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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
IL-17A is a key inducer of fibrosis in several organ systems, including lung, liver, kidney, heart, and skin.
“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]
A monoclonal antibody targeting integrin αVβ6 protects mice from radiation-induced fibrosis.
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
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 · see citing works
Self-citationYu, Q., & Stamenkovic, I. (2000) · PubMed · Cited by 1,952 · see citing works
Yu, Q., & Stamenkovic, I. (2000) · Genes & Development · doi:10.1101/gad.14.2.163 · Cited by 1,754 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 649 · see citing works
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 · see citing works
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 · see citing works
Branton, M., & Kopp, J. (1999) · Microbes and Infection · doi:10.1016/s1286-4579(99)00250-6 · Cited by 574 · see citing works
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 · see citing works
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 · see citing works
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 487 · see citing works
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 404 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 321 · see citing works
Self-citationHuang, 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 · see citing works
Jenkins, G. R. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27183 · Cited by 314 · see citing works
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 · see citing works
Kojima, S., Nara, K., & Rifkin, D. B. (1993) · The Journal of Cell Biology · doi:10.1083/jcb.121.2.439 · Cited by 283 · see citing works
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 · see citing works
Disorders of lung matrix remodeling
Chapman, H. A. (2004) · Journal of Clinical Investigation · doi:10.1172/jci20729 · Cited by 213 · see citing works
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 199 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Self-citationSharplin, J., & Franko, A. J. (1989) · Radiation Research · doi:10.2307/3577364 · Cited by 131 · see citing works
Wu, 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 130 · see citing works
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 · see citing works
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 · see citing works
Sharplin, J., & Franko, A. J. (1989) · Radiation Research · doi:10.2307/3577363 · Cited by 109 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Radiation effects on the respiratory system
Hill, R. P. (2005) · British Journal of Radiology · doi:10.1259/bjr/34124307 · Cited by 88 · see citing works
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 · see citing works
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 · see citing works
Disorders of lung matrix remodeling
Chapman, H. A. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200420729 · Cited by 67 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The Tumour Microenvironment after Radiotherapy: Mechanisms of Resistance and Recurrence
Barker, H. E., Paget, J. T. E., Khan, A. A., & Harrington, K. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc3958 · Cited by 2,144 · see citing works
Fibrosis: from mechanisms to medicines
Henderson, N. C., Rieder, F., & Wynn, T. A. (2020) · Nature · doi:10.1038/s41586-020-2938-9 · Cited by 1,868 · see citing works
Targeting integrin pathways: mechanisms and advances in therapy
Pang, X., He, X., Qiu, Z., Zhang, H., Xie, R., Liu, Z., Gu, Y., Zhao, N., Xiang, Q., & Cui, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01259-6 · Cited by 1,275 · see citing works
Targeting the tumour stroma to improve cancer therapy
Valkenburg, K. C., de Groot, A. E., & Pienta, K. J. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-018-0007-1 · Cited by 1,084 · see citing works
Fibroblasts and myofibroblasts in wound healing
Desmouliere, A., Darby, I. A., Laverdet, B., & Bonté, F. (2014) · Clinical, Cosmetic and Investigational Dermatology · doi:10.2147/ccid.s50046 · Cited by 1,039 · see citing works
