The Role of WNT5a and TGF-β1 in Airway Remodelling and Severe Asthma

IF 12 1区医学 Q1 ALLERGY

Allergy Pub Date : 2025-01-03 DOI:10.1111/all.16445

Tariq Daud, Sheree Roberts, Nazanin Zounemat Kermani, Matthew Richardson, Liam G. Heaney, Ian M. Adcock, Yassine Amrani, Peter Bradding, Salman Siddiqui

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引用次数: 0

Abstract

Background

Airway remodelling is a feature of severe asthma with airway epithelial damage observed frequently. We evaluated the role of WNT5a and TGF-β₁ in asthmatic airway biopsies and in sputum and bronchial brushings assessed their role in remodelling.

Methods

WNT5a and TGF-β₁ 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-β₁ 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).

Results

WNT5a and TGF-β₁ 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_s = 0.54, p = 0.001) and % denuded epithelium (r_s = −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-β₁, 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.

Conclusion

WNT5a is associated with both airway remodelling and severe asthma.

Trial Registration

ClinicalTrials.gov identifier: NCT01982162

Abstract Image

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WNT5a和TGF-β1在气道重塑和重度哮喘中的作用。

背景：气道重塑是严重哮喘的一个特征，经常观察到气道上皮损伤。我们评估了哮喘患者气道活检组织中 WNT5a 和 TGF-β1 的作用，并评估了痰液和支气管刷状物中 WNT5a 和 TGF-β1 在重塑过程中的作用：方法：在哮喘患者（GINA 1-3，n-8；GINA 4-5，n-14）和健康人（n-9）的固有膜上皮细胞中评估 WNT5a 和 TGF-β1 蛋白表达，同时评估相关重塑标记物。在体外评估了 WNT5a 和 TGF-β1 对 BEAS-2B 上皮细胞伤口愈合和分化的影响。结果显示，WNT5a 和 TGF-β1 对 BEAS-2B 上皮细胞伤口愈合和分化的影响在体外进行了评估，并在痰液（n = 120）和支气管刷（n = 147）中的 "预测呼吸系统疾病结果的无偏生物标记物（U-BIOPRED）"研究中进行了复制：结果：在并发气流受限或病情严重的哮喘患者中，气道上皮和固有膜中的 WNT5a 和 TGF-β1 蛋白表达明显增加。此外，固有膜中 WNT5a 蛋白表达与组织嗜酸性粒细胞和血管重塑相关。气道上皮 WNT5a 主要与气道基底细胞共定位，并与 Th17 基因表达（r = 0.40，p = 0.025）以及完整上皮细胞百分比（rs = 0.54，p = 0.001）和变性上皮细胞百分比（rs = -0.39，p = 0.003）相关。在 BEAS-2B 细胞中进行的实验证实，最大生理浓度（1 μg/mL）的 WNT5a 能促进上皮伤口愈合，而不依赖于 TGF-β1，还能诱导类似 EMT 的形态。在 U-BIOPRED 中，WNT5a mRNA 与严重哮喘、气流受限、痰中嗜酸性粒细胞增多、Th2、Th17 和中性粒细胞活化转录组相关：结论：WNT5a与气道重塑和严重哮喘有关：试验注册：ClinicalTrials.gov identifier：NCT01982162。

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来源期刊

Allergy 医学-过敏

CiteScore

26.10

自引率

9.70%

发文量

393

审稿时长

2 months

期刊介绍： Allergy is an international and multidisciplinary journal that aims to advance, impact, and communicate all aspects of the discipline of Allergy/Immunology. It publishes original articles, reviews, position papers, guidelines, editorials, news and commentaries, letters to the editors, and correspondences. The journal accepts articles based on their scientific merit and quality. Allergy seeks to maintain contact between basic and clinical Allergy/Immunology and encourages contributions from contributors and readers from all countries. In addition to its publication, Allergy also provides abstracting and indexing information. Some of the databases that include Allergy abstracts are Abstracts on Hygiene & Communicable Disease, Academic Search Alumni Edition, AgBiotech News & Information, AGRICOLA Database, Biological Abstracts, PubMed Dietary Supplement Subset, and Global Health, among others.