Pulmonary fibrosis is the consequence of a variety of diseases with no satisfying treatment option. Therapy-induced fibrosis also limits the efficacy of chemotherapy and radiotherapy in numerous cancers. Here, we studied the potential of platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitors (RTKIs) to attenuate radiation-induced pulmonary fibrosis. Thoraces of C57BL/6 mice were irradiated (20 Gy), and mice were treated with three distinct PDGF RTKIs (SU9518, SU11657, or Imatinib). Irradiation was found to induce severe lung fibrosis resulting in dramatically reduced mouse survival. Treatment with PDGF RTKIs markedly attenuated the development of pulmonary fibrosis in excellent correlation with clinical, histological, and computed tomography results. Importantly, RTKIs also prolonged the life span of irradiated mice. We found that radiation up-regulated expression of PDGF (A–D) isoforms leading to phosphorylation of PDGF receptor, which was strongly inhibited by RTKIs. Our findings suggest a pivotal role of PDGF signaling in the pathogenesis of pulmonary fibrosis and indicate that inhibition of fibrogenesis, rather than inflammation, is critical to antifibrotic treatment. This study points the way to a potential new approach for treating idiopathic or therapy-related forms of lung fibrosis.
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21 March 2005
Article|
March 21 2005
Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis
Amir Abdollahi,
Amir Abdollahi
1Department of Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
5Department of Radiation Oncology, University of Heidelberg Medical School, Heidelberg 69120, Germany
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Minglun Li,
Minglun Li
1Department of Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
5Department of Radiation Oncology, University of Heidelberg Medical School, Heidelberg 69120, Germany
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Gong Ping,
Gong Ping
1Department of Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
5Department of Radiation Oncology, University of Heidelberg Medical School, Heidelberg 69120, Germany
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Christian Plathow,
Christian Plathow
2Diagnostic Radiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
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Sophie Domhan,
Sophie Domhan
1Department of Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
5Department of Radiation Oncology, University of Heidelberg Medical School, Heidelberg 69120, Germany
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Fabian Kiessling,
Fabian Kiessling
2Diagnostic Radiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
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Leslie B. Lee,
Leslie B. Lee
4SUGEN, Inc., South San Francisco, CA 94080
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Gerald McMahon,
Gerald McMahon
4SUGEN, Inc., South San Francisco, CA 94080
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Hermann-Josef Gröne,
Hermann-Josef Gröne
3Molecular Pathology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
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Kenneth E. Lipson,
Kenneth E. Lipson
4SUGEN, Inc., South San Francisco, CA 94080
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Peter E. Huber
Peter E. Huber
1Department of Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
5Department of Radiation Oncology, University of Heidelberg Medical School, Heidelberg 69120, Germany
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Amir Abdollahi
1Department of Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
5Department of Radiation Oncology, University of Heidelberg Medical School, Heidelberg 69120, Germany
Minglun Li
1Department of Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
5Department of Radiation Oncology, University of Heidelberg Medical School, Heidelberg 69120, Germany
Gong Ping
1Department of Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
5Department of Radiation Oncology, University of Heidelberg Medical School, Heidelberg 69120, Germany
Christian Plathow
2Diagnostic Radiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
Sophie Domhan
1Department of Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
5Department of Radiation Oncology, University of Heidelberg Medical School, Heidelberg 69120, Germany
Fabian Kiessling
2Diagnostic Radiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
Leslie B. Lee
4SUGEN, Inc., South San Francisco, CA 94080
Gerald McMahon
4SUGEN, Inc., South San Francisco, CA 94080
Hermann-Josef Gröne
3Molecular Pathology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
Kenneth E. Lipson
4SUGEN, Inc., South San Francisco, CA 94080
Peter E. Huber
1Department of Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
5Department of Radiation Oncology, University of Heidelberg Medical School, Heidelberg 69120, Germany
CORRESPONDENCE Peter Huber: [email protected]
Abbreviations used: CT, computed tomography; HLMVEC, human lung microvascular endothelial cell; HU, hounsfield units; HUVEC, human umbilical vein endothelial cell; IP, immunoprecipitation; IPF, idiopathic pulmonary fibrosis; IP-western, IP Western blotting; PDGF, platelet-derived growth factor; RT, radiation; RTKI, receptor tyrosine kinase inhibitor.
Received:
July 12 2004
Accepted:
January 05 2005
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2005
J Exp Med (2005) 201 (6): 925–935.
Article history
Received:
July 12 2004
Accepted:
January 05 2005
Citation
Amir Abdollahi, Minglun Li, Gong Ping, Christian Plathow, Sophie Domhan, Fabian Kiessling, Leslie B. Lee, Gerald McMahon, Hermann-Josef Gröne, Kenneth E. Lipson, Peter E. Huber; Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis . J Exp Med 21 March 2005; 201 (6): 925–935. doi: https://doi.org/10.1084/jem.20041393
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