Pathobiology of liver fibrosis: a translational success story
Lee, Y. A., Wallace, M. C., & Friedman, S. L. (2015) · Gut · doi:10.1136/gutjnl-2014-306842 · Cited by 894 · see citing works
TGF-β1 Signaling and Tissue Fibrosis
Kim, K. K., Sheppard, D., & Chapman, H. A. (2018) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a022293 · Cited by 800 · see citing works
The Impact of TGF-β on Lung Fibrosis: From Targeting to Biomarkers
Fernandez, I. E., & Eickelberg, O. (2012) · Proceedings of the American Thoracic Society · doi:10.1513/pats.201203-023aw · Cited by 682 · see citing works
Radiation-induced fibrosis: mechanisms and implications for therapy
Straub, J. M., New, J., Hamilton, C. D., Lominska, C., Shnayder, Y., & Thomas, S. M. (2015) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-015-1974-6 · Cited by 677 · see citing works
Integrin–TGF‐β crosstalk in fibrosis, cancer and wound healing
Margadant, C., & Sonnenberg, A. (2010) · The EMBO Reports · doi:10.1038/embor.2009.276 · Cited by 653 · see citing works
Evasion of apoptosis by myofibroblasts: a hallmark of fibrotic diseases
Hinz, B., & Lagares, D. (2019) · Nature Reviews Rheumatology · doi:10.1038/s41584-019-0324-5 · Cited by 616 · see citing works
Developmental pathways in the pathogenesis of lung fibrosis
Chanda, D., Otoupalova, E., Smith, S. R., Volckaert, T., Langhe, S. D., & Thannickal, V. J. (2018) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2018.08.004 · Cited by 513 · see citing works
Partial Inhibition of Integrin αvβ6 Prevents Pulmonary Fibrosis without Exacerbating Inflammation
Horan, G. S., Wood, S., Ona, V., Li, D. J., Lukashev, M. E., Weinreb, P. H., Simon, K. J., Hahm, K., Allaire, N. E., Rinaldi, N. J., et al. (2008) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200706-805oc · Cited by 420 · see citing works
Self-citationMolecular and cellular mechanisms of pulmonary fibrosis
Todd, N. W., Luzina, I. G., & Atamas, S. P. (2012) · Fibrogenesis & Tissue Repair · doi:10.1186/1755-1536-5-11 · Cited by 418 · see citing works
Regulation of the Bioavailability of TGF-β and TGF-β-Related Proteins
Robertson, I. B., & Rifkin, D. B. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a021907 · Cited by 403 · see citing works
Role of Transforming Growth Factor–β in Airway Remodeling in Asthma
Halwani, R., Al‐Muhsen, S., Al-Jahdali, H. H., & Hamid, Q. A. (2010) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2010-0027tr · Cited by 404 · see citing works
Emerging evidence for adapting radiotherapy to immunotherapy
Galluzzi, L., Aryankalayil, M. J., Coleman, C. N., & Formenti, S. C. (2023) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-023-00782-x · Cited by 381 · see citing works
Self-citationCross Talk among TGF- Signaling Pathways, Integrins, and the Extracellular Matrix
Munger, J. S., & Sheppard, D. (2011) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a005017 · Cited by 372 · see citing works
Self-citationThe role of proteases in transforming growth factor-β activation
Jenkins, G. R. (2008) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2007.11.026 · Cited by 358 · see citing works
Transforming growth factor β—at the centre of systemic sclerosis
Lafyatis, R. (2014) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2014.137 · Cited by 334 · see citing works
TGF ‐β as a driver of fibrosis: physiological roles and therapeutic opportunities
Budi, E. H., Schaub, J. R., Decaris, M. L., Turner, S., & Derynck, R. (2021) · The Journal of Pathology · doi:10.1002/path.5680 · Cited by 300 · see citing works
Transforming growth factor β as a therapeutic target in systemic sclerosis
Varga, J., & Pasche, B. (2009) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2009.26 · Cited by 295 · see citing works
Fibrosis of two: Epithelial cell-fibroblast interactions in pulmonary fibrosis
Sakai, N., & Tager, A. M. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.03.001 · Cited by 286 · see citing works
Radiation Pulmonary Toxicity: From Mechanisms to Management
Graves, P. R., Siddiqui, F., Anscher, M. S., & Movsas, B. (2010) · Seminars in Radiation Oncology · doi:10.1016/j.semradonc.2010.01.010 · Cited by 281 · see citing works
The pathogenesis of idiopathic pulmonary fibrosis
