Radiobiological Study Of Radiation-induced Lung Injury

Background:Normal lung tissue tolerance constitutes a limiting factor in delivering the required dose of radiotherapy to cure thoracic and chest wall malignancies.Radiation-induced lung injury(RILI)is considered the most critical determinant for estimating the late normal tissue complication probability(NTCP).Materials&methods:Escalted dose series of photons and carbon-ions were delivered to the whole thorax of C57BL6 mice.Fibrosis development followed a slow kinetic with maximum lung fibrosis levels detected at 24-week post radiation insult.Radiological,histopathological,transcriptional,proteomic as well as molecular biological investigation was incorporated into multi-scale RILI analysis.Results:A non-invasive inhalation anesthesia based immobilization device was developed for precision thoracic irradiation.Quantitative CT measurement of fibrosis related parameters,i.e.,averaged lung density and volume were proposed on the basis of single and fractionated experiments.Those two radiological surrogates were verified transcriptionally and pathohistologically.A good linear correlation between those two radiological parameters was also demonstrated,leading to a dual-CT-parameter based 3D-BED model for stratification and prediction of pulmonary fibrosis development.Furthermore,transcriptional gene-signatures for prediting both early and late radiation lung toxicities were investigated.In parallel,specific gene-sets for acute and persistant responses following high-LET carbon-ions exposure were further studied,highlighting the dominant role of apoptosis and programmed cell death in patheay enrichment analysis.Conclusions:The present study established the dose-response models toward an improved knowledge of dose and fractionation effects in lung fibrosis development.Genome-wide transcriptional studies shed the lights on future clinical and radiation protection related development of gene-signatures for RILI.A systematic radiobiological characterization of RILI marks an important step towards quantitative tolerance dose analysis and precise risk estimation for pulmonary toxicity.