Abstract
BackgroundThe reticular basement membrane (Rbm) in smokers and especially smokers with COPD is fragmented with "clefts" containing cells staining for the collagenase matrix-metalloproteinase-9 (MMP-9) and fibroblast protein, S100A4. These cells are also present in the basal epithelium. Such changes are likely hallmarks of epithelial mesenchymal transition (EMT). We aimed to confirm the epithelial origin of these Rbm cells, and to exclude potential confounding by infiltrating inflammatory cells.MethodsEndobronchial biopsy sections from 17 COPD current smokers, with documented Rbm splitting and cellularity were stained for neutrophil elastase (neutrophil marker), CD68 (macrophage/mature fibroblasts), CD4+/CD8+ T lymphocytes, CD19 (B-cells), CD11c (dendritic cells/inflammatory cells), and S100 (Langerhans cells). The number of cells in the Rbm and epithelium staining for these "inflammatory" cell markers were then compared to numbers staining for S100A4, "a documented EMT epitope". Slides were double stained for S100A4 and cytokeratin(s).ResultsIn the basal epithelium significantly more cells stained for S100A4 compared to infiltrating macrophages, fibroblasts or immune cells: median, 26 (21.3 - 37.3) versus 0 (0 - 9.6) per mm, p < 0.003. Markedly more S100A4 staining cells were also observed in the Rbm compared to infiltrating macrophages, neutrophils, fibroblasts or immune cells or any sub-type: 58 (37.3 - 92.6) versus 0 (0 - 4.8) cells/mm Rbm, p < 0.003. Cells in the basal epithelium 26 (21.3 - 37.3) per mm) and Rbm (5.9 (2.3 - 13.8) per mm) frequently double stained for both cytokeratin and S100A4.ConclusionsThese data provide additional support for active EMT in COPD airways.
Highlights
One of the features of chronic inflammatory airway diseases, including COPD, is airway remodelling [1]
This analysis demonstrated that all cells in the epithelium stained for cytokeratin as might be expected, while about 13.8% of these stained for S100A4; all of the S100A4 cells stained for cytokeratin-(s)
In summary, double staining of cells by both epithelial and mesenchymal markers in both the basal layer of the epithelium and within the fragmented reticular basement membrane (Rbm) is supportive of our hypothesis that epithelial mesenchymal transition (EMT) is likely to be an active process in the airways in smokers, and especially those of current-smoking COPD patients
Summary
One of the features of chronic inflammatory airway diseases, including COPD, is airway remodelling [1]. As a likely hallmark of EMT, we showed that the reticular basement membrane (Rbm) in smokers and COPD is highly fragmented, with elongated spaces or cracks, which we termed “clefts” [7,13], again typical of EMT as described in the literature [10,11,12,14,15] These elongated spaces and cracks or clefts in the Rbm were often not empty, but frequently contained cells, which we found were positive for the mesenchymal markers S100A4, vimentin and MMP-9. The reticular basement membrane (Rbm) in smokers and especially smokers with COPD is fragmented with “clefts” containing cells staining for the collagenase matrix-metalloproteinase-9 (MMP-9) and fibroblast protein, S100A4 These cells are present in the basal epithelium. We aimed to confirm the epithelial origin of these Rbm cells, and to exclude potential confounding by infiltrating inflammatory cells
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