Abstract
BackgroundChronic persistent asthma is characterized by ongoing airway inflammation and airway remodeling. The processes leading to airway remodeling are poorly understood, and there is increasing evidence that even aggressive anti-inflammatory therapy does not completely prevent this process. We sought to investigate whether TGFβ1 stimulates bronchial epithelial cells to undergo transition to a mesenchymal phenotype, and whether this transition can be abrogated by corticosteroid treatment or enhanced by the pro-inflammatory cytokine IL-1β.MethodsBEAS-2B and primary normal human bronchial epithelial cells were stimulated with TGFβ1 and expression of epithelial and mesenchymal markers assessed by quantitative real-time PCR, immunoblotting, immunofluorescence microscopy and zymography. In some cases the epithelial cells were also incubated with corticosteroids or IL-1β. Results were analyzed using non-parametric statistical tests.ResultsTreatment of BEAS-2B or primary human bronchial epithelial cells with TGFβ1 significantly reduced the expression level of the epithelial adherence junction protein E-cadherin. TGFβ1 then markedly induced mesenchymal marker proteins such as collagen I, tenascin C, fibronectin and α-smooth muscle actin mRNA in a dose dependant manner. The process of mesenchymal transition was accompanied by a morphological change towards a more spindle shaped fibroblast cell type with a more motile and invasive phenotype. Corticosteroid pre-treatment did not significantly alter the TGFβ1 induced transition but IL-1β enhanced the transition.ConclusionOur results indicate, that TGFβ1 can induce mesenchymal transition in the bronchial epithelial cell line and primary cells. Since asthma has been strongly associated with increased expression of TGFβ1 in the airway, epithelial to mesenchymal transition may contribute to the contractile and fibrotic remodeling process that accompanies chronic asthma.
Highlights
Chronic persistent asthma is characterized by ongoing airway inflammation and airway remodeling
Cells stimulated with TGFβ1 developed a spindle fibroblast-like morphology with reduced cell-cell contact, while cells in media alone maintained the typical epithelial cobblestone pattern
TGF 1 induces gene expression characteristic of epithelial to mesenchymal transition (EMT) EMT is defined by changes in gene expression in which epithelial markers such as E-cadherin decrease while mesenchymal markers such as αSMA increase
Summary
Chronic persistent asthma is characterized by ongoing airway inflammation and airway remodeling. The processes leading to airway remodeling are poorly understood, and there is increasing evidence that even aggressive anti-inflammatory therapy does not completely prevent this process. Persistent asthma is characterized by structural changes termed airway remodeling This ongoing remodeling and reconstruction of the asthmatic lung includes (page number not for citation purposes). While the impact of corticosteroid treatment on airway remodeling is controversial, even aggressive anti-inflammatory therapy with corticosteroids does not appear to fully prevent remodeling and these long term effects [3]. It is important, to understand both the processes that contribute to remodeling in asthma as well as the impact of corticosteroids on these processes
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