Pneumologie 2013; 67 - P269
DOI: 10.1055/s-0033-1334757

Protease-activated receptors 1 and 3 drive epithelial-mesenchymal transition in pulmonary fibrosis

M Wygrecka 1, S Berscheid 1, K Piskulak 2, M Didiasova 1, B Taborski 1, B Kwapiszewska 3, KT Preissner 1, P Markart 2
  • 1Biochemisches Institut, University of Gießen Lung Center
  • 2Zentrum für Innere Medizin, University of Gießen Lung Center
  • 3Ludwig Boltzmann Institute for Lung Vascular Research, Graz

Rationale: Extravascular activation of the coagulation cascade in the lung is commonly observed in pulmonary fibrosis. Coagulation proteases exert profibrotic cellular effects via protease-activated receptors (PARs)-1 and -2.

Objective: We investigated for the first time the potential role of two other members of the PAR family, namely PAR-3 and PAR-4, in the pathogenesis of idiopathic pulmonary fibrosis (IPF).

Results: Elevated expression of PAR-3, but not PAR-4, was detected in the lungs of IPF patients and bleomycin-challenged mice. Increased PAR-3 expression in fibrotic lungs was mainly attributable to alveolar type II (ATII) cells. Stimulation of primary mouse ATII cells and MLE15 cells with thrombin (FIIa) induced epithelial-mesenchymal transition (EMT) evidenced by morphological alterations and by expression changes of epithelial and mesenchymal phenotype markers. Single knockdown of FIIa receptors, PAR-1, PAR-3, or PAR-4, did not inhibit FIIa-induced EMT, and simultaneous knockdown of PAR-1 and PAR-4 or PAR-3 and PAR-4 had only a partial effect on this process. Simultaneous depletion of PAR-1 and PAR-3, however, completely blocked FIIa-induced EMT. Furthermore, colocalisation of PAR-1 and PAR-3 was observed in ATII cells.

Conclusions: Our study provides first evidence that PAR-3 via its ability to potentiate FIIa-induced EMT may contribute to the pathogenesis of pulmonary fibrosis.