Coward, W. R., Saini, G., & Jenkins, G. R. (2010) · Therapeutic Advances in Respiratory Disease · doi:10.1177/1753465810379801 · Cited by 271 · see citing works
TGF-β Activation and Lung Fibrosis
Tatler, A. L., & Jenkins, G. R. (2012) · Proceedings of the American Thoracic Society · doi:10.1513/pats.201201-003aw · Cited by 264 · see citing works
Immunomodulation by radiotherapy in tumour control and normal tissue toxicity
Cytlak, U., Dyer, D. P., Honeychurch, J., Williams, K. J., Travis, M. A., & Illidge, T. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-021-00568-1 · Cited by 262 · see citing works
Transforming Growth Factor-β Signaling in Fibrotic Diseases and Cancer-Associated Fibroblasts
Shi, X., Young, C. D., Zhou, H., & Wang, X. (2020) · Biomolecules · doi:10.3390/biom10121666 · Cited by 256 · see citing works
Integrins as Therapeutic Targets: Successes and Cancers
Raab-Westphal, S., Marshall, J. F., & Goodman, S. L. (2017) · Cancers · doi:10.3390/cancers9090110 · Cited by 242 · see citing works
Bouquet, F., Pal, A., Pilones, K. A., Demaria, S., Hann, B. C., Akhurst, R. J., Babb, J. S., Lonning, S. M., DeWyngaert, J. K., Formenti, S. C., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-0544 · Cited by 240 · see citing works
Self-citationAhluwalia, N., Shea, B. S., & Tager, A. M. (2014) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201403-0509pp · Cited by 233 · see citing works
Oxidative stress, extracellular matrix targets, and idiopathic pulmonary fibrosis
Kliment, C. R., & Oury, T. D. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.04.036 · Cited by 233 · see citing works
Knipe, R. S., Tager, A. M., & Liao, J. K. (2015) · Pharmacological Reviews · doi:10.1124/pr.114.009381 · Cited by 233 · see citing works
Narrative Review: Fibrotic Diseases: Cellular and Molecular Mechanisms and Novel Therapies
Rosenbloom, J., Castro, S. V., & Jimenez, S. A. (2010) · Annals of Internal Medicine · doi:10.7326/0003-4819-152-3-201002020-00007 · Cited by 225 · see citing works
Aluwihare, P., Mu, Z., Zhao, Z., Yu, D., Weinreb, P. H., Horan, G. S. B., Violette, S. M., & Munger, J. S. (2008) · Journal of Cell Science · doi:10.1242/jcs.035246 · Cited by 224 · see citing works
Self-citationIntegrin-mediated regulation of TGFβ in fibrosis
Henderson, N. C., & Sheppard, D. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2012.10.005 · Cited by 209 · see citing works
Schnittert, J., Bansal, R., Storm, G., & Prakash, J. (2018) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.01.020 · Cited by 186 · see citing works
Current concepts in clinical radiation oncology
Orth, M., Lauber, K., Niyazi, M., Friedl, A. A., Li, M., Maihöfer, C., Schüttrumpf, L., Ernst, A., Niemoeller, O. M., & Belka, C. (2013) · Radiation and Environmental Biophysics · doi:10.1007/s00411-013-0497-2 · Cited by 177 · see citing works
Matrix Stiffness: the Conductor of Organ Fibrosis
Santos, A., & Lagares, D. (2018) · Current Rheumatology Reports · doi:10.1007/s11926-018-0710-z · Cited by 179 · see citing works
Désogère, P. A., Tapias, L. F., Hariri, L. P., Rotile, N. J., Rietz, T. A., Probst, C. K., Blasi, F., Day, H., Mino-Kenudson, M. A., Weinreb, P., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf4696 · Cited by 175 · see citing works
Self-citationStrategies for anti-fibrotic therapies
Rosenbloom, J., Mendoza, F. A., & Jiménez, S. A. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2012.12.007 · Cited by 171 · see citing works
Unraveling SSc Pathophysiology; The Myofibroblast
van Caam, A., Vonk, M., van den Hoogen, F., van Lent, P., & van der Kraan, P. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02452 · Cited by 153 · see citing works
Nishimura, S. L. (2009) · American Journal Of Pathology · doi:10.2353/ajpath.2009.090393 · Cited by 155 · see citing works
Effects of CTGF Blockade on Attenuation and Reversal of Radiation-Induced Pulmonary Fibrosis
Bickelhaupt, S., Erbel, C., Timke, C., Wirkner, U., Dadrich, M., Flechsig, P., Tietz, A., Pföhler, J., Groß, W., Peschke, P., et al. (2016) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djw339 · Cited by 151 · see citing works
Combination therapy: the future of management for idiopathic pulmonary fibrosis?
