Mirodenafil ameliorates skin fibrosis in bleomycin-induced mouse model of systemic sclerosis
Jong Seong Roh1, Hoim Jeong2, Beomgu Lee2
1Department of Herbal Prescription, College of Korean Medicine, Daegu Haany University, Gyeongsan, Republic of Korea.
Abstract:
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.
Insights
Mirodenafil, a PDE5 inhibitor, reduced fibrosis in a systemic sclerosis mouse model. It suppressed collagen production and the TGF-β/Smad pathway, showing potential for treating systemic sclerosis fibrosis.
Area of Science:
- Immunology
- Dermatology
- Pharmacology
Background:
- Systemic sclerosis (SSc) is a chronic autoimmune disease causing significant fibrosis.
- Current SSc treatments lack effective antifibrotic therapies.
- Phosphodiesterase 5 (PDE5) inhibitors are explored for antifibrotic potential.
Purpose of the Study:
- To investigate mirodenafil's efficacy in treating SSc-associated fibrosis.
- To elucidate the mechanism underlying mirodenafil's antifibrotic effects.
Main Methods:
- A bleomycin (BLM)-induced mouse model of SSc was utilized.
- Dermal fibrosis was assessed via histological staining (H&E, Masson's trichrome).
- Fibroblast cultures were treated with TGF-β and mirodenafil to analyze gene expression and signaling pathways.
Main Results:
- Mirodenafil significantly ameliorated dermal fibrosis in the SSc mouse model.
- It downregulated key fibrosis markers like COL1A1 and α-SMA.
- Mirodenafil reduced collagen and profibrotic gene expression in fibroblasts and inhibited TGF-β-induced Smad2/3 phosphorylation.
Conclusions:
- Mirodenafil demonstrates therapeutic potential for SSc fibrosis.
- Its mechanism involves suppressing the TGF-β/Smad signaling pathway.
- Further research into mirodenafil as an SSc antifibrotic agent is warranted.
