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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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Munger, J. S., Huang, X., Kawakatsu, H., Griffiths, M. J. D., Dalton, S. L., Wu, J., Pittet, J.-F., Kaminski, N., Garat, C., Matthay, M. A., et al. (1999) · Cell · doi:10.1016/s0092-8674(00)80545-0 · Cited by 2,076
Self-citationYu, Q., & Stamenkovic, I. (2000) · PubMed · Cited by 1,952
Yu, Q., & Stamenkovic, I. (2000) · Genes & Development · doi:10.1101/gad.14.2.163 · Cited by 1,754
Making sense of latent TGFβ activation
Annes, J. P., Munger, J. S., & Rifkin, D. B. (2002) · Journal of Cell Science · doi:10.1242/jcs.00229 · Cited by 1,624
Self-citationA simplified method for the analysis of hydroxyproline in biological tissues
Reddy, G. K., & Enwemeka, C. S. (1996) · Clinical Biochemistry · doi:10.1016/0009-9120(96)00003-6 · Cited by 1,299
Thrombospondin-1 Is a Major Activator of TGF-β1 In Vivo
Crawford, S. E., Stellmach, V. M., Murphy-Ullrich, J. E., Ribeiro, S. M. F., Lawler, J., Hynes, R. O., Boivin, G. P., & Bouck, N. (1998) · Cell · doi:10.1016/s0092-8674(00)81460-9 · Cited by 1,176
Sime, P. J., Xing, Z., Graham, F. L., Csaky, K. G., & Gauldie, J. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119590 · Cited by 1,050
Datto, M., Li, Y., Panus, J. F., Howe, D. J., Xiong, Y., & Wang, X. F. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.12.5545 · Cited by 945
The integrin αvβ8 mediates epithelial homeostasis through MT1-MMP–dependent activation of TGF-β1
Mu, D., Cambier, S., Fjellbirkeland, L., Baron, J. L., Munger, J. S., Kawakatsu, H., Sheppard, D., Broaddus, V. C., & Nishimura, S. L. (2002) · The Journal of Cell Biology · doi:10.1083/jcb.200109100 · Cited by 729
Self-citationA perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis
Rubin, P., Johnston, C. J., Williams, J. P., McDonald, S. A., & Finkelstein, J. N. (1995) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/0360-3016(95)00095-g · Cited by 648
Smad3 as a mediator of the fibrotic response
Flanders, K. C. (2004) · International Journal of Experimental Pathology · doi:10.1111/j.0959-9673.2004.00377.x · Cited by 610
Activation of latent TGF-β by thrombospondin-1: mechanisms and physiology
Murphy-Ullrich, J. E., & Poczatek, M. H. (2000) · Cytokine & Growth Factor Reviews · doi:10.1016/s1359-6101(99)00029-5 · Cited by 590
Branton, M., & Kopp, J. (1999) · Microbes and Infection · doi:10.1016/s1286-4579(99)00250-6 · Cited by 574
Loss of integrin αvβ6-mediated TGF-β activation causes Mmp12-dependent emphysema
Morris, D. G., Huang, X., Kaminski, N., Wang, Y., Shapiro, S. D., Dolganov, G., Glick, A. B., & Sheppard, D. (2003) · Nature · doi:10.1038/nature01413 · Cited by 500
Integrin αVβ6-mediated activation of latent TGF-β requires the latent TGF-β binding protein-1
Annes, J. P., Chen, Y., Munger, J. S., & Rifkin, D. B. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200312172 · Cited by 500
Self-citationTGF-β is a critical mediator of acute lung injury
Pittet, J., Griffiths, M., Geiser, T., Kaminski, N., Dalton, S. L., Huang, X., Brown, L. A. S., Gotwals, P. J., Koteliansky, V., Matthay, M. A., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci11963 · Cited by 482
Yang, Y.-A., Dukhanina, O. I., Tang, B., Mamura, M., Letterio, J. J., MacGregor, J., Patel, S. C., Khozin, S., Liu, Z.-Y., Green, J. D., et al. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15333 · Cited by 411
Yang, Y.-A., Dukhanina, O., Tang, B., Mamura, M., Letterio, J. J., MacGregor, J., Patel, S. C., Khozin, S., Liu, Z.-Y., Green, J., et al. (2002) · Journal of Clinical Investigation · doi:10.1172/jci200215333 · Cited by 404
Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis
Abdollahi, A., Li, M., Ping, G., Plathow, C., Domhan, S., Kiessling, F. M., Lee, L. B., McMahon, G., Gröne, H., Lipson, K. E., et al. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20041393 · Cited by 390
Latent TGF-β Binding Proteins: Extracellular Matrix Association and Roles in TGF-β Activation
Hyytiäinen, M. M., Penttinen, C., & Keski‐Oja, J. (2004) · Critical Reviews in Clinical Laboratory Sciences · doi:10.1080/10408360490460933 · Cited by 351
Absence of integrin-mediated TGFβ1 activation in vivo recapitulates the phenotype of TGFβ1-null mice
Yang, Z., Mu, Z., Dabovic, B., Jurukovski, V., Yu, D., Sung, J. J., Xiong, X., & Munger, J. S. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200611044 · Cited by 330
Self-citationJenkins, G. R. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27183 · Cited by 322
Huang, X., Wu, J. F., Cass, D. L., Erle, D. J., Corry, D. B., Young, S. G., Farese, R. V., & Sheppard, D. (1996) · The Journal of Cell Biology · doi:10.1083/jcb.133.4.921 · Cited by 316
