Abstract
The goal of this study was to develop a potential druggable target for lung injury after SABR through the small animal model. Utilising the model, a radiation dose of 70 Gy or 90 Gy was focally (small volume) delivered to the left lung of mice. The highly expressed phosphorylation form of C-Raf was discovered through a protein array experiment, with the protein being extracted from the area of radiated mouse lung tissue, and was confirmed by IHC and western blot. C-Raf activation, along with morphological change and EMT (Epithelial to Mesenchymal Transition) marker expression, was observed after radiation to the mouse type II alveolar cell line MLE-12. C-Raf inhibitor GW5074 was able to reverse the EMT in cells effectively, and was found to be dependent on Twist1 expression. In the animal experiment, pretreatment of GW5074 alleviated EMT and lung injury after 70 Gy radiation was focally delivered to the lung of mice. Conclusively, these results demonstrate that C-Raf inhibitor GW5074 inhibits high-dose small-volume radiation-induced EMT via the C-Raf/Twist1 signalling pathway in mice. Therefore, pharmacological C-Raf inhibitors may be used effectively as inhibitors of SABR-induced lung fibrosis.
Highlights
The goal of this study was to develop a potential druggable target for lung injury after Stereotactic ablative radiotherapy (SABR) through the small animal model
Recent studies have concentrated on epithelial cells that are able to transverse themselves into myofibroblasts through an approach of “epithelial–mesenchymal transition (EMT)”, which has been demonstrated in RIPF3,4
We tried to explore the possible target of inhibiting SABR-induced EMT; experiments were conducted under the condition of high-dose small-volume (HDSV) radiation, which represents the SABR system
Summary
The goal of this study was to develop a potential druggable target for lung injury after SABR through the small animal model. Pretreatment of GW5074 alleviated EMT and lung injury after 70 Gy radiation was focally delivered to the lung of mice These results demonstrate that C-Raf inhibitor GW5074 inhibits high-dose small-volume radiation-induced EMT via the C-Raf/Twist[1] signalling pathway in mice. In a previous study[6], we established an experimental model and an image-guided animal radiation system in order to study high-dose-per-fraction radiation such as SABR at volumes analogous to those used in human beings. With this animal model we observed that the lung complications induced by SABR are remarkably different from C FRT7. We tried to (i) understand the role of C-Raf in SABR-induced EMT in mice, and (ii) analyse cell signalling events involved in the inhibitory effect of GW5074 on high-dose-induced EMT
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