Late treatment with imatinib mesylate ameliorates radiation-induced lung fibrosis in a mouse model

Minglun Li,Peter E Huber,Kenneth E Lipson,Amir Abdollahi,Claus Belka,Hermann-Josef Gröne

doi:10.1186/1748-717x-4-66

Abstract

BackgroundWe 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.MethodsWhole 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.ResultsIrradiation 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.ConclusionsOur 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.

Highlights

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
We have shown that PDGF receptor tyrosine kinase inhibitors (RTKI) including imatinib can attenuate radiation-induced pulmonary fibrosis if the drug administration starts before the toxic event or within three days after the insult [27]
In the present study we chose a late drug treatment starting at the time when the primary inflammation has subsided, to rule out direct and indirect effects associated with acute inflammation, we report here the full results of the imatinib experiments including the data on the late imatinib administration arm starting two weeks after radiation, at a time when the acute inflammation has already completely subsided

Summary

Introduction

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 beneficial antifibrotic effects. A cascade of many cytokines leading to lung fibrosis after radiation injury has been described [12,13]. A number of new regulators in radiation-induced lung injury such as intercellular adhesion molecules (ICAM-1) and the CD95 ligand system have been reported [14,15]. The PDGF/PDGFR system can be considered as a promising target for treating fibrotic diseases [22,23,24,25,26]

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Conclusion