PM2.5 Induces Airway Remodeling in Chronic Obstructive Pulmonary Diseases via the Wnt5a/β-Catenin Pathway

Abstract

Weifeng Zou,1 Xiaoqian Wang,2 Ruiting Sun,3 Jinxing Hu,1 Dong Ye,4 Ge Bai,3 Sha Liu,5 Wei Hong,6 Meihua Guo,1 Pixin Ran3 1State Key Laboratory of Respiratory Disease, Guangzhou Chest Hospital, Guangzhou, Guangdong, People’s Republic of China; 2The Third Hospital of Mianyang, Mianyang, Sichuan, People’s Republic of China; 3National Center for Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 4State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 5The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, People’s Republic of China; 6GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of ChinaCorrespondence: Pixin RanNational Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Yuexiu District, Guangzhou, Guangdong, 510120, People’s Republic of ChinaTel [phone]Email [email protected]: Fine-particulate matter ≤ 2.5 μm in diameter (PM2.5)-associated airway remodeling has recently been recognized as a central feature of COPD. Activation of the Wnt/β-catenin pathway is closely related to the occurrence of airway remodeling. Accordingly, the goal of this study was to determine whether the Wnt5a/β-Catenin pathway is involved in PM2.5-induced smooth muscle proliferation in vivo and in vitro, which promotes the development of airway remodeling in subjects with COPD.Methods: The effect of Wnt5a on β-Catenin-mediated airway remodeling was assessed using an in vivo model of PM2.5-induced COPD and PM2.5-exposed human bronchial smooth muscle cells (HBSMCs) in vitro. Small animal spirometry was used to measure lung function in mice. H&E staining and immunohistochemistry were performed to inspect emphysema and airway remodeling indices. Real-time PCR was used to detect Wnt5a, β-Catenin, TGF-β 1, CyclinD1 and c-myc mRNA expression. The CCK8 assay was performed to detect cellular activity. Western blotting was performed to assess PCNA, α-SMA, Wnt5a, β-Catenin, PDGFRβ and TenascinC protein expression. β-Catenin expression was detected using cellular immunofluorescence.Results: Exposure to PM2.5 led to emphysema, airway wall thickening, an increased smooth muscle layer thickness, decreased lung function and increased expression of the Wnt5a, β-Catenin, PDGFRβ and Tenascin C proteins in the mouse lung tissue. BOX5 (a Wnt5a antagonist) alleviated these PM2.5-induced outcomes in mice. Moreover, PM2.5 induced the expression of the Wnt5a, β-Catenin, TGF-β 1, CyclinD1 and c-myc mRNAs in HBSMCs. BOX5 also inhibited the PM2.5-induced increases in PCNA, α-SMA, Wnt5a, β-Catenin, PDGFRβ and Tenascin C protein expression in HBSMCs.Conclusion: Our findings suggest that PM2.5 exposure induces HBSMC proliferation, contributing to airway remodeling via the Wnt5a/β-Catenin signaling pathway in vivo and in vitro, which might be a target for COPD treatment.Keywords: COPD, airway remodeling, PM2.5, Wnt5a/β-Catenin

Keywords

• copd
• airway remodeling
• pm2.5
• wnt5a/β-catenin