial bronchial brushing samples of three large cohorts of severe asthma patients and non-asthmatic were analysed: U-BIOPRED (GSE76226, n = 105), SARP (GSE63142, n = 81) and IMSA (GSE158752, n = 42). We focused on cilia-associated genes to highlight common differentially expressed genes in all three cohorts, comparing the non-asthmatic and severe asthma groups. Localisation and expression of the three most dysregulated genes were then validated on ex vivo and in vitro samples and correlated to epithelial airway remodelling features and clinical data.
Results: Seventeen genes were significantly dysregulated between the non-asthma and severe asthma groups in all three datasets. We identified the three most dysregulated: PHLDB2 (12.7% [4.6–22.4], p < 0.05), NEK6 (8.4% [5.5–12.8], p < 0.05) and SCNN1G (6.8% [4.3–9.9], p < 0.05) as molecular candidates. In ex vivo severe asthma bronchial biopsies, the protein levels were upregulated 1.2-fold for PHLDB2 (p = 0.2844), 2.4-fold (p < 0.01) for NEK6, and 2.0-fold for SCNN1G (p < 0.05). The expressions of these candidates were correlated with epithelial remodelling features in both groups. In vitro, the expression of SCNN1G was upregulated in airway epithelial cells upon IL-13 stimulation, suggesting that SCNN1G may be dynamically regulated during epithelial differentiation under pro-inflammatory conditions. Finally, protein expression of PHLDB2, NEK6 and SCNN1G in fully differentiated air-liquid interface culture was associated with epithelial remodelling features with or without inflammatory stimulation.
Conclusion: This study highlights the dysregulation of three cilia-associated genes, PHLDB2, NEK6, and SCNN1G, in the bronchial epithelium of patients with SA. Their association with epithelial remodelling features and altered differentiation under inflammatory conditions highlights their potential involvement in asthma pathogenesis and their potential as predictive biomarkers or therapeutic targets in severe asthma.
Keywords: Airways; Asthma; Cilia; Epithelial cells; NEK6; PHLDB2; SCNN1G.
背景：哮喘是一种以慢性炎症和气道重塑为特征的疾病。哮喘患者气道上皮的功能发生异常改变，提示气道上皮在疾病发生发展过程中发挥核心作用。既往研究已报道哮喘患者气道上皮存在纤毛相关异常，但其具体机制仍不清楚。本研究旨在探讨重度哮喘患者中纤毛相关异常的分子特征，通过分析多个重度哮喘队列，筛选并鉴定驱动气道上皮重塑的关键分子调控因子。
方法：研究纳入三个大型重度哮喘队列及非哮喘对照队列的支气管刷检上皮细胞转录组数据进行分析：U-BIOPRED队列（GSE76226，n = 105）、SARP队列（GSE63142，n = 81）和IMSA队列（GSE158752，n = 42）。研究重点关注纤毛相关基因，比较重度哮喘组与非哮喘组之间的差异表达情况，并筛选三个队列中共同存在的差异表达基因。随后，在体外实验样本中验证差异最显著的三个候选基因的表达与定位，并分析其与气道上皮重塑特征及临床指标之间的相关性。
结果：在三个数据集中，共发现17个基因在重度哮喘组与非哮喘组之间呈显著差异表达。其中差异最显著的三个候选基因为：PHLDB2（12.7% [4.6–22.4]，p < 0.05）、NEK6（8.4% [5.5–12.8]，p < 0.05）和SCNN1G（6.8% [4.3–9.9]，p < 0.05）。在重度哮喘患者支气管活检组织中：PHLDB2蛋白水平上调1.2倍（p = 0.2844），NEK6上调2.4倍（p < 0.01），SCNN1G上调2.0倍（p < 0.05）。进一步分析发现：上述三个候选基因的表达均与气道上皮重塑特征显著相关，并且这种相关性在重度哮喘组和非哮喘组中均可观察到。体外实验结果显示：在IL-13刺激下，气道上皮细胞中SCNN1G表达明显上调，提示SCNN1G可能在促炎环境下参与调控上皮细胞分化过程。此外，在完全分化的气液界面培养模型中，无论是否给予炎症刺激，PHLDB2、NEK6和SCNN1G蛋白表达均与上皮重塑特征相关。
结论：本研究发现，重度哮喘患者支气管上皮中三种纤毛相关基因：PHLDB2、NEK6、SCNN1G存在明显表达失调。这些基因与气道上皮重塑特征密切相关，并且在炎症环境下参与上皮细胞分化调控过程，提示其可能参与重度哮喘的发病机制。因此，PHLDB2、NEK6和SCNN1G不仅可能成为重度哮喘的重要生物学驱动因子，也有望作为疾病预测生物标志物或潜在治疗靶点。
关键词：气道，哮喘，纤毛，上皮细胞，NEK6，PHLDB2，SCNN1G
（南方医科大学南方医院 凌嘉骏 赵海金）
