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

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.

A Brief Exposure to Tryptase or Thrombin Potentiates Fibrocyte Differentiation in the Presence of Serum or Serum Amyloid P

“…Tryptase, thrombin, PAR-1 signaling, and PAR-2 signaling have been implicated in the development of fibrosis through their effects on fibroblasts (25, 31, 32, 37, 40, 75–78). Both PAR-1 and −2 have been implicated in liver fibrosis in mice (79, 80), and both PAR-1 knockout mice and PAR-2 knockout mice are less susceptible to both induced heart disease and inflammation (81–83).…”

“…This suggests that the fibrocyte potentiation caused by proteases relies on a suitable protein additive, not solely albumin. Albumin is increased in fibrotic lesions (25) and healing wounds (102), and is decreased in chronic, non-healing wounds (103–105), implying that albumin’s presence may mediate the protease signaling that, by activating fibrocyte differentiation, may initiate key aspects of wound healing and fibrosis.…”

“…One of the events preceding scar tissue formation in a healing wound is the clotting cascade, in which the protease thrombin cleaves fibrinogen to fibrin. Thrombin activity is upregulated in fibrotic lesions (25) and immediately after wounding (26). Thrombin causes inflammation when added to mouse lungs, increased concentrations of thrombin within lungs exacerbate fibrosis, and inhibition of thrombin attenuates fibrosis (27–30).…”

Protease‐activated receptor‐1 contributes to renal injury and interstitial fibrosis during chronic obstructive nephropathy

“…Subsequent transmembrane signalling leads, amongst others, to EMT of alveolar epithelial cells and retinal pigment epithelial cells . Moreover, PAR‐1‐dependent signalling drives fibroblast proliferation and extracellular matrix production in vitro, whereas PAR‐1 deficiency limits liver, lung and skin fibrosis in experimental animal models . In the kidney, PAR‐1 is expressed by endothelial cells, podocytes, mesangial cells, and tubular epithelial cells and we recently showed that PAR‐1 potentiates diabetic nephropathy by inducing mesangial cell proliferation and extracellular matrix production …”

“…[9][10][11] Moreover, PAR-1-dependent signalling drives fibroblast proliferation and extracellular matrix production in vitro, whereas PAR-1 deficiency limits liver, lung and skin fibrosis in experimental animal models. [12][13][14][15] In the kidney, PAR-1 is expressed by endothelial cells, podocytes, mesangial cells, and tubular epithelial cells 16 and we recently showed that PAR-1 potentiates diabetic nephropathy by inducing mesangial cell proliferation and extracellular matrix production. 17 Based on the key role of PAR-1 in fibroproliferative disease, it is thus tempting to speculate that PAR-1 may be a key factor driving the pathogenesis of renal fibrosis.…”