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Updated: May 23, 2026
A Mouse Model of Pulmonary Fibrosis Induced by Nasal Bleomycin Nebulization
Published on: January 20, 2023
A neutrophil elastase inhibitor prevents bleomycin-induced pulmonary fibrosis in mice
Akihiro Takemasa1, Yoshiki Ishii, Takeshi Fukuda
1Dokkyo Medical University School of Medicine, Tochigi, Japan.
Abstract:
Neutrophil elastase plays pivotal roles in the pathogenesis of pulmonary fibrosis. The neutrophil elastase inhibitor, sivelestat, could alleviate pulmonary fibrosis; however, the antifibrotic mechanisms have not yet been clarified. We examined the antifibrotic mechanisms, mainly focusing on a key fibrotic cytokine, transforming growth factor (TGF)-β1, in this study. To elucidate the antifibrotic mechanisms of sivelestat, we examined a murine model of bleomycin-induced early-stage pulmonary fibrosis. After intratracheal instillation of bleomycin, sivelestat was administered intraperitoneally once a day for 7 or 14 days. Bronchoalveolar lavage fluid and lung samples were examined on day 7 or day 14 after bleomycin instillation. In the bleomycin-induced early-stage pulmonary fibrosis model, the neutrophil elastase level was increased in the lungs. Sivelestat significantly inhibited the increase in lung collagen content, fibrotic changes, the numbers of total cells (including macrophages, neutrophils and lymphocytes), the levels of the active form of TGF-β1 and phospho-Smad2 in bleomycin-induced early-stage pulmonary fibrosis. The total TGF-β1 levels and relative changes of TGF-β1 mRNA expression, however, were not decreased significantly by sivelestat. These results suggest that sivelestat alleviated bleomycin-induced pulmonary fibrosis via inhibition of both TGF-β activation and inflammatory cell recruitment in the lung.
Insights
Sivelestat, a neutrophil elastase inhibitor, reduces pulmonary fibrosis by inhibiting transforming growth factor-beta 1 (TGF-β1) activation and inflammatory cell infiltration in the lungs.
Area of Science:
- Pulmonary Medicine
- Fibrosis Research
- Pharmacology
Background:
- Neutrophil elastase is implicated in pulmonary fibrosis pathogenesis.
- Sivelestat is a neutrophil elastase inhibitor with potential antifibrotic effects.
- The precise antifibrotic mechanisms of sivelestat, particularly concerning TGF-β1, require elucidation.
Purpose of the Study:
- To investigate the antifibrotic mechanisms of sivelestat in early-stage pulmonary fibrosis.
- To determine the effect of sivelestat on transforming growth factor-beta 1 (TGF-β1) signaling.
- To analyze the impact of sivelestat on inflammatory cell recruitment in a murine model.
Main Methods:
- A murine model of bleomycin-induced pulmonary fibrosis was utilized.
- Sivelestat was administered daily for 7 or 14 days post-bleomycin instillation.
- Analysis included lung collagen content, fibrotic changes, cell counts in bronchoalveolar lavage fluid, and TGF-β1/phospho-Smad2 levels.
Main Results:
- Sivelestat significantly reduced lung collagen content and fibrotic changes.
- Sivelestat inhibited the increase in total cells, including macrophages, neutrophils, and lymphocytes.
- Sivelestat suppressed the levels of active TGF-β1 and phospho-Smad2, but not total TGF-β1 or its mRNA expression.
Conclusions:
- Sivelestat alleviates bleomycin-induced pulmonary fibrosis.
- The antifibrotic effects are attributed to the inhibition of TGF-β1 activation.
- Sivelestat also exerts antifibrotic effects by reducing inflammatory cell recruitment in the lungs.
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