Department of Radiation Science, Hirosaki University Graduate School of Health Sciences, 66-1 Hon-cho, Hirosaki, Aomori, 036-8564, Japan.
Stem Cell Res Ther. 2020 Aug 3;11(1):339. doi: 10.1186/s13287-020-01861-x.
It has been reported that the high-dosage administration of domestically approved pharmaceutical drugs, especially granulocyte colony-stimulating factor (G-CSF) and romiplostim (RP), is a rapid and appropriate medical treatment for preventing severe acute radiation syndrome (ARS) of victims exposed to lethal total-body irradiation (TBI). However, it remains unclear whether or not the clinical dosage administration of these drugs can ameliorate TBI-induced ARS and related high mortality in order to find various drug treatment options and less toxic optimum protocol depending on the situation surrounding the radiological accidents.
We assessed the clinical dosage administration in combination with G-CSF and RP as intraperitoneal injection in C57BL/6 J mice exposed to more than 7-Gy lethal dose of X-ray TBI for the survival study evaluated by the log-rank test. Bone marrow and splenic cells were collected on the 21st day, when 1 week has passed from last administration, to detect the level of cell apoptosis, intracellular reactive oxygen species (ROS), and nuclear factor erythroid 2-related factor 2 (Nrf2)-related anti-oxidative gene expressions, and enzyme-linked immune sorbent assay using sera was performed for cell senescence and inflammation status analyzed with one-way ANOVA and Tukey-Kramer or Bonferroni/Dunn multiple comparison tests.
The combined once-daily administration of 10 μg/kg G-CSF for 4 times and 10 μg/kg RP once a week for 3 times improve the 30-day survival rate of lethal TBI mice compared with untreated TBI mice, accompanied by a gradual increase in the body weight and hematopoietic cell numbers. The radio-mitigative effect is probably attributed to the scavenging of ROS and the reduction in cell apoptosis. These changes were associated with the upregulation of Nrf2 and its downstream anti-oxidative targets in TBI mice. Furthermore, this combination modulated TBI-induced cell senescence an d inflammation markers.
This study suggested that the clinical dosage administration in combination with G-CSF and RP may also have radio-mitigative effects on mice exposed to lethal TBI and may be a potent therapeutic agent for mitigating radiation-induced severe ARS.
据报道，高剂量使用国内批准的药物，特别是粒细胞集落刺激因子（G-CSF）和罗米司亭（RP），是预防暴露于致死全身照射（TBI）的受害者发生严重急性辐射综合征（ARS）的快速而合适的医疗手段。然而，这些药物的临床剂量是否能改善 TBI 引起的 ARS 和相关高死亡率尚不清楚，以便根据放射事故周围的情况找到各种药物治疗选择和毒性较小的最佳方案。
我们评估了 G-CSF 和 RP 联合腹腔注射的临床剂量，在 C57BL/6J 小鼠中，给予超过 7Gy 的致死剂量 X 射线 TBI 照射后，通过对数秩检验进行生存研究。在末次给药后 1 周，即第 21 天，采集骨髓和脾细胞，以检测细胞凋亡水平、细胞内活性氧（ROS）和核因子红细胞 2 相关因子 2（Nrf2）相关抗氧化基因表达，并用酶联免疫吸附试验检测血清中的细胞衰老和炎症状态，用单因素方差分析和 Tukey-Kramer 或 Bonferroni/Dunn 多重比较检验进行分析。
每天 10μg/kg G-CSF 联合使用 4 次，每周 10μg/kg RP 联合使用 3 次，可提高致死性 TBI 小鼠的 30 天存活率，与未治疗的 TBI 小鼠相比，体重和造血细胞数量逐渐增加。放射缓解作用可能归因于 ROS 的清除和细胞凋亡的减少。这些变化与 TBI 小鼠中 Nrf2 及其下游抗氧化靶基因的上调有关。此外，这种联合疗法还调节了 TBI 诱导的细胞衰老和炎症标志物。
本研究表明，G-CSF 和 RP 联合使用的临床剂量对暴露于致死性 TBI 的小鼠也可能具有放射缓解作用，可能是一种减轻辐射引起的严重 ARS 的有效治疗药物。
