The role of uPAR in epithelial-mesenchymal transition in small airway epithelium of patients with chronic obstructive pulmonary disease

Qin Wang,Yuke Zhang,Yi Zhang,Wei Xiao,Yunshan Wang

doi:10.1186/1465-9921-14-67

Qin Wang, Yuke Zhang + Show 3 more

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https://doi.org/10.1186/1465-9921-14-67

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Abstract

BackgroundEpithelial-mesenchymal transition (EMT) plays a crucial role in small airway fibrosis of patients with chronic obstructive pulmonary disease (COPD). Increasing evidence suggests that the urokinase plasminogen activator receptor (uPAR) is involved in the pathogenesis of COPD. Increased uPAR expression has been implicated in the promotion of EMT in numerous cancers; however the role of uPAR in EMT in small airway epithelial cells of patients with COPD remains unclear. In this study, we investigated the degree of EMT and uPAR expression in lung epithelium of COPD patients, and verified the effect of uPAR on cigarette smoke extract (CSE)-induced EMT in vitro.MethodsThe expression of EMT biomarkers and uPAR was assessed in lung epithelium specimens from non-smokers (n = 25), smokers (n = 25) and non-smokers with COPD (n = 10) and smokers with COPD (n = 18). The role of uPAR on CSE-induced EMT in human small airway epithelial cells (HSAEpiCs) was assessed by silencing uPAR expression in vitro.ResultsMarkers of active EMT and uPAR expression were significantly increased in the small airway epithelium of patients with COPD compared with controls. We also observed a significant correlation between uPAR and vimentin expression in the small airway epithelium. In vitro, CSE-induced EMT in HSAEpiCs was associated with high expression of uPAR, and targeted silencing of uPAR using shRNA inhibited CSE-induced EMT. Finally, we demonstrate that the PI3K/Akt signaling pathway is required for uPAR-mediated EMT in HSAEpiCs.ConclusionsA uPAR-dependent signaling pathway is required for CSE-induced EMT, which contributes to small airway fibrosis in COPD. We propose that increased uPAR expression in the small airway epithelium of patients with COPD participates in an active EMT process.

Highlights

Epithelial-mesenchymal transition (EMT) plays a crucial role in small airway fibrosis of patients with chronic obstructive pulmonary disease (COPD)
Our results demonstrate a significant increase in urokinase plasminogen activator receptor (uPAR) expression levels and in the degree of active EMT in the small airway epithelium of patients with COPD compared with non-smokers and smokers with normal lung function
We showed that uPAR, which can promote EMT in several tumor cell systems [30,31,32], is highly expressed in the small airway epithelium of patients with COPD compared with controls [10]

Summary

Introduction

Epithelial-mesenchymal transition (EMT) plays a crucial role in small airway fibrosis of patients with chronic obstructive pulmonary disease (COPD). McCormack and colleagues proposed that acquisition of an EMT-like phenotype by AECs is a normal aspect of wound repair They suggest that diseases involving fibrosis may arise because the EMT phase of repair is prolonged by chronic injury/inflammation [7]. Sohal et al provide evidence that EMT is an active process in the airways of smokers, in those of current-smoking COPD patients. This was based on immunohistochemical analysis of epithelial and mesenchymal markers in the basal layer of the epithelium and in the fragmented reticular basement membrane (Rbm) [9]. Active airway EMT in COPD patients may be related to subsequent fibrotic activity in the sub-epithelial tissue, the mechanisms involved in this process remain to be elucidated

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