Protease-Activated Receptor-2 Induces Myofibroblast Differentiation and Tissue Factor Up-Regulation during Bleomycin-Induced Lung Injury Potential Role in Pulmonary Fibrosis

K Borensztajn, PJC (Paula) Bresser, C van der Loos, I Bot, B Blink, Michael den Bakker, J Daalhuisen, AP Groot, Maikel Peppelenbosch, Jan von der Thüsen, CA Spek

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Abstract

Idiopathic pulmonary fibrosis constitutes the most devastating form of fibrotic lung disorders and re mains refractory to current therapies The coagula non 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 (among others) coagulation factor (F)Xa plays a key role in fibrotic disease consequently we assessed the role of PAR 2 m the development of pulmonary fibrosis in this study We show that PAR 2 is up regulated in the lungs of patients with idiopathic pulmonary fibrosis and that bronchoalveolar lavage fluid from these patients displays increased procoagulant activity that triggers fibroblast survival Using a bleomycin model of pulmonary fibrosis we show that bleomycin induces PAR 2 expression as well as both myofibroblast differentiation and collagen synthesis In PAR 2-/- mice both the extent and severity of fibrotic lesions are reduced whereas myofibroblast differentiation is diminished and collagen expression is decreased. Moreover fibrin deposition m the lungs of fibrotic PAR 2-/- mice is reduced compared with wild type mice due to differential tissue factor expression in response to bleomycin Taken together these results suggest an important role for PAR 2 in the development of pulmonary fibrosis and the inhibition of the PAR 2 coagulation axis may pro vide a novel therapeutic approach to treat this devastating disease (Am J Pathol 2010 177 2753-2764 DOI 10 2353/ajpath 2010 091107)
Original languageUndefined/Unknown
Pages (from-to)2753-2764
Number of pages12
JournalAmerican Journal of Pathology
Volume177
Issue number6
DOIs
Publication statusPublished - 2010

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