Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis.
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.
Abdollahi
Amir
A
Department of Radiation Oncology, German Cancer Research Center, Heidelberg 69120, Germany.
Li
Minglun
M
Ping
Gong
G
Plathow
Christian
C
Domhan
Sophie
S
Kiessling
Fabian
F
Lee
Leslie B
LB
McMahon
Gerald
G
Gröne
Hermann-Josef
HJ
Lipson
Kenneth E
KE
Huber
Peter E
PE
D000818:Animals; D005260:Female; D005720:Gamma Rays / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D051379:Mice; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011658:Pulmonary Fibrosis / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects* / Q000528:radiation effects; D014916:Whole-Body Irradiation
D010982:Platelet-Derived Growth Factor; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D017479:Receptors, Platelet-Derived Growth Factor