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Pivotal role of Protease‐activated receptor‐2 in bleomycin‐induced pulmonary fibrosis
Author(s) -
Borensztajn Keren Sarah,
Bresser Paul,
Thusen Jan,
Loos Chris,
Blink Bernt,
Bakker Michael,
Daalhuisen Joost,
Groot Angelique,
Peppelenbosch Maikel,
Spek Arnold
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.31.8
Subject(s) - bleomycin , pulmonary fibrosis , idiopathic pulmonary fibrosis , bronchoalveolar lavage , myofibroblast , medicine , fibrosis , lung , pathology , thrombin , fibrin , transforming growth factor , coagulation , immunology , cancer research , platelet , chemotherapy
Idiopathic pulmonary fibrosis (IPF) constitutes the most devastating form of fibrotic lung disorders, and remains refractory to current therapies. The coagulation cascade is frequently activated during pulmonary fibrosis, but this observation has so far resisted a mechanistic explanation. Recent data suggest that protease‐activated receptor (PAR)‐2, a receptor activated by coagulation factor(F) Xa, plays a key role in fibrotic disease. Here, we assessed the role of PAR‐2 in pulmonary fibrosis. We show that PAR‐2 is upregulated in the lungs of IPF patients. The bronchoalveolar lavage fluid of these patients displays increased procoagulant‐dependant mitogenic activity. In a murine model of pulmonary fibrosis, we show that bleomycin induces PAR‐2 expression, myofibroblast differentiation and collagen synthesis. In PAR‐2−/− mice, the extent and severity of fibrotic lesions is reduced whereas myofibroblast differentiation is abolished and collagen expression is decreased. Moreover, fibrin deposition in lungs of fibrotic PAR‐2−/− mice is reduced compared to wild type mice due to differential tissue factor expression in response to bleomycin. Finally, anticoagulant targeting FXa significantly reduced fibrosis development. Taken together, PAR‐2 is instrumental in pulmonary fibrosis, and inhibition of the PAR‐2‐coagulation axis may provide a novel therapeutic approach for this devastating disease.