Jobling, M. F., Mott, J. D., Finnegan, M. T., Jurukovski, V., Erickson, A. C., Walian, P. J., Taylor, S. E., Ledbetter, S., Lawrence, C. M., Rifkin, D. B., et al. (2006) · Radiation Research · doi:10.1667/rr0695.1 · Cited by 300
Kojima, S., Nara, K., & Rifkin, D. B. (1993) · The Journal of Cell Biology · doi:10.1083/jcb.121.2.439 · Cited by 283
Disorders of lung matrix remodeling
Chapman, H. A. (2004) · Journal of Clinical Investigation · doi:10.1172/jci20729 · Cited by 225
Ma, L., Yang, H., Gaspert, A., Carlesso, G., Barty, M. M., Davidson, J. M., Sheppard, D., & Fogo, A. B. (2003) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63486-4 · Cited by 214
Radiation-induced hypoxia may perpetuate late normal tissue injury
Vujašković, Ž., Anscher, M. S., Feng, Q.-F., Rabbani, Z. N., Amin, K., Samulski, T. V., Dewhirst, M. W., & Haroon, Z. A. (2001) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/s0360-3016(01)01593-0 · Cited by 202
αvβ6 Integrin Regulates Renal Fibrosis and Inflammation in Alport Mouse
Hahm, K., Lukashev, M. E., Luo, Y., Yang, W. J., Dolinski, B. M., Weinreb, P. H., Simon, K. J., Chun Wang, L., Leone, D. R., Lobb, R. R., et al. (2007) · The American Journal of Pathology · doi:10.2353/ajpath.2007.060158 · Cited by 190
Self-citationKong, F., Haken, R. K. T., Eisbruch, A., & Lawrence, T. S. (2005) · Seminars in Oncology · doi:10.1053/j.seminoncol.2005.03.009 · Cited by 175
The integrin αVβ6 binds and activates latent TGFβ3
Annes, J. P., Rifkin, D. B., & Munger, J. S. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)03280-x · Cited by 173
Self-citationFunction-blocking Integrin αvβ6 Monoclonal Antibodies
Weinreb, P. H., Simon, K. J., Rayhorn, P., Yang, W. J., Leone, D. R., Dolinski, B. M., Pearse, B. R., Yokota, Y., Kawakatsu, H., Atakilit, A., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m312103200 · Cited by 149
Self-citationWu, D. T., Bitzer, M., Ju, W., Mundel, P. H., & Diaeresisttinger, E. P. B. (2005) · Journal of the American Society of Nephrology · doi:10.1681/asn.2004121055 · Cited by 131
Sharplin, J., & Franko, A. J. (1989) · Radiation Research · doi:10.2307/3577364 · Cited by 131
Anscher, M. S., Thrasher, B. A., Rabbani, Z. N., Teicher, B. A., & Vujašković, Ž. (2006) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2006.02.051 · Cited by 121
Identification of Novel p53 Target Genes in Ionizing Radiation Response
Jen, K., & Cheung, V. G. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-1039 · Cited by 119
Sharplin, J., & Franko, A. J. (1989) · Radiation Research · doi:10.2307/3577363 · Cited by 109
Overexpression of extracellular superoxide dismutase reduces acute radiation induced lung toxicity
Rabbani, Z. N., Anscher, M. S., Folz, R. J., Archer, E., Huang, H., Chen, L., Golson, M. L., Samulski, T. V., Dewhirst, M. W., & Vujašković, Ž. (2005) · BMC Cancer · doi:10.1186/1471-2407-5-59 · Cited by 99
All- trans -Retinoic Acid Prevents Radiation- or Bleomycin-induced Pulmonary Fibrosis
Tabata, C., Kadokawa, Y., Tabata, R., Takahashi, M., Okoshi, K., Sakai, Y., Mishima, M., & Kubo, H. (2006) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200606-862oc · Cited by 99
Differential Regulation of Airway Epithelial Integrins by Growth Factors
Wang, A., Yokosaki, Y., Ferrando, R. E., Balmes, J. R., & Sheppard, D. (1996) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/ajrcmb.15.5.8918373 · Cited by 98
Radiation effects on the respiratory system
Hill, R. P. (2005) · British Journal of Radiology · doi:10.1259/bjr/34124307 · Cited by 88
Adawi, A., Zhang, Y., Baggs, R. B., Rubin, P., Williams, J. P., Finkelstein, J. N., & Phipps, R. P. (1998) · Clinical Immunology and Immunopathology · doi:10.1006/clin.1998.4606 · Cited by 83
Haston, C. K., Zhou, X., Gumbiner-Russo, L., Irani, R. A., Dejournett, R. E., Gu, X., Weil, M. M., Amos, C. I., & Travis, E. L. (2002) · PubMed · Cited by 80
Disorders of lung matrix remodeling
Chapman, H. A. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200420729 · Cited by 67
Zhou, T., Chou, J. W., Simpson, D. A., Zhou, Y., Mullen, T. E., Medeiros, M., Bushel, P. R., Paules, R. S., Yang, X., Hurban, P., et al. (2005) · Environmental Health Perspectives · doi:10.1289/ehp.8026 · Cited by 63
Haiping, Z., Takayama, K., Uchino, J., Harada, A., Adachi, Y., Kura, S., Caicun, Z., Tsuzuki, T., & Nakanishi, Y. (2006) · Cancer Gene Therapy · doi:10.1038/sj.cgt.7700959 · Cited by 34
Plasma TGFβ level in rats after hemithoracic irradiation
Vujašković, Ž., Down, J. D., van Waarde, M. A. W. H., van Assen, A. J., Szabó, B. G., & Konings, A. W. T. (1997) · Radiotherapy and Oncology · doi:10.1016/s0167-8140(97)00075-3 · Cited by 18
Research works printed but not linked: 4
- 2002, Cancer Res, 62, 3782
- 1989, Radiat Res, 119, 1
- 2005, Semin Oncol, 32, S42
- 2005, BJR Suppl, 27, 75
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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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