The Journal of Experimental Medicine
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Published 21 March 2005. doi:10.1084/jem.20041393
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 6, 925-935
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ARTICLE

 Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis

Amir Abdollahi1,5, Minglun Li1,5, Gong Ping1,5, Christian Plathow2, Sophie Domhan1,5, Fabian Kiessling2, Leslie B. Lee4, Gerald McMahon4, Hermann-Josef Gröne3, Kenneth E. Lipson4, and Peter E. Huber1,5

1 Department of Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
2 Diagnostic Radiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
3 Molecular Pathology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
4 SUGEN, Inc., South San Francisco, CA 94080
5 Department of Radiation Oncology, University of Heidelberg Medical School, Heidelberg 69120, Germany

CORRESPONDENCE Peter Huber: p.huber{at}dkfz.de

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.

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.


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