Wuyts, W. A., Antoniou, K. M., Borensztajn, K., Costabel, U., Cottin, V., Crestani, B., Grutters, J. C., Maher, T. M., Poletti, V., Richeldi, L., et al. (2014) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(14)70232-2 · Cited by 150 · see citing works
αv integrins: key regulators of tissue fibrosis
Conroy, K. P., Kitto, L. J., & Henderson, N. C. (2016) · Cell and Tissue Research · doi:10.1007/s00441-016-2407-9 · Cited by 146 · see citing works
Watanabe, Y., Tsuchiya, A., & Terai, S. (2020) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2020.0194 · Cited by 146 · see citing works
Biomechanics of TGFβ‐induced epithelial‐mesenchymal transition: implications for fibrosis and cancer
O’Connor, J. W., & Gomez, E. W. (2014) · Clinical and Translational Medicine · doi:10.1186/2001-1326-3-23 · Cited by 131 · see citing works
Role of Radiation-induced TGF-beta Signaling in Cancer Therapy
Dancea, H. C. (2009) · Molecular and Cellular Pharmacology · doi:10.4255/mcpharmacol.09.06 · Cited by 124 · see citing works
Role of integrin-mediated TGFβ activation in the pathogenesis of pulmonary fibrosis
Goodwin, A. T., & Jenkins, G. R. (2009) · Biochemical Society Transactions · doi:10.1042/bst0370849 · Cited by 119 · see citing works
Lander, V. E., Belle, J. I., Kingston, N. L., Herndon, J. M., Hogg, G. D., Liu, X., Kang, L.-I., Knolhoff, B. L., Bogner, S. J., Baer, J. M., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-0192 · Cited by 114 · see citing works
Krisnawan, V. E., Stanley, J. A., Schwarz, J. K., & DeNardo, D. G. (2020) · Cancers · doi:10.3390/cancers12102916 · Cited by 114 · see citing works
Expression of Integrin αvβ6 and TGF-β in Scarless vs Scar-forming Wound Healing
Eslami, A., Gallant‐Behm, C. L., Hart, D. A., Wiebe, C., Honardoust, D., Gardner, H., Häkkinen, L., & Larjava, H. (2009) · Journal of Histochemistry & Cytochemistry · doi:10.1369/jhc.2009.952572 · Cited by 111 · see citing works
Giacomini, M. M., Travis, M. A., Kudo, M., & Sheppard, D. (2012) · Experimental Cell Research · doi:10.1016/j.yexcr.2012.01.020 · Cited by 107 · see citing works
Biological Significance of Local TGF-β Activation in Liver Diseases
Hayashi, H., & Sakai, T. (2012) · Frontiers in Physiology · doi:10.3389/fphys.2012.00012 · Cited by 110 · see citing works
Future treatments in systemic sclerosis
Asano, Y. (2010) · The Journal of Dermatology · doi:10.1111/j.1346-8138.2009.00758.x · Cited by 103 · see citing works
Fibrogenic Reactions in Lung Disease
Araya, J., & Nishimura, S. L. (2010) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev.pathol.4.110807.092217 · Cited by 108 · see citing works
Varga, J., & Pasche, B. (2008) · Current Opinion in Rheumatology · doi:10.1097/bor.0b013e32830e48e8 · Cited by 107 · see citing works
αvβ6 integrin may be a potential prognostic biomarker in interstitial lung disease
Saini, G., Porte, J., Weinreb, P. H., Violette, S. M., Wallace, W. A., McKeever, T. M., & Jenkins, G. (2015) · European Respiratory Journal · doi:10.1183/09031936.00210414 · Cited by 106 · see citing works
Self-citationThe Cellular and Molecular Mechanism of Radiation-Induced Lung Injury
Huang, Y., Zhang, W., Yu, F., & Gao, F. (2017) · Medical Science Monitor · doi:10.12659/msm.902353 · Cited by 107 · see citing works
TGF-β: Titan of Lung Fibrogenesis.
Yue, X., Shan, B., & Lasky, J. A. (2010) · PubMed · doi:10.2174/10067 · Cited by 105 · see citing works
Raghu, G., Mouded, M., Chambers, D. C., Martínez, F. J., Richeldi, L., LANCASTER, L. H., Hamblin, M. J., Gibson, K. F., Rosas, I. O., Prasse, A., et al. (2022) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202112-2824oc · Cited by 102 · see citing works
Self-citationJackson, I. L., Vujašković, Ž., & Down, J. D. (2009) · Radiation Research · doi:10.1667/rr1911.1 · Cited by 101 · see citing works
Dong, C., Góngora, R., Sosulski, M. L., Luo, F., & Sánchez, C. G. (2016) · Respiratory Research · doi:10.1186/s12931-016-0320-0 · Cited by 100 · see citing works
Combined inhibition of TGFβ and PDGF signaling attenuates radiation-induced pulmonary fibrosis
