Abstract
Eosinophilic inflammation and remodeling of the airways including subepithelial fibrosis and myofibroblast hyperplasia are characteristic pathological findings of bronchial asthma. Epithelial to mesenchymal transition (EMT) plays a critical role in airway remodelling. In this study, we hypothesized that infiltrating eosinophils promote airway remodelling in bronchial asthma. To demonstrate this hypothesis we evaluated the effect of eosinophils on EMT by in vitro and in vivo studies. EMT was assessed in mice that received intra-tracheal instillation of mouse bone marrow derived eosinophils and in human bronchial epithelial cells co-cultured with eosinophils freshly purified from healthy individuals or with eosinophilic leukemia cell lines. Intra-tracheal instillation of eosinophils was associated with enhanced bronchial inflammation and fibrosis and increased lung concentration of growth factors. Mice instilled with eosinophils pre-treated with transforming growth factor(TGF)-β1 siRNA had decreased bronchial wall fibrosis compared to controls. EMT was induced in bronchial epithelial cells co-cultured with human eosinophils and it was associated with increased expression of TGF-β1 and Smad3 phosphorylation in the bronchial epithelial cells. Treatment with anti-TGF-β1 antibody blocked EMT in bronchial epithelial cells. Eosinophils induced EMT in bronchial epithelial cells, suggesting their contribution to the pathogenesis of airway remodelling.
Highlights
Bronchial asthma is a chronic inflammatory disorder of the airways with a high worldwide prevalence [1]
Johnson et al reported that house dust mite exposure induces epithelial to mesenchymal transition (EMT) in large airways in mice [15]. These findings suggest that Transforming growth factor (TGF)-b1 released by eosinophils may induce EMT leading to airway remodelling
Intra-tracheal instillation of bone marrow-derived eosinophils led to increased number of total cell count, macrophages and lymphocytes in bronchoalveolar lavage fluid (BALF) on day 9 as compared with mice receiving saline instillation (Figure 1A, B)
Summary
Bronchial asthma is a chronic inflammatory disorder of the airways with a high worldwide prevalence [1]. Bronchial eosinophilic inflammation is a cardinal pathological feature of acute asthma [2], and airway remodeling, that is characterized by subepithelial fibrosis, myofibroblast hyperplasia, thickening of the lamina reticularis and increased smooth muscle mass, is a common consequence of chronic asthma [3]. The number of myofibroblasts increases in the proximity of the smooth muscle layer and the lamina reticularis in asthmatic patients [4]. They are rich source of collagens types I, III, and V, fibronectin and tenascin that accumulate in the airway walls causing thickening of the lamina reticularis [5,6]. EMT is currently recognized as an important mechanism for the increased number of myofibroblasts in cancer and fibrotic diseases [8]
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