Protease-activated receptor-2 induces myofibroblast differentiation and tissue factor up-regulation during bleomycin-induced lung injury: potential role in pulmonary fibrosis.
Idiopathic pulmonary fibrosis 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 (among others) coagulation factor (F)Xa, plays a key role in fibrotic disease; consequently, we assessed the role of PAR-2 in 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 in 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 provide a novel therapeutic approach to treat this devastating disease.
Center for Experimental and Molecular Medicine, Academic Medical Center, Meibergdreef 9, NL-1105 AZ, Amsterdam, The Netherlands. K.S.Borensztajn@amc.uva.nl
Keren
K
Borensztajn
Paul
P
Bresser
Chris
C
van der Loos
Ilze
I
Bot
Bernt
B
van den Blink
Michael A
MA
den Bakker
Joost
J
Daalhuisen
Angelique P
AP
Groot
Maikel P
MP
Peppelenbosch
Jan H
JH
von der Thüsen
C Arnold
CA
Spek
D000328:Adult; D000368:Aged; D000818:Animals; D001761:Bleomycin; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D006801:Humans; D055370:Lung Injury / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D058628:Myofibroblasts / Q000378:metabolism / Q000502:physiology*; D011658:Pulmonary Fibrosis / Q000235:genetics* / Q000473:pathology; D044464:Receptor, PAR-2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013925:Thromboplastin / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
D044464:Receptor, PAR-2; D001761:Bleomycin; D013925:Thromboplastin