Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Int J Mol Sci. 2021 Sep 15;22(18):9964. doi: 10.3390/ijms22189964.
Radiation-induced abscopal effect (RIAE) outside of radiation field is becoming more attractive. However, the underlying mechanisms are still obscure. This work investigated the deleterious effect of thoracic irradiation (Th-IR) on distant bone marrow and associated signaling factors by irradiating the right thorax of mice with fractionated doses (8 Gy × 3). It was found that this localized Th-IR increased apoptosis of bone marrow cells and micronucleus formation of bone marrow polychromatic erythrocytes after irradiation. Tandem mass tagging (TMT) analysis and ELISA assay showed that the concentrations of TNF-α and serum amyloid A (SAA) in the mice were significantly increased after Th-IR. An immunohistochemistry assay revealed a robust increase in SAA expression in the liver rather than in the lungs after Th-IR. In vitro experiments demonstrated that TNF-α induced SAA expression in mouse hepatoma Hepa1-6 cells, and these two signaling factors induced DNA damage in bone marrow mesenchymal stem cells (BMSCs) by increasing reactive oxygen species (ROS). On the other hand, injection with TNF-α inhibitor before Th-IR reduced the secretion of SAA and attenuated the abscopal damage in bone marrow. ROS scavenger NAC could also mitigated Th-IR/SAA-induced bone marrow damage in mice. Our findings indicated that Th-IR triggered TNF-α release from lung, which further promoted SAA secretion from liver in a manner of cascade reaction. Consequently, these signaling factors resulted in induction of abscopal damage on bone marrow of mice.
远隔效应（RIAE）是指在放射治疗野之外的部位产生的效应，这种效应越来越受到关注。然而，其潜在机制尚不清楚。本研究通过对小鼠右侧胸部进行分次照射（8Gy×3），探讨了胸部照射（Th-IR）对远处骨髓的有害影响及其相关信号因子。结果发现，这种局部 Th-IR 增加了骨髓细胞的凋亡和骨髓多染红细胞的微核形成。串联质量标签（TMT）分析和 ELISA 检测显示，Th-IR 后小鼠血清中 TNF-α和血清淀粉样蛋白 A（SAA）的浓度明显升高。免疫组化检测显示，Th-IR 后 SAA 在肝脏而非肺部的表达明显增加。体外实验表明，TNF-α诱导小鼠肝癌 Hepa1-6 细胞中 SAA 的表达，这两种信号因子通过增加活性氧（ROS）导致骨髓间充质干细胞（BMSCs）中的 DNA 损伤。另一方面，在 Th-IR 前注射 TNF-α抑制剂可减少 SAA 的分泌，并减轻骨髓的远隔损伤。ROS 清除剂 NAC 也可减轻 Th-IR/SAA 诱导的小鼠骨髓损伤。我们的研究结果表明，Th-IR 触发了来自肺部的 TNF-α释放，进而以级联反应的方式促进了来自肝脏的 SAA 分泌。因此，这些信号因子导致了小鼠骨髓的远隔损伤。
