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.
Highlights
Skin fibrosis is a devastating pathology that occurs during different human pathologies, that is, systemic sclerosis (SSc), an autoimmune disease of unknown etiology characterized by progressive fibrosis of the skin and internal organs [1], or wound-associated skin repair [2]
To assess whether protease-activated receptor-1 (PAR-1) drives fibrotic responses in vitro, human dermal fibroblasts (HDF) were cultured in the presence or absence of thrombin and/or transforming growth factor (TGF)-β
In our in vitro experiments (Figure 1), we showed that Protease activated receptor (PAR)-1 drives fibroblast proliferation and, we determined the number of proliferating cells in the dermis of bleomycin-treated wild-type and PAR-1-deficient mice
Summary
Skin fibrosis is a devastating pathology that occurs during different human pathologies, that is, systemic sclerosis (SSc), an autoimmune disease of unknown etiology characterized by progressive fibrosis of the skin and internal organs [1], or wound-associated skin repair [2]. The clinical appearance of the different skin disorders might differ, the activation, proliferation and migration of resident fibroblasts at the site of trauma which induces deposition of extracellular matrix (ECM) proteins like fibronectin and collagen is a common pathway in these disorders [3,4,5]. PAR-1 induces proliferation, migration and ECM production of fibroblasts and PAR-1 deficiency (either genetic or pharmacologic) limits experimental fibrosis in lung [8,9] and liver [10]. The functional consequence of PAR-1 expression in the skin remains elusive accelerated wound healing in RESEARCH ARTICLE mice after topical PAR-1 activation pinpoints PAR-1 as an important receptor in the skin [13]
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