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Molecular Medicine

, Volume 20, Issue 1, pp 410–416 | Cite as

Protease Activated Receptor-1 Deficiency Diminishes Bleomycin-Induced Skin Fibrosis

  • Jan Willem Duitman
  • Roberta R. Ruela-de-Sousa
  • Kun Shi
  • Onno J. de Boer
  • Keren S. Borensztajn
  • Sandrine Florquin
  • Maikel P. Peppelenbosch
  • C. Arnold Spek
Research Article

Abstract

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.

Notes

Acknowledgments

This study was supported by Grant 09.102 from the Dutch Burns Foundation to J Duitman. The authors like to thank Marieke ten Brink and Joost Daalhuisen for their technical assistance during the animal experiments.

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Authors and Affiliations

  • Jan Willem Duitman
    • 1
  • Roberta R. Ruela-de-Sousa
    • 1
  • Kun Shi
    • 1
  • Onno J. de Boer
    • 2
  • Keren S. Borensztajn
    • 3
  • Sandrine Florquin
    • 2
  • Maikel P. Peppelenbosch
    • 4
  • C. Arnold Spek
    • 1
  1. 1.Center for Experimental and Molecular Medicine (CEMM), Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
  2. 2.Department of Pathology, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
  3. 3.Physiopathologie et Epidémiologie de L’Insuffisance Respiratoire, Faculté de Médecine Xavier BichatUnité INSERM 700ParisFrance
  4. 4.Department of Gastroenterology and HepatologyErasmus Medical CenterRotterdamThe Netherlands

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