Protease-activated receptors (PAR)-1 and -3 drive epithelial-mesenchymal transition of alveolar epithelial cells – potential role in lung fibrosis

Malgorzata Wygrecka; Miroslava Didiasova; Sebastian Berscheid; Katarzyna Piskulak; Brigitte Taborski; Dariusz Zakrzewicz; Grazyna Kwapiszewska; Klaus T. Preissner; Philipp Markart

doi:10.1160/TH12-11-0854

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2013; 110(02): 295-307
DOI: 10.1160/TH12-11-0854

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Protease-activated receptors (PAR)-1 and -3 drive epithelial-mesenchymal transition of alveolar epithelial cells – potential role in lung fibrosis

Malgorzata Wygrecka^*

¹Department of Biochemistry, Justus-Liebig-University Giessen, Germany

,

Miroslava Didiasova

¹Department of Biochemistry, Justus-Liebig-University Giessen, Germany

,

Sebastian Berscheid

¹Department of Biochemistry, Justus-Liebig-University Giessen, Germany

,

Katarzyna Piskulak

²Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), Germany

,

Brigitte Taborski

¹Department of Biochemistry, Justus-Liebig-University Giessen, Germany

,

Dariusz Zakrzewicz

¹Department of Biochemistry, Justus-Liebig-University Giessen, Germany

,

Grazyna Kwapiszewska

³Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria

,

Klaus T. Preissner^*

¹Department of Biochemistry, Justus-Liebig-University Giessen, Germany

,

Philipp Markart^*

²Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), Germany

› Institutsangaben

Abstract

Summary

Extravascular activation of the coagulation cascade in the lung is commonly observed in pulmonary fibrosis. Coagulation proteases may exert profibrotic cellular effects via protease-activated receptors (PARs)-1 and -2. Here, we investigated the potential role of two other members of the PAR family, namely PAR-3 and PAR-4, in the pathobiology of lung fibrosis. Elevated expression of PAR-3, but not PAR-4, was detected in the lungs of idiopathic pulmonary fibrosis (IPF) patients and in bleomycin-induced lung fibrosis in mice. Increased PAR-3 expression in fibrotic lungs was mainly attributable to alveolar type II (ATII) cells. Stimulation of primary mouse ATII, MLE15 and A549 cells with thrombin (FIIa) – that may activate PAR-1, PAR-3 and PAR-4 – induced epithelial-mesenchymal transition (EMT), a process that has been suggested to be a possible mechanism underlying the expanded (myo)fibroblast pool in lung fibrosis. EMT was evidenced by morphological alterations, expression changes of epithelial and mesenchymal phenotype markers, and functional changes. Single knockdown of FIIa receptors, PAR-1, PAR-3, or PAR-4, had no major impact on FIIa-induced EMT. Simultaneous depletion of PAR-1 and PAR-3, however, almost completely inhibited this process, whereas only a partial effect on FIIa-mediated EMT was observed when PAR-1 and PAR-4, or PAR-3 and PAR-4 were knocked down. PAR-1 and PAR-3 co-localise within ATII cells with both being predominantely plasma membrane associated. In conclusion, our study indicates that PARs synergise to mediate FIIa-induced EMT and provides first evidence that PAR-3 via its ability to potentiate FIIa-triggered EMT could potentially contribute to the pathogenesis of pulmonary fibrosis.

Keywords

Coagulation proteases - thrombin - protease-activated receptors - pulmonary fibrosis - epithelial-mesenchymal transition

Volltext

Referenzen

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