table1_Gamma Tocotrienol Protects Mice From Targeted Thoracic Radiation Injury.docx

Radiation injury will result in multiorgan dysfuntion leading to multiorgan failure. In addition to many factors such as radiation dose, dose rate, the severity of the injury will also depend on organ systems which are exposed. Here, we report the protective property of gamma tocotrienol (GT3) in total as well as partial body irradiation (PBI) model in C3H/HeN male mice. We have carried out PBI by targeting thoracic region (lung-PBI) using Small Animal Radiation Research Platform, an X-ray irradiator with capabilities of an image guided irradiation with a variable collimator with minimized exposure to non-targeted tissues and organs. Precise and accurate irradiation of lungs was carried out at either 14 or 16 Gy at an approximate dose rate of 2.6 Gy/min. Though a low throughput model, it is amenable to change the field size on the spot. No damage to other non-targeted organs was observed in histopathological evaluation. There was no significant change in peripheral blood counts of irradiated mice in comparison to naïve mice. Femoral bone marrow cells had no damage in irradiated mice. As expected, damage to the targeted tissue was observed in the histopathological evaluation and non-targeted tissue was found normal. Regeneration and increase of cellularity and megakaryocytes on GT3 treatment was compared to significant loss of cellularity in saline group. Peak alveolitis was observed on day 14 post-PBI and protection from alveolitis by GT3 was noted. In irradiated lung tissue, thirty proteins were found to be differentially expressed but modulated by GT3 to reverse the effects of irradiation. We propose that possible mode of action of GT3 could be Angiopoietin 2-Tie2 pathway leading to AKT/ERK pathways resulting in disruption in cell survival/angiogenesis.

辐射损伤可引发多器官功能障碍（multiorgan dysfunction），进而导致多器官衰竭。除辐射剂量、剂量率等诸多因素外，损伤严重程度还取决于受照射的器官系统。本研究报告了γ-生育三烯酚（gamma tocotrienol，GT3）对C3H/HeN雄性小鼠全身照射及部分躯体照射（partial body irradiation，PBI）模型的防护作用。

本研究借助小动物辐射研究平台（Small Animal Radiation Research Platform）——一款具备图像引导辐照能力、配备可变准直器且可最大限度减少非靶组织与器官受照剂量的X射线辐照仪——对胸部区域进行靶向照射以构建肺型部分躯体照射（lung-PBI）模型。研究以约2.6 Gy/min的剂量率，对肺部实施14 Gy或16 Gy的精准辐照。尽管该模型通量较低，但可现场实时调整照射野尺寸。组织病理学评估显示，其余非靶器官未出现损伤。与空白对照小鼠（naïve mice）相比，受辐照小鼠的外周血细胞计数无显著变化。受辐照小鼠的股骨骨髓细胞未出现损伤。正如预期，组织病理学评估显示靶组织出现损伤，而非靶组织则表现正常。

GT3处理组可见细胞构成与巨核细胞（megakaryocytes）的再生及增多，而生理盐水对照组（saline group）则出现显著的细胞构成丢失。PBI造模后第14天可见肺泡炎（alveolitis）峰值，GT3可对肺泡炎起到防护作用。在受辐照的肺组织中，共有30种蛋白质呈现差异表达（differentially expressed），而GT3可调控这些蛋白以逆转辐照带来的影响。本研究推测，GT3的潜在作用机制可能为通过血管生成素2-Tie2（Angiopoietin 2-Tie2）通路调控AKT/ERK信号通路，进而影响细胞存活与血管生成（angiogenesis）过程。