Abstract
BackgroundThe airway epithelium of chronic obstructive pulmonary disease (COPD) patients undergoes aberrant repair and remodeling after repetitive injury following exposure to environmental factors. Abnormal airway regeneration observed in COPD is thought to originate in the stem/progenitor cells of the airway epithelium, the basal cells (BCs). However, the molecular mechanisms underlying these changes remain unknown. Here, trophoblast cell surface antigen 2 (TROP2), a protein implicated in the regulation of stem cell activity, was examined in lung tissue samples from COPD patients.MethodsThe expression of TROP2 and hyperplasia index Ki67 was assessed in lung epithelium specimens from non-smokers (n = 24), smokers (n = 24) and smokers with COPD (n = 24). Primary airway BCs were isolated by bronchoscopy from healthy individuals and COPD patients and subsequently transfected with pcDNA3.1-TROP2 or siRNA sequence in vitro. The functional consequences of TROP2 overexpression in BCs were explored.ResultsImmunohistochemistry and immunofluorescence revealed increased TROP2 expression in airway BCs in smokers with COPD compared to nonsmokers and smokers without COPD, and staining was highly localized to hyperplastic regions containing Ki67 positive cells. TROP2 expression was also inversely correlated with airflow limitation in patients with COPD (r = −0.53, P < 0.01). pcDNA3.1-TROP2-BCs in vitro exhibited improved proliferation with activation of ERK1/2 phosphorylation signaling pathway. In parallel, changes in vimentin and E-cadherin in pcDNA3.1-TROP2-BCs were consistent with an epithelial-mesenchymal transition (EMT)-like change, and secretion of inflammatory factors IL-1β, IL-8 and IL-6 was increased. Moreover, down-regulation of TROP2 by siRNA significantly attenuated the proliferation of BCs derived from COPD patients. EMT-like features and cytokine levels of COPD basal cells were also weakened following the down-regulation of TROP2.ConclusionThe results indicate that TROP2 may play a crucial role in COPD by affecting BC function and thus airway remodeling through increased BC hyperplasia, EMT-like change, and introduction of inflammatory molecules into the microenvironment.
Highlights
The airway epithelium of chronic obstructive pulmonary disease (COPD) patients undergoes aberrant repair and remodeling after repetitive injury following exposure to environmental factors
Our results demonstrate that increased expression of trophoblast cell surface antigen 2 (TROP2) occurs in the basal cells (BCs) compartment of lung tissue samples, indicating that the protein might play a role in aberrant airway repair and remodeling that are characteristic of Chronic obstructive pulmonary disease (COPD)
The forced expiratory volume in first second percentage (FEV1%) of predicted and the Forced expiratory volume in first second (FEV1)/forced vital capacity (FVC) ratios were significantly reduced in smoking patients with COPD compared to healthy controls (P < 0.01 for both comparisons)
Summary
The airway epithelium of chronic obstructive pulmonary disease (COPD) patients undergoes aberrant repair and remodeling after repetitive injury following exposure to environmental factors. Abnormal airway regeneration observed in COPD is thought to originate in the stem/progenitor cells of the airway epithelium, the basal cells (BCs). BCs include multipotent stem/progenitor progenitor cells of bronchial airway epithelium and make a major contribution to the regeneration of bronchial epithelium [6, 7]. These cells play a key role in the maintenance of the normal airway epithelial architecture through their capacity to self-renew, differentiate into ciliated and secretory cells, and establish interactions with mesenchymal cells [8,9,10,11]. Little is known about the molecular mechanisms underlying the abnormal biological behavior of BCs in COPD
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