Quantitative assessment of radiation dose and fractionation effects on normal tissue by utilizing a novel lung fibrosis index model

Abstract

BackgroundNormal lung tissue tolerance constitutes a limiting factor in delivering the required dose of radiotherapy to cure thoracic and chest wall malignancies. Radiation-induced lung fibrosis (RILF) is considered a critical determinant for late normal tissue complications. While RILF mouse models are frequently approached e.g., as a single high dose thoracic irradiation to investigate lung fibrosis and candidate modulators, a systematic radiobiological characterization of RILF mouse model is urgently needed to compare relative biological effectiveness (RBE) of particle irradiation with protons, helium-, carbon and oxygen ions now available at HIT. We aimed to study the dose-response relationship and fractionation effect of photon irradiation in development of pulmonary fibrosis in C57BL/6 mouse.MethodsLung fibrosis was evaluated 24 weeks after single and fractionated whole thoracic irradiation by quantitative assessment of lung alterations using CT. The fibrosis index (FI) was determined based on 3D-segmentation of the lungs considering the two key fibrosis parameters affected by ionizing radiation i.e., a dose/fractionation dependent reduction of the total lung volume and increase of the mean lung density.ResultsThe effective dose required to induce 50% of the maximal possible fibrosis (ED 50) was 14.55 ± 0.34Gy and 27.7 ± 1.22Gy, for single and five- fractions irradiation, respectively. Applying a deterministic model an α/β = 4.49 ± 0.38 Gy for the late lung radiosensitivity was determined. Intriguingly, we found that a linear-quadratic model could be applied to in-vivo log transformed fibrosis (FI) vs. irradiation doses. The LQ model revealed an α/β for lung radiosensitivity of 4.4879 Gy for single fraction and 3.9474 for 5-fractions. Our FI based data were in good agreement with a meta-analysis of previous lung radiosensitivity data derived from different clinical endpoints and various mouse strains. The effect of fractionation on RILF development was further estimated by the biologically effective dose (BED) model with threshold BED (BED Tr) = 30.33 Gy and BED ED50 = 61.63 Gy, respectively.ConclusionThe systematic radiobiological characterization of RILF in the C57BL/6 mouse reported in this study marks an important step towards precise estimation of dose-response for development of lung fibrosis. These radiobiological parameters combined with a large repertoire of genetically engineered C57BL/6 mouse models, build a solid foundation for further biologically individualized risk assessment of RILF and functional RBE prediction on novel of particle qualities.Electronic supplementary materialThe online version of this article (10.1186/s13014-017-0912-y) contains supplementary material, which is available to authorized users.

rhCygb reverses bleomycin-induced established pulmonary fibrosis in rats

“…It is known that CT MLD provide prognostic estimation of disease severity in patients with IPF and other ILDs and high MLD values may indicate severe IPF. [25] Consistent with these bene cial effects of rhCygb (4 mg/kg) treatment in our lung brosis rats, we found a marked attenuation of the HA, LN, P NP and C levels in serum and HYP concentration in rat lungs compared to BLM-treated rats.…”

“…The MLD was assessed with quantitative determination of the overall lung Houns eld units (Hu). [25] Before scanning, the MLD for air was calibrated as −1000, while the water was 0.…”

Modeling and multiscale characterization of the quantitative imaging based fibrosis index reveals pathophysiological, transcriptome and proteomic correlates of lung fibrosis induced by fractionated irradiation

“…Whole thoracic irradiation was administrated to 8–10 weeks old female C57BL/6 mice as described previously . In brief, photons beam was delivered by a 6 MV Artiste Linac (Siemens) at a dose rate of 3 Gy/min.…”

“…Whole thoracic irradiation was administrated to 8-10 weeks old female C57BL/6 mice as described previously. 11 In brief, photons beam was delivered by a 6 MV Artiste Linac (Siemens) at a dose rate of 3 Gy/min. The prescribed doses were including a single dose of 20 Gy in the pilot study and a fractionated irradiation of 10-40 Gy total dose in 2, 4, 6, 8 Gy per fractions administered over 5 consecutive days.…”

Personalized Assessment of Normal Tissue Radiosensitivity via Transcriptome Response to Photon, Proton and Carbon Irradiation in Patient-Derived Human Intestinal Organoids

“…Normal tissue is aimed to be spared by high-precision irradiation with particles. However, compared to conventional photon irradiation, uncertainties of relative biological effectiveness (RBE) of protons, and even more so for heavier ions with higher linear energy transfer (LET) such as carbon radiotherapy exist [14,15]. We here have evaluated the feasibility of human intestinal organoids (HIO) to recapitulate patient radio-sensitivity.…”