Inhibition of TGFβ1 activation prevents radiation-induced lung fibrosis

被引:12
作者
Yi, Minxiao [1 ]
Yuan, Ye [2 ]
Ma, Li [1 ]
Li, Long [1 ]
Qin, Wan [1 ]
Wu, Bili [1 ]
Zheng, Bolong [2 ]
Liao, Xin [1 ,3 ]
Hu, Guangyuan [1 ,4 ]
Liu, Bo [1 ,4 ]
机构
[1] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Oncol, Wuhan, Peoples R China
[2] Huazhong Univ Sci & Technol, Sch Comp Sci & Technol, Wuhan, Peoples R China
[3] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Integrat Med, Wuhan, Peoples R China
[4] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Oncol, 1095 Jiefang Ave, Wuhan 430030, Hubei, Peoples R China
基金
中国国家自然科学基金;
关键词
cilengitide; radiation-induced pulmonary fibrosis; transforming growth factor beta 1; alpha v integrin; PHARMACOLOGICAL INHIBITION; LATENT TGF-BETA-1; OPEN-LABEL; PHASE-II; CILENGITIDE; ALPHA-V-BETA-3; CANCER; GENE; BETA;
D O I
10.1002/ctm2.1546
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: Radiotherapy is the main treatment modality for thoracic tumours, but it may induce pulmonary fibrosis. Currently, the pathogenesis of radiation-induced pulmonary fibrosis (RIPF) is unclear, and effective treatments are lacking. Transforming growth factor beta 1 (TGF beta 1) plays a central role in RIPF. We found that activated TGF beta 1 had better performance for radiation pneumonitis (RP) risk prediction by detecting activated and total TGF beta 1 levels in patient serum. alpha v integrin plays key roles in TGF beta 1 activation, but the role of alpha v integrin-mediated TGF beta 1 activation in RIPF is unclear. Here, we investigated the role of alpha v integrin-mediated TGF beta 1 activation in RIPF and the application of the integrin antagonist cilengitide to prevent RIPF.Methods: Itgav(loxP/loxP);Pdgfrb-Cre mice were generated by conditionally knocking out Itgav in myofibroblasts, and wild-type mice were treated with cilengitide or placebo. All mice received 16 Gy of radiation or underwent a sham radiation procedure. Lung fibrosis was measured by a modified Ashcroft score and microcomputed tomography (CT). An enzyme-linked immunosorbent assay (ELISA) was used to measure the serum TGF beta 1 concentration, and total Smad2/3 and p-Smad2/3 levels were determined via Western blotting.Results: Conditional Itgav knockout significantly attenuated RIPF (p < .01). Hounsfield units (HUs) in the lungs were reduced in the knockout mice compared with the control mice (p < .001). Conditional Itgav knockout decreased active TGF beta 1 secretion and inhibited fibroblast p-Smad2/3 expression. Exogenous active TGF beta 1, but not latent TGF beta 1, reversed these reductions. Furthermore, cilengitide treatment elicited similar results and prevented RIPF.Conclusions: The present study revealed that conditional Itgav knockout and cilengitide treatment both significantly attenuated RIPF in mice by inhibiting alpha v integrin-mediated TGF beta 1 activation.
引用
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页数:19
相关论文
共 33 条
[21]   αv integrins on mesenchymal cells regulate skeletal and cardiac muscle fibrosis [J].
Murray, I. R. ;
Gonzalez, Z. N. ;
Baily, J. ;
Dobie, R. ;
Wallace, R. J. ;
Mackinnon, A. C. ;
Smith, J. R. ;
Greenhalgh, S. N. ;
Thompson, A. I. ;
Conroy, K. P. ;
Griggs, D. W. ;
Ruminski, P. G. ;
Gray, G. A. ;
Singh, M. ;
Campbell, M. A. ;
Kendall, T. J. ;
Dai, J. ;
Li, Y. ;
Iredale, J. P. ;
Simpson, H. ;
Huard, J. ;
Peault, B. ;
Henderson, N. C. .
NATURE COMMUNICATIONS, 2017, 8
[22]   Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study [J].
Nabors, L. Burt ;
Fink, Karen L. ;
Mikkelsen, Tom ;
Grujicic, Danica ;
Tarnawski, Rafal ;
Nam, Do Hyun ;
Mazurkiewicz, Maria ;
Salacz, Michael ;
Ashby, Lynn ;
Zagonel, Vittorina ;
Depenni, Roberta ;
Perry, James R. ;
Hicking, Christine ;
Picard, Martin ;
Hegi, Monika E. ;
Lhermitte, Benoit ;
Reardon, David A. .
