Related Experiment Video
Updated: Dec 27, 2025
Oropharyngeal Administration of Bleomycin in the Murine Model of Pulmonary Fibrosis
Published on: May 9, 2025
Antifibrogenic effects of C-C chemokine receptor type 2 antagonist in a bleomycin-induced scleroderma model
Masato Ishikawa1, Toshiyuki Yamamoto1
1Department of Dermatology, Fukushima Medical University, Fukushima, Japan.
Abstract:
There have been several studies on the role of the monocyte chemotactic protein-1/C-C chemokine receptor type 2 (CCR2) signalling pathway in fibrotic diseases, which identified the blockade of this pathway as a potential therapeutic target for treating fibrosis. We examined the efficacy of CCR2 antagonist (RS-504393) in a mouse model of scleroderma induced by bleomycin. RS-504393 was administered via intradermal injection 6 hours prior to bleomycin injection, in the same sites. Histopathological examination showed that RS-504393 treatment suppressed dermal fibrosis and decreased dermal thickness. The numbers of mast cells and myofibroblasts in the skin of RS-504393-treated mice were significantly lower compared with those in PBS-treated mice. Moreover, the amount of collagen in the skin of RS-504393-treated mice was significantly lower compared with that in the PBS-treated mice. Additionally, mRNA levels of TGF-β1 and collagen I alpha 1 in sclerotic skin were significantly decreased by RS-504393, and semiquantitative histopathological scoring of the lungs showed inhibition of fibrosis in RS-504393-treated mice. The amount of collagen in the lung of the RS-504393-treated mice was lower compared with that in the PBS-treated mice. These data suggest that CCR2 antagonist RS-504393 may be a therapeutic agent for human scleroderma.
Insights
A CCR2 antagonist (RS-504393) effectively reduced fibrosis in a mouse model of scleroderma. This treatment suppressed dermal thickness, collagen levels, and key fibrotic markers, suggesting potential for treating human scleroderma.
Area of Science:
- Immunology
- Dermatology
- Pathology
Background:
- The monocyte chemotactic protein-1/C-C chemokine receptor type 2 (CCR2) signaling pathway is implicated in fibrotic diseases.
- Blocking this pathway presents a potential therapeutic strategy for fibrosis.
Purpose of the Study:
- To evaluate the efficacy of the CCR2 antagonist RS-504393 in a bleomycin-induced mouse model of scleroderma.
- To assess the impact of RS-504393 on dermal fibrosis, cellular infiltration, collagen deposition, and fibrotic gene expression.
Main Methods:
- Mice were treated with RS-504393 via intradermal injection prior to bleomycin administration.
- Histopathological examinations assessed dermal thickness, mast cell and myofibroblast counts, and collagen levels.
- mRNA levels of TGF-β1 and collagen I alpha 1 were quantified.
- Lung fibrosis was evaluated using semiquantitative histopathological scoring and collagen content analysis.
Main Results:
- RS-504393 treatment significantly suppressed dermal fibrosis and reduced skin thickness.
- A significant decrease in mast cells and myofibroblasts was observed in RS-504393-treated mice.
- RS-504393 treatment led to significantly lower collagen levels in both skin and lungs.
- mRNA levels of TGF-β1 and collagen I alpha 1 were significantly reduced in sclerotic skin.
Conclusions:
- The CCR2 antagonist RS-504393 demonstrates significant anti-fibrotic effects in a mouse model of scleroderma.
- RS-504393 effectively inhibits key cellular and molecular components of fibrosis, including collagen deposition and inflammatory cell infiltration.
- These findings suggest that RS-504393 holds promise as a therapeutic agent for human scleroderma.
