title: Late treatment with imatinib mesylate ameliorates radiation-induced lung fibrosis in a mouse model.
abstract: BACKGROUND
  We have previously shown that small molecule PDGF receptor tyrosine kinase inhibitors (RTKI) can drastically attenuate radiation-induced pulmonary fibrosis if the drug administration starts at the time of radiation during acute inflammation with present but limited effects against acute inflammation. To rule out interactions of the drug with acute inflammation, we investigated here in an interventive trial if a later drug administration start at a time when the acute inflammation has subsided--has also beneficial antifibrotic effects.
  
  
  METHODS
  Whole thoraces of C57BL/6 mice were irradiated with 20 Gy and treated with the RTKI imatinib starting either 3 days after radiation (during acute inflammation) or two weeks after radiation (after the acute inflammation has subsided as demonstrated by leucocyte count). Lungs were monitored and analyzed by clinical, histological and in vivo non-invasive computed tomography as a quantitative measure for lung density and lung fibrosis.
  
  
  RESULTS
  Irradiation induced severe lung fibrosis resulting in markedly reduced mouse survival vs. non-irradiated controls. Both early start of imatinib treatment during inflammation and late imatinib start markedly attenuated the development of pulmonary fibrosis as demonstrated by clinical, histological and qualitative and quantitative computed tomography results such as reduced lung density. Both administration schedules resulted in prolonged lifespans. The earlier drug treatment start resulted in slightly stronger beneficial antifibrotic effects along all measured endpoints than the later start.
  
  
  CONCLUSIONS
  Our findings show that imatinib, even when administered after the acute inflammation has subsided, attenuates radiation-induced lung fibrosis in mice. Our data also indicate that the fibrotic fate is not only determined by the early inflammatory events but rather a complex process in which secondary events at later time points are important. Because of the clinical availability of imatinib or similar compounds, a meaningful attenuation of radiation-induced lung fibrosis in patients seems possible.
authors.affiliation: Department of Radiation Oncology German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg 69120, Germany. minglun.li@med.uni-muenchen.de
authors.forename: Minglun
authors.initials: M
authors.lastname: Li
authors.forename: Amir
authors.initials: A
authors.lastname: Abdollahi
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Lipson
authors.forename: Claus
authors.initials: C
authors.lastname: Belka
authors.forename: Peter E
authors.initials: PE
authors.lastname: Huber
mesh_terms: D000818:Animals; D001549:Benzamides; D005260:Female; D000068877:Imatinib Mesylate; D051379:Mice; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D017564:Radiation Pneumonitis / Q000517:prevention & control*
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate