| Autor: |
Duitman J; Center for Experimental and Molecular Medicine (CEMM), University of Amsterdam, Amsterdam, the Netherlands., Ruela-de-Sousa RR; Center for Experimental and Molecular Medicine (CEMM), University of Amsterdam, Amsterdam, the Netherlands., Shi K; Center for Experimental and Molecular Medicine (CEMM), University of Amsterdam, Amsterdam, the Netherlands., de Boer OJ; Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands., Borensztajn KS; Unité INSERM 700, Physiopathologie et Epidémiologie de L'Insuffisance Respiratoire, Faculté de Médecine Xavier Bichat, Paris, France., Florquin S; Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands., Peppelenbosch MP; Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, the Netherlands., Spek CA; Center for Experimental and Molecular Medicine (CEMM), University of Amsterdam, Amsterdam, the Netherlands. |
| Abstrakt: |
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. |
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