Dadrich, M., Nicolay, N. H., Flechsig, P., Bickelhaupt, S., Hoeltgen, L., Roeder, F., Hauser, K., Tietz, A., Jenne, J., Perez, R. L., et al. (2015) · OncoImmunology · doi:10.1080/2162402x.2015.1123366 · Cited by 98 · see citing works
Advances in pathogenic mechanisms and management of radiation-induced fibrosis
Wang, B., Wei, J., Meng, L., Wang, H., Qu, C., Chen, X., Xin, Y., & Jiang, X. M. (2019) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2019.109560 · Cited by 98 · see citing works
Advances in Molecular Mechanisms and Treatment of Radiation-Induced Pulmonary Fibrosis
Chen, Z., Wu, Z., & Ning, W. (2018) · Translational Oncology · doi:10.1016/j.tranon.2018.09.009 · Cited by 96 · see citing works
Challenges for inhaled drug discovery and development: Induced alveolar macrophage responses
Forbes, B., O’Lone, R. B., Pribul, P. K., Cahn, A. P., Clarke, C. J., Collinge, M., Dailey, L. A., Donnelly, L., Dybowski, J. A., Hassall, D. G., et al. (2014) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2014.02.001 · Cited by 95 · see citing works
Kang, J. H., Jung, M., Choudhury, M., & Leof, E. B. (2019) · The FASEB Journal · doi:10.1096/fj.201902354r · Cited by 93 · see citing works
John, A. E., Luckett, J., Tatler, A. L., Awais, R. O., Desai, A., Habgood, A., Ludbrook, S. B., Blanchard, A. D., Perkins, A. C., Jenkins, G. R., et al. (2013) · Journal of Nuclear Medicine · doi:10.2967/jnumed.113.120592 · Cited by 93 · see citing works
Degryse, A. L., Tanjore, H., Xu, X. C., Polosukhin, V. V., Jones, B. R., Boomershine, C. S., Ortiz, C., Sherrill, T. P., McMahon, F. B., Gleaves, L. A., et al. (2011) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00397.2010 · Cited by 91 · see citing works
Epigenetics in radiation-induced fibrosis
Weigel, C., Schmezer, P., Plass, C., & Popanda, O. (2014) · Oncogene · doi:10.1038/onc.2014.145 · Cited by 90 · see citing works
Eberlein, C. A., Kendrew, J., McDaid, K., Alfred, A., Kang, J., Jacobs, V. N., Ross, S. J., Rooney, C., Smith, N. R., Rinkenberger, J. L., et al. (2012) · Oncogene · doi:10.1038/onc.2012.460 · Cited by 87 · see citing works
Li, Y., Fan, W., Link, F., Wang, S., & Dooley, S. (2021) · JHEP Reports · doi:10.1016/j.jhepr.2021.100397 · Cited by 88 · see citing works
Myofibroblast Differentiation and Enhanced Tgf-B Signaling in Cystic Fibrosis Lung Disease
Harris, W. T., Kelly, D. R., Zhou, Y., Wang, D., MacEwen, M. W., Hagood, J. S., Clancy, J. P., Ambalavanan, N., & Sorscher, E. J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0070196 · Cited by 84 · see citing works
Yang, J., Velikoff, M., CANALIS, E. M., Horowitz, J. C., & Kim, K. K. (2014) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00243.2013 · Cited by 84 · see citing works
Uncoupling of the profibrotic and hemostatic effects of thrombin in lung fibrosis
Shea, B. S., Probst, C. K., Brazee, P. L., Rotile, N. J., Blasi, F., Weinreb, P. H., Black, K. E., Sosnovik, D. E., Cott, E. M. V., Violette, S. M., et al. (2017) · JCI Insight · doi:10.1172/jci.insight.86608 · Cited by 85 · see citing works
Self-citationBeyond the Matrix: The Many Non-ECM Ligands for Integrins
LaFoya, B., Munroe, J. A., Miyamoto, A., Detweiler, M., Crow, J. J., Gazdik, T. R., & Albig, A. R. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19020449 · Cited by 84 · see citing works
Sheppard, D. (2015) · Annals of the American Thoracic Society · doi:10.1513/annalsats.201406-245mg · Cited by 81 · see citing works
Locally Advanced Non-small Cell Lung Cancer: The Past, Present, and Future
Govindan, R., Bogart, J. A., & Vokes, E. E. (2008) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e318180270b · Cited by 78 · see citing works
Vittal, R., Mickler, E. A., Fisher, A. J., Zhang, C., Rothhaar, K., Gu, H., Brown, K. M., Emtiazdjoo, A., Lott, J. M., Frye, S. B., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0076451 · Cited by 77 · see citing works
Hove, I. V., Hu, T., Beets, K., Bergen, T. V., Etienne, I., Stitt, A. W., Vermassen, E., & Feyen, J. H. M. (2021) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2021.100966 · Cited by 79 · see citing works
