Systemic sclerosis (SSc) is a chronic
autoimmune disease characterized by
fibrosis of the skin and internal organs. Despite the recent advances in the pathogenesis and treatment of SSc, effective
therapies for
fibrosis caused by SSc have not yet been established. In this study, we investigated the potential role of
mirodenafil, a potent
phosphodiesterase 5 (
PDE5) inhibitor, in the treatment of
fibrosis in SSc. We used a
bleomycin (BLM)-induced SSc mouse model to mimic the typical features of
fibrosis in human SSc and examined the dermal thickness to assess the degree of skin
fibrosis after staining with
hematoxylin and
eosin or Masson's trichrome stains. The effect of
mirodenafil on the expression of profibrotic genes was also analyzed by treating fibroblasts with
transforming growth factor (TGF)-β and
mirodenafil. We showed that
mirodenafil ameliorated dermal
fibrosis and downregulated the
protein levels of
fibrosis markers including COL1A1 and α-SMA in the BLM-induced SSc mouse model. Further, using mouse embryonic fibroblasts and human lung fibroblasts, we demonstrated that the expression of
collagen and profibrotic genes was reduced by treatment with
mirodenafil. Finally, we showed that
mirodenafil inhibited TGF-β-induced phosphorylation of Smad2/3 in fibroblasts, which suggested that this
drug may ameliorate
fibrosis by suppressing the TGF-β/Smad signaling pathway. Our findings suggest that
mirodenafil possesses a therapeutic potential for treating
fibrosis in SSc.