Daud Tariq, Roberts Sheree, Zounemat Kermani Nazanin, Richardson Matthew, Heaney Liam G, Adcock Ian M, Amrani Yassine, Bradding Peter, Siddiqui Salman
Department of Respiratory Sciences, College of Life Sciences, and NIHR Biomedical Research Centre (Respiratory Theme), Glenfield Hospital, Leicester, UK.
Data Science Institute, Imperial College, London, UK.
Allergy. 2025 Apr;80(4):1025-1037. doi: 10.1111/all.16445. Epub 2025 Jan 3.
Airway remodelling is a feature of severe asthma with airway epithelial damage observed frequently. We evaluated the role of WNT5a and TGF-β in asthmatic airway biopsies and in sputum and bronchial brushings assessed their role in remodelling.
WNT5a and TGF-β protein expression were assessed in the lamina propria epithelium of people with asthma (GINA 1-3, n-8 and GINA 4-5, n-14) and healthy subjects (n-9), alongside relevant remodelling markers. The effects of WNT5a and TGF-β on BEAS-2B epithelial cell wound healing and differentiation were assessed in vitro. Replication was performed in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) study in sputum (n = 120) and bronchial brushes (n = 147).
WNT5a and TGF-β protein expression were significantly increased in the airway epithelium and lamina propria in asthma patients with concurrent airflow limitation or severe disease. Furthermore, WNT5a protein expression in the lamina propria correlated with tissue eosinophils and vascular remodelling. Airway epithelial WNT5a was co-localised predominantly to airway basal cells and correlated with Th17 gene expression (r = 0.40, p = 0.025) and both the % intact (r = 0.54, p = 0.001) and % denuded epithelium (r = -0.39, p = 0.003). Experiments in BEAS-2B cells confirmed that WNT5a at maximal physiological concentrations (1 μg/mL), promoted epithelial wound healing, independently of TGF-β, as well as induction of EMT-like morphology. WNT5a mRNA was associated with severe asthma, airflow limitation, sputum eosinophilia and Th2, and Th17 and neutrophil activation transcriptomes in sputum in U-BIOPRED.
WNT5a is associated with both airway remodelling and severe asthma.
ClinicalTrials.gov identifier: NCT01982162.
气道重塑是重度哮喘的一个特征，常伴有气道上皮损伤。我们评估了WNT5a和TGF-β在哮喘气道活检组织以及痰液和支气管刷检样本中的作用，以确定它们在气道重塑中的角色。
评估哮喘患者（全球哮喘防治创议1-3级，n = 8；全球哮喘防治创议4-5级，n = 十四）和健康受试者（n = 9）固有层上皮中WNT5a和TGF-β蛋白表达情况，同时检测相关重塑标志物。体外评估WNT5a和TGF-β对BEAS-2B上皮细胞伤口愈合和分化的影响。在预测呼吸系统疾病结局的无偏倚生物标志物（U-BIOPRED）研究中对痰液（n = 120）和支气管刷检样本（n = 147）进行了重复实验。
在伴有气流受限或重症的哮喘患者气道上皮和固有层中，WNT5a和TGF-β蛋白表达显著增加。此外，固有层中WNT5a蛋白表达与组织嗜酸性粒细胞及血管重塑相关。气道上皮WNT5a主要定位于气道基底细胞，与Th17基因表达相关（r = 0.40，p = 0.025），与完整上皮百分比（r = 0.54，p = 0.001）和剥脱上皮百分比（r = -0.39，p = 0.003）均相关。BEAS-2B细胞实验证实，最大生理浓度（1μg/mL）的WNT5a可促进上皮伤口愈合，且不依赖TGF-β，还可诱导上皮-间质转化样形态。在U-BIOPRED研究中，WNT5a mRNA与重度哮喘、气流受限、痰液嗜酸性粒细胞增多以及痰液中的Th2、Th17和中性粒细胞激活转录组相关。
WNT5a与气道重塑和重度哮喘均相关。
ClinicalTrials.gov标识符：NCT0198
