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Updated: Apr 21, 2026
Refined Murine Model of Idiopathic Pulmonary Fibrosis
Published on: June 17, 2025
Fibrosis, vascular activation, and immune abnormalities resembling systemic sclerosis in bleomycin-treated
Takashi Taniguchi1, Yoshihide Asano, Kaname Akamata
1University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Objective:
Fli-1, a potential predisposing factor for systemic sclerosis (SSc), is constitutively down-regulated in the lesional skin of patients with SSc by an epigenetic mechanism. To investigate the impact of Fli-1 deficiency on the induction of an SSc phenotype in various cell types, we generated bleomycin-induced skin fibrosis in Fli-1(+/-) mice and investigated the molecular mechanisms underlying its phenotypic alterations.
Methods:
Messenger RNA (mRNA) levels and protein expression of target molecules were examined by quantitative reverse transcription-polymerase chain reaction and immunostaining. Transforming growth factor β (TGFβ) bioassay was used to evaluate the activation of latent TGFβ. The binding of Fli-1 to the target gene promoters was assessed with chromatin immunoprecipitation.
Results:
Bleomycin induced more severe dermal fibrosis in Fli-1(+/-) mice than in wild-type mice. Fli-1 haploinsufficiency activated dermal fibroblasts via the up-regulation of αvβ3 and αvβ5 integrins and activation of latent TGFβ. Dermal fibrosis in Fli-1(+/-) mice was also attributable to endothelial-to-mesenchymal transition, which is directly induced by Fli-1 deficiency and amplified by bleomycin. Th2/Th17-skewed inflammation and increased infiltration of mast cells and macrophages were seen, partly due to the altered expression of cell adhesion molecules in endothelial cells as well as the induction of the skin chemokines. Fli-1(+/-) mouse macrophages preferentially differentiated into an M2 phenotype upon stimulation with interleukin-4 (IL-4) or IL-13.
Conclusion:
Our findings provide strong evidence for the fundamental role of Fli-1 deficiency in inducing SSc-like phenotypic alterations in dermal fibroblasts, endothelial cells, and macrophages in a manner consistent with human disease.
Insights
Fli-1 deficiency exacerbates skin fibrosis and induces systemic sclerosis (SSc)-like changes in mice. This study reveals Fli-1
Area of Science:
- Molecular biology
- Immunology
- Dermatology
Background:
- Fli-1 is epigenetically downregulated in systemic sclerosis (SSc) skin.
- Investigating Fli-1's role in SSc pathogenesis is crucial.
Purpose of the Study:
- To examine the impact of Fli-1 deficiency on SSc phenotype induction.
- To elucidate molecular mechanisms in bleomycin-induced skin fibrosis.
Main Methods:
- Generated bleomycin-induced skin fibrosis in Fli-1(+/-) mice.
- Assessed mRNA and protein expression via qPCR and immunostaining.
- Evaluated TGFβ activation and Fli-1 binding using bioassays and ChIP.
Main Results:
- Fli-1 haploinsufficiency worsened dermal fibrosis and activated fibroblasts.
- Endothelial-to-mesenchymal transition and Th2/Th17 inflammation were observed.
- Macrophages in Fli-1(+/-) mice showed M2 polarization.
Conclusions:
- Fli-1 deficiency plays a fundamental role in inducing SSc-like phenotypes.
- Altered fibroblasts, endothelial cells, and macrophages contribute to SSc.
- Findings align with human SSc disease characteristics.
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