Protease activated receptor-1 deficiency diminishes bleomycin-induced skin fibrosis.
Accumulating evidence shows that protease-activated receptor-1 (PAR-1) plays an important role in the development of fibrosis, including lung fibrosis. However, whether PAR-1 also plays a role in the development of skin fibrosis remains elusive. The aim of this study was to determine the role of PAR-1 in the development of skin fibrosis. To explore possible mechanisms by which PAR-1 could play a role, human dermal fibroblasts and keratinocytes were stimulated with specific PAR-1 agonists or antagonists. To investigate the role of PAR-1 in skin fibrosis, we subjected wild-type and PAR-1-deficient mice to a model of bleomycin-induced skin fibrosis. PAR-1 activation leads to increased proliferation and extra cellular matrix (ECM) production, but not migration of human dermal fibroblasts (HDF) in vitro. Moreover, transforming growth factor (TGF)-β production was increased in keratinocytes upon PAR-1 activation, but not in HDF. The loss of PAR-1 in vivo significantly attenuated bleomycin-induced skin fibrosis. The bleomycin-induced increase in dermal thickness and ECM production was reduced significantly in PAR-1-deficient mice compared with wild-type mice. Moreover, TGF-β expression and the number of proliferating fibroblasts were reduced in PAR-1-deficient mice although the difference did not reach statistical significance. This study demonstrates that PAR-1 contributes to the development of skin fibrosis and we suggest that PAR-1 potentiates the fibrotic response mainly by inducing fibroblast proliferation and ECM production.
Center for Experimental and Molecular Medicine (CEMM), University of Amsterdam, Amsterdam, the Netherlands.
JanWillem
J
Duitman
Center for Experimental and Molecular Medicine (CEMM), University of Amsterdam, Amsterdam, the Netherlands.
Roberta R
RR
Ruela-de-Sousa
Center for Experimental and Molecular Medicine (CEMM), University of Amsterdam, Amsterdam, the Netherlands.
Kun
K
Shi
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Onno J
OJ
de Boer
Unité INSERM 700, Physiopathologie et Epidémiologie de L'Insuffisance Respiratoire, Faculté de Médecine Xavier Bichat, Paris, France.
Keren S
KS
Borensztajn
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Sandrine
S
Florquin
Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, the Netherlands.
Maikel P
MP
Peppelenbosch
Center for Experimental and Molecular Medicine (CEMM), University of Amsterdam, Amsterdam, the Netherlands.
C Arnold
CA
Spek
D000818:Animals; D001761:Bleomycin; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D005355:Fibrosis; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044463:Receptor, PAR-1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000187:drug effects / Q000473:pathology*; D012871:Skin Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D010975:Platelet Aggregation Inhibitors
D044463:Receptor, PAR-1; D001761:Bleomycin; D010975:Platelet Aggregation Inhibitors