Abstract
In COPD, epithelial changes are prominent features in the airways, such as goblet cell hyperplasia and squamous metaplasia. In contrast, it remains unclear whether ciliated cells are reduced and which pathways dysregulate epithelial differentiation. We hypothesized that bronchial epithelial cell lineage specification is dysregulated in COPD because of an aberrant reprogramming through transforming growth factor (TGF)-β1. Surgical lung tissue from 81 COPD and 61 control (smokers and non-smokers) patients was assessed for bronchial epithelial cell phenotyping by immunohistochemistry, both in situ and in vitro in reconstituted air-liquid interface (ALI) cultures. The role of TGF-β1 was studied in vitro. COPD epithelium in large airways, when compared to controls, showed decreased β-tubulin IV + ciliated cells (4.4%, 2.5–8.8% versus 8.5%, 6.3–11.8% of surface staining, median and IQR, p = 0.0009) and increased MUC5AC + goblet cells (34.8%, 24.4–41.9% versus 10.3%, 5.1–17.6%, p < 0.0001). Both features were recapitulated in the ALI-cultured epithelium from COPD patients. Exogenous TGF-β1 reduced mucociliary differentiation while neutralizing TGF-β1 during ALI increased both specialized cell types. The COPD airway epithelium displays altered differentiation for ciliated cells, which recapitulates in vitro, at least in part through TGF-β1.
Highlights
Chronic obstructive pulmonary disease (COPD) is a frequent and major respiratory disease, characterized by a progressive and poorly reversible airflow limitation in subjects exposed to noxious particles and gases, most frequently from cigarette smoke
These data show that goblet cell hyperplasia in COPD is closely related to smoking, whereas the decrease in ciliated cells is observed in COPD
We found that the bronchial epithelium reconstituted from large airway tissue of COPD patients cultured upon air-liquid interface (ALI) for 2 weeks, recapitulated the epithelial features observed in situ, namely increased MUC5AC and decreased β-tubulin IV expression with no change in p63 expression (Fig. 3A–D)
Summary
Chronic obstructive pulmonary disease (COPD) is a frequent and major respiratory disease, characterized by a progressive and poorly reversible airflow limitation in subjects exposed to noxious particles and gases, most frequently from cigarette smoke. An important hallmark of the disease is the excess of mucus, due to increases in goblet cells and in mucus secretion[13,14] which have been directly related to cigarette smoke exposure[15] and to the activation by inflammatory mediators such as interleukin (IL)-4, IL-1316, IL-1717, tumour necrosis factor, neutrophil elastase[18] and S100 proteins[19]. Besides IL-13, which may promote goblet cell hyperplasia and loss of cilia in vitro[25] with relevance to asthma, transforming growth factor (TGF)-β is upregulated in the bronchial epithelium and in air-liquid interface (ALI)-human bronchial epithelial cells (HEBC) from COPD patients[26] and has a central role in the remodeling of the epithelium in this disease[27].
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