NEURO-ONCOLOGY, 2015, 17 (05) :708-717
[23]   Suppression of the fibrotic encapsulation of silicone implants by inhibiting the mechanical activation of pro-fibrotic TGF-β [J].
Noskovicova, Nina ;
Schuster, Ronen ;
van Putten, Sander ;
Ezzo, Maya ;
Koehler, Anne ;
Boo, Stellar ;
Coelho, Nuno M. ;
Griggs, David ;
Ruminski, Peter ;
McCulloch, Christopher A. ;
Hinz, Boris .
NATURE BIOMEDICAL ENGINEERING, 2021, 5 (12) :1437-1456
[24]   Pharmacological inhibition of the vitronectin receptor abrogates PDGF-BB-induced hepatic stellate cell migration and activation in vitro [J].
Patsenker, Eleonora ;
Popov, Yury ;
Wiesner, Matthias ;
Goodman, Simon L. ;
Schuppan, Detlef .
JOURNAL OF HEPATOLOGY, 2007, 46 (05) :878-887
[25]   Pharmacological Inhibition of Integrin αvβ3 Aggravates Experimental Liver Fibrosis and Suppresses Hepatic Angiogenesis [J].
Patsenker, Eleonora ;
Popov, Yury ;
Stickel, Felix ;
Schneider, Vreni ;
Ledermann, Monika ;
Saegesser, Hans ;
Niedobitek, Gerald ;
Goodman, Simon L. ;
Schuppan, Detlef .
HEPATOLOGY, 2009, 50 (05) :1501-1511
[26]   Inhibition of integrin αvβ6, an activator of latent transforming growth factor-β, prevents radiation-induced lung fibrosis [J].
Puthawala, Khalid ;
Hadjiangelis, Nicos ;
Jacoby, Steven C. ;
Bayongan, Emmanuel ;
Zhao, Zhicheng ;
Yang, Zhiwei ;
Devitt, Mary Louise ;
Horan, Gerald S. ;
Weinreb, Paul H. ;
Lukashev, Matvey E. ;
Violette, Shelia M. ;
Grant, Kristen S. ;
Colarossi, Cristina ;
Formenti, Silvia C. ;
Munger, John S. .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2008, 177 (01) :82-90
[27]   Antifibrotic Agent Pirfenidone Protects against Development o Radiation-Induced Pulmonary Fibrosis in a Murine Model [J].
Qin, Wan ;
Liu, Bo ;
Yi, Minxiao ;
Li, Long ;
Tang, Yang ;
Wu, Bili ;
Yuan, Xianglin .
RADIATION RESEARCH, 2018, 190 (04) :396-403
[28]   The αvβ1 integrin plays a critical in vivo role in tissue fibrosis [J].
Reed, Nilgun I. ;
Jo, Hyunil ;
Chen, Chun ;
Tsujino, Kazuyuki ;
Arnold, Thomas D. ;
DeGrado, William F. ;
Sheppard, Dean .
SCIENCE TRANSLATIONAL MEDICINE, 2015, 7 (288)
[29]   Integrins in wound healing, fibrosis and tumor stroma: High potential targets for therapeutics and drug delivery [J].
Schnittert, Jonas ;
Bansal, Ruchi ;
Storm, Gert ;
Prakash, Jai .
ADVANCED DRUG DELIVERY REVIEWS, 2018, 129 :37-53
[30]   Cilengitide combined with cetuximab and platinum-based chemotherapy as first-line treatment in advanced non-small-cell lung cancer (NSCLC) patients: results of an open-label, randomized, controlled phase II study (CERTO) [J].
Vansteenkiste, J. ;
Barlesi, F. ;
Waller, C. F. ;
Bennouna, J. ;
Gridelli, C. ;
Goekkurt, E. ;
Verhoeven, D. ;
Szczesna, A. ;
Feurer, M. ;
Milanowski, J. ;
Germonpre, P. ;
Lena, H. ;
Atanackovic, D. ;
Krzakowski, M. ;
Hicking, C. ;
Straub, J. ;
Picard, M. ;
Schuette, W. ;
O'Byrne, K. .
ANNALS OF ONCOLOGY, 2015, 26 (08) :1734-1740