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Inhibition of Integrin αvβ6, an Activator of Latent Transforming Growth Factor-β, Prevents Radiation-induced Lung Fibrosis
Open accessAbstract
Rationale: In experimental models, lung fibrosis is dependent on transforming growth factor (TGF)-β signaling. TGF-β is secreted in a latent complex with its propeptide, and TGF-β activators release TGF-β from this complex. Because the integrin αvβ6 is a major TGF-β activator in the lung, inhibition of αvβ6-mediated TGF-β activation is a logical strategy to treat lung fibrosis. Objectives: To determine, by genetic and pharmacologic approaches, whether murine radiation-induced lung fibrosis is dependent on αvβ6. Methods: Wild-type mice, αvβ6-deficient (Itgb6−/−) mice, and mice heterozygous for a Tgfb1 mutation that eliminates integrin-mediated activation (Tgfb1+/RGE) were exposed to 14 Gy thoracic radiation. Some mice were treated with an anti-αvβ6 monoclonal antibody or a soluble TGF-β receptor fusion protein. αvβ6 expression was determined by immunohistochemistry. Fibrosis, inflammation, and gene expression patterns were assessed 20–32 weeks postirradiation. Measurements and Main Results: β6 Integrin expression increased within the alveolar epithelium 18 weeks postirradiation, just before onset of fibrosis. Itgb6−/− mice were completely protected from fibrosis, but not from late radiation-induced mortality. Anti-αvβ6 therapy (1–10 mg/kg/wk) prevented fibrosis, but only higher doses (6–10 mg/kg/wk) caused lung inflammation similar to that in Itgb6−/− mice. Tgfb1-haploinsufficient mice were also protected from fibrosis. Conclusions: αvβ6-Mediated TGF-β activation is required for radiation-induced lung fibrosis. Together with previous data, our results demonstrate a robust requirement for αvβ6 in distinct fibrosis models. Inhibition of αvβ6-mediated TGF-β activation is a promising new approach for antifibrosis therapy.
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“The pro-inflammatory cytokine IL-17A was identified as a key inducer of fibrosis in several different organ systems, including the lung, liver, kidney, heart, and skin109–114”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [113]
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“In addition, a monoclonal antibody targeting integrin αVβ6 has been shown to protect mice from radiation induced fibrosis (203).”
From Unraveling SSc Pathophysiology; The Myofibroblast (2018) · cites this paper as [203]
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Metadata
- Authors
- Puthawala, K., Hadjiangelis, N., Jacoby, S. C., Bayongan, E., Zhao, Z., Yang, Z., Devitt, M. L., Horan, G. S., Weinreb, P. H., Lukashev, M. E., Violette, S. M., Grant, K. S., Colarossi, C., Formenti, S. C., & Munger, J. S.
- Affiliations
- York University (US)
- Departments of Medicine
- Cell Biology, and
- New York University (US)
- Biogen (United States) (US)
- Corresponding author
- Munger, John S.
- ORCID
- Venue
- American Journal of Respiratory and Critical Care Medicine
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-01-01
- Volume
- 177
- Issue
- 1
- Pages
- 82-90
- ISSN
- 1073-449X (ISSN-L)
- 1535-4970
- PMC
- PMC2176115
- OpenAlex
- W2155139007
- Cited by
- 272
- References
- 45
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 13 · 2023: 12 · 2022: 15 · 2021: 15 · 2020: 14 · 2019: 7 · 2018: 16 · 2017: 15 · 2016: 16 · 2015: 13 · 2014: 30 · 2013: 16 · 2012: 18
- FWCI
- 11.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Respiratory and Critical Care Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Biogen
- National Institutes of Health (5r01hl077526-04)
- National Heart, Lung, and Blood Institute (HL063786, HL077526, R01HL063786)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- radiation-induced pulmonary fibrosis, TGF-beta activation, radiation-induced mortality, lung inflammation, antifibrotic therapy, alveolar epithelium
- MeSH terms
- Animals, Antibodies, Monoclonal, Antigens, Neoplasm, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Gene Expression Regulation, Haplotypes, Heterozygote, Mice, Inbred C57BL, Pulmonary Alveoli, Pulmonary Fibrosis, Signal Transduction, Integrins, Transforming Growth Factor beta, Radiation Pneumonitis, Mice, Knockout, Mice, Transforming Growth Factor beta1
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