（Devilliers MA, Saber Cherif L, Brisebarre A, Chouquet R, Bralet L, Ancel J, Vivien A, Luczka-Majérus E, Bonnomet A, Lalun N, Taillé C, Dubernard X, Mérol JC, Ruaux C, Polette M, Deslée G, Perotin JM, Dormoy V. Identification and validation of cilia-associated molecular candidates deregulated in severe asthma. Respir Res. 2026 Feb 9;27(1):128. doi: 10.1186/s12931-026-03548-y. PMID: 41664127; PMCID: PMC12983791.）
Abstract
Background: Asthma is characterised by a chronic inflammation and airway remodelling. The functionality of the asthma airway epithelium is altered, suggesting a central role in the pathophysiology. Cilia-associated abnormalities have been reported in the airway epithelium of asthmatic patients, but the mechanisms remain elusive. This study investigated cilia-associated dysregulations in cohorts of patients with severe asthma to identify and characterize key molecular drivers of epithelial airway remodelling.
Methods: Transcriptomic data from epithelial bronchial brushing samples of three large cohorts of severe asthma patients and non-asthmatic were analysed: U-BIOPRED (GSE76226, n = 105), SARP (GSE63142, n = 81) and IMSA (GSE158752, n = 42). We focused on cilia-associated genes to highlight common differentially expressed genes in all three cohorts, comparing the non-asthmatic and severe asthma groups. Localisation and expression of the three most dysregulated genes were then validated on ex vivo and in vitro samples and correlated to epithelial airway remodelling features and clinical data.
Results: Seventeen genes were significantly dysregulated between the non-asthma and severe asthma groups in all three datasets. We identified the three most dysregulated: PHLDB2 (12.7% [4.6–22.4], p < 0.05), NEK6 (8.4% [5.5–12.8], p < 0.05) and SCNN1G (6.8% [4.3–9.9], p < 0.05) as molecular candidates. In ex vivo severe asthma bronchial biopsies, the protein levels were upregulated 1.2-fold for PHLDB2 (p = 0.2844), 2.4-fold (p < 0.01) for NEK6, and 2.0-fold for SCNN1G (p < 0.05). The expressions of these candidates were correlated with epithelial remodelling features in both groups. In vitro, the expression of SCNN1G was upregulated in airway epithelial cells upon IL-13 stimulation, suggesting that SCNN1G may be dynamically regulated during epithelial differentiation under pro-inflammatory conditions. Finally, protein expression of PHLDB2, NEK6 and SCNN1G in fully differentiated air-liquid interface culture was associated with epithelial remodelling features with or without inflammatory stimulation.
Conclusion: This study highlights the dysregulation of three cilia-associated genes, PHLDB2, NEK6, and SCNN1G, in the bronchial epithelium of patients with SA. Their association with epithelial remodelling features and altered differentiation under inflammatory conditions highlights their potential involvement in asthma pathogenesis and their potential as predictive biomarkers or therapeutic targets in severe asthma.
Keywords: Airways; Asthma; Cilia; Epithelial cells; NEK6; PHLDB2; SCNN1G.
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IL-13/ATF4/S100P轴调控气道上皮屏障：嗜酸性粒细胞哮喘的新靶点
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重度哮喘中贝那利珠单抗选择性抑制ILC2而非Th2：基线Th2产IL-4与疗效负相关