Jackson, I. L., Vujašković, Ž., & Down, J. D. (2011) · Radiation Research · doi:10.1667/rr2421.1 · Cited by 73 · see citing works
Current and novel drug therapies for idiopathic pulmonary fibrosis
Maher, T. M., & Adamali, H. I. (2012) · Drug Design Development and Therapy · doi:10.2147/dddt.s29928 · Cited by 73 · see citing works
Integrins and cadherins as therapeutic targets in fibrosis
Agarwal, S. K. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00131 · Cited by 71 · see citing works
Terai, S., & Tsuchiya, A. (2016) · Journal of Gastroenterology · doi:10.1007/s00535-016-1258-1 · Cited by 71 · see citing works
Immunoglobulin light chains generate proinflammatory and profibrotic kidney injury
Ying, W., Li, X., Rangarajan, S., Feng, W., Curtis, L. M., & Sanders, P. W. (2019) · Journal of Clinical Investigation · doi:10.1172/jci125517 · Cited by 68 · see citing works
Latella, G., & Rieder, F. (2017) · Current Opinion in Gastroenterology · doi:10.1097/mog.0000000000000363 · Cited by 67 · see citing works
Therapeutic pro-fibrogenic signaling pathways in fibroblasts
Cannito, S., Novo, E., & Parola, M. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2017.05.017 · Cited by 60 · see citing works
Plaas, A., Velasco, J., Gorski, D. J., Li, J., Cole, A. A., Christopherson, K. W., & Sandy, J. D. (2011) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2011.05.003 · Cited by 60 · see citing works
Eberlein, C. A., Rooney, C., Ross, S. J., Farren, M. R., Weir, H. M., & Barry, S. T. (2014) · Oncogene · doi:10.1038/onc.2013.600 · Cited by 60 · see citing works
Li, H., Zheng, J., Fan, H., Li, H., Gao, Z., & Chen, D. (2013) · Journal of Oral Pathology and Medicine · doi:10.1111/jop.12044 · Cited by 58 · see citing works
The αvβ6 integrin in cancer cell‐derived small extracellular vesicles enhances angiogenesis
Krishn, S. R., Salem, I., Quaglia, F., Naranjo, N. M., Agarwal, E., Liu, Q., Sarker, S., Kopenhaver, J. S., McCue, P. A., Weinreb, P. H., et al. (2020) · Journal of Extracellular Vesicles · doi:10.1080/20013078.2020.1763594 · Cited by 58 · see citing works
Self-citationIntegrins: An Important Link between Angiogenesis, Inflammation and Eye Diseases
Mrugacz, M., Bryl, A., Falkowski, M., & Zorena, K. (2021) · Cells · doi:10.3390/cells10071703 · Cited by 57 · see citing works
Loss of Matrix Metalloproteinase-13 Attenuates Murine Radiation-Induced Pulmonary Fibrosis
Flechsig, P., Hartenstein, B., Teurich, S., Dadrich, M., Hauser, K., Abdollahi, A., Gröne, H., Angel, P. E., & Huber, P. E. (2010) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2009.12.043 · Cited by 55 · see citing works
Inhibition of the αvβ6 integrin leads to limited alteration of TGF-α-induced pulmonary fibrosis
Madala, S. K., Korfhagen, T. R., Schmidt, S., Davidson, C. R., Edukulla, R., Ikegami, M., Violette, S. M., Weinreb, P. H., Sheppard, D., & Hardie, W. D. (2014) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00357.2013 · Cited by 52 · see citing works
Self-citationKriete, A., Mayo, K. L., Yalamanchili, N., Beggs, W. R., Bender, P. K., Kari, C., & Rodeck, U. (2008) · Immunity & Ageing · doi:10.1186/1742-4933-5-5 · Cited by 53 · see citing works
Tomos, I. P., Tzouvelekis, A., Aidinis, V., Manali, E. D., Bouros, E., Bouros, D. E., & Papiris, S. A. (2017) · Expert Review of Respiratory Medicine · doi:10.1080/17476348.2017.1300533 · Cited by 51 · see citing works
Wang, B., Liu, W., Liu, C., Du, K., Guo, Z., Zhang, G., Huang, Z., Lin, S., Cen, B., Tian, Y., et al. (2022) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2022.12.029 · Cited by 52 · see citing works
Tissue and matrix influences on airway smooth muscle function
Burgess, J. K., Ceresa, C., Johnson, S. R., Kanabar, V., Moir, L. M., Nguyen, T. T. B., Oliver, B. G. G., Schuliga, M. J., & Ward, J. (2008) · Pulmonary Pharmacology & Therapeutics · doi:10.1016/j.pupt.2008.12.007 · Cited by 52 · see citing works
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
