Mirodenafil ameliorates skin fibrosis in bleomycin-induced mouse model of systemic sclerosis

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.

Hub genes, diagnostic model, and predicted drugs in systemic sclerosis by integrated bioinformatics analysis

“…Evidence showed that PDE inhibitors could reduce skin fibrosis as well. Mirodenafil, a potent PDE5 inhibitor, ameliorated dermal fibrosis in the BLM-induced mice and downregulated the expression of profibrotic genes and collagen in fibroblasts, possibly by suppressing TGF-β/Smad signalling pathway ( Roh et al, 2021 ). Sildenafil, a well-known PDE5 inhibitor, prevents ROS-induced instability in human dermal fibroblasts isolated by SSc patients ( Di Luigi et al, 2020 ).…”

Ginsenoside Rg3 attenuates pulmonary fibrosis by inhibiting endothelial to mesenchymal transition

“…Unfortunately, it has been reported that the number of patients with IPF has increased over time (Liu et al 2017 ). Pulmonary fibrosis (PF) is characterized by abnormal accumulation of the extracellular matrix (ECM), alveolar epithelial cell damage, vascular remodeling, and irreversible lung damage (Todd et al 2012 ; Liu et al 2017 ; Roh et al 2021 ). Previous studies have focused on inflammation as an important cause of pathogenesis; however, myofibroblasts, which are significant mediators of fibrosis known to produce ECM proteins, have been receiving more attention in recent years (Todd et al 2012 ; Liu et al 2017 ).…”

Chemical fluorescence-based dye staining for 3-dimensional histopathology analysis

“…As normal histopathological tests often involve general staining such as hematoxylin–eosin (H&E) staining (No et al 2021 ; Roh et al 2021 ), the development of a fluorescence staining equivalent to H&E staining is important. Eosin labels cytosol in red and exhibits red fluorescence via the conventional rhodamine filter setup of a fluorescence microscope.…”