RT Journal Article
SR Electronic
T1 Protease-activated receptor-2 triggers epithelial to mesenchymal transition: Potential relevance in pulmonary fibrosis
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP p782
VO 38
IS Suppl 55
A1 Keren Borensztajn
A1 Jan von der Thüsen
A1 Maikel Peppelenbosch
A1 Arnold Spek
YR 2011
UL http://erj.ersjournals.com/content/38/Suppl_55/p782.abstract
AB Idiopathic pulmonary fibrosis (IPF) constitutes the most devastating form of fibrotic lung disorders. The destructive fibroblast foci characteristic of IPF originate, at least partly, via epithelial to mesenchymal transition (EMT). The extracellular signals and cellular receptors triggering EMT in IPF remain incompletely understood however. Recently, we showed that protease-activated receptor-2 (PAR-2), a transmembrane G-protein-coupled receptor expressed ubiquitously in the lung, is an essential player in fibrotic lung disorders by directly targeting fibroblasts. Here, we explore the role of PAR-2 on epithelial cells by focussing on PAR-2-induced EMT in pulmonary fibrosis. Immunostaining of lung biopsies of IPF patients showed prominent PAR-2 expression by fibroblasts and epithelial cells overlying fibroblast foci. Double stainings indicated that PAR-2 co-localized on cells expressing both epithelial (cytokeratins) and mesenchymal (vimentin) markers, indeed suggesting a role of PAR-2 in EMT in IPF. Subsequent in vitro experiments showed that PAR-2 stimulation induced a fibroblast-like morphology in type II lung epithelial cells, the expression of the myofibroblast markers vimentin and α-SMA, and the secretion of collagen. Interestingly, PAR-2 stimulation triggered β-catenin accumulation and translocation to the nucleus. In conclusion, PAR-2 triggers EMT of epithelial cells and PAR-2 dependent activation of the β-catenin/WNT signaling pathway is probably the main driver of PAR-2-induced EMT. Overall our data thus suggest that inhibition of the PAR-WNT axis may be a clinically relevant treatment option in IPF but also in other disorders in which EMT is essential.