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A neutrophil elastase inhibitor prevents bleomycin-induced pulmonary fibrosis in mice
Open accessAbstract
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.
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“Furthermore, pharmacological inhibition of neutrophil elastase by sivelestat protects mice from bleomycin induced lung fibrosis (167), demonstrating that at least in lungs, neutrophil elastase is pro-fibrotic.”
From Unraveling SSc Pathophysiology; The Myofibroblast (2018) · cites this paper as [167]
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Metadata
- Authors
- Takemasa, A., Ishii, Y., & Fukuda, T.
- Affiliations
- Dokkyo Medical University (JP)
- Dokkyo University (JP)
- Venue
- European Respiratory Journal
- Publisher
- European Respiratory Society (ERS)
- Published
- 2012-03-22
- Volume
- 40
- Issue
- 6
- Pages
- 1475-1482
- ISSN
- 0903-1936 (ISSN-L)
- 1399-3003
- OpenAlex
- W2137335759
- Cited by
- 140
- References
- 28
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 13 · 2023: 10 · 2022: 14 · 2021: 13 · 2020: 11 · 2019: 11 · 2018: 11 · 2017: 7 · 2016: 7 · 2015: 7 · 2014: 8 · 2013: 3 · 2012: 3
- FWCI
- 5.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Respiratory Journal (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Chronic Obstructive Pulmonary Disease (COPD) Research
- Keywords
- neutrophil elastase, sivelestat, pulmonary fibrosis, bleomycin-induced lung injury, TGF-β1 activation, Smad2 phosphorylation, lung inflammation, antifibrotic mechanism, collagen deposition, neutrophil elastase inhibitor
- MeSH terms
- Animals, Bleomycin, Collagen, Fibrosis, Glycine, Inflammation, Lung, Male, Mice, Inbred C57BL, Phosphorylation, Pulmonary Fibrosis, Sulfonamides, Time Factors, Serine Proteinase Inhibitors, Bronchoalveolar Lavage, Leukocyte Elastase, Mice, Smad2 Protein, Transforming Growth Factor beta1
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