Sildenafil attenuates the fibrotic phenotype of skin fibroblasts in patients with systemic sclerosis

Clin Immunol. 2015 Dec;161(2):333-8. doi: 10.1016/j.clim.2015.09.010. Epub 2015 Sep 24.


Systemic sclerosis (SSc) is a multi-organ fibrotic disease that affects the skin and various internal organs. Therapeutic strategies for tissue fibrosis have not been established; however, aberrantly activated fibroblasts in affected lesions are key targets for modulating fibrosis. Recently, increased intracellular cyclic GMP (cGMP) levels were demonstrated to improve fibrosis levels in various diseases. The purpose of this study was to assess the anti-fibrotic properties of cGMP in cultured fibroblasts from patients with SSc. The phosphodiesterase (PDE) 5 inhibitor sildenafil increased the intracellular cGMP levels in skin fibroblasts in a dose-dependent manner. Sildenafil treatment also significantly decreased the expression of several pro-fibrotic factors that were upregulated by TGF-β1 treatment in SSc skin fibroblasts. These inhibitory effects occurred via non-canonical TGF-β signaling. Our findings revealed that sildenafil might be a novel strategy to treat tissue fibrosis and vasculopathy in SSc.

Keywords: CGMP; Fibrosis; Sildenafil; Systemic sclerosis.

MeSH terms

  • Adult
  • Aged
  • Blotting, Western
  • Cells, Cultured
  • Collagen Type I / genetics
  • Collagen Type I / metabolism
  • Collagen Type I, alpha 1 Chain
  • Connective Tissue Growth Factor / genetics
  • Connective Tissue Growth Factor / metabolism
  • Cyclic GMP / metabolism*
  • Dose-Response Relationship, Drug
  • Female
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • Fibrosis / prevention & control
  • Humans
  • Male
  • Middle Aged
  • Phosphodiesterase 5 Inhibitors / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Scleroderma, Systemic / genetics
  • Scleroderma, Systemic / metabolism
  • Scleroderma, Systemic / pathology
  • Sildenafil Citrate / pharmacology*
  • Skin / metabolism
  • Skin / pathology*
  • Transforming Growth Factor beta1 / pharmacology


  • CCN2 protein, human
  • COL1A2 protein, human
  • Collagen Type I
  • Collagen Type I, alpha 1 Chain
  • Phosphodiesterase 5 Inhibitors
  • Transforming Growth Factor beta1
  • Connective Tissue Growth Factor
  • Sildenafil Citrate
  • Cyclic GMP