Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Myelo Therapeutics GmbH, Berlin, Germany.
Int J Radiat Biol. 2023;99(7):1130-1138. doi: 10.1080/09553002.2023.2170491. Epub 2023 Jan 25.
A mass casualty disaster involving radiological or nuclear agents continues to be a public health concern which requires consideration of both acute and late tissue toxicities in exposed victims. With the advent of advanced treatment options for the mitigation of hematological injuries, there are likely to be survivors of total body irradiation (TBI) exposures as high as 8-10 Gy. These survivors are at risk for a range of delayed multi-organ morbidities including progressive renal failure.
Here, we established the WAG/RijCmcr rat as an effective model for the evaluation of medical countermeasures (MCM) for acute hematologic radiation syndrome (H-ARS). The LD dose for adult and pediatric WAG/RijCmcr rats was determined for both sexes. We then confirmed the FDA-approved MCM pegfilgrastim (peg-GCSF, Neulasta®) mitigates H-ARS in adult male and female rats. Finally, we evaluated survival and renal dysfunction up to 300 d post-TBI in male and female adult rats.
In the WAG/RijCmcr rat model, 87.5% and 100% of adult rats succumb to lethal hematopoietic acute radiation syndrome (H-ARS) at TBI doses of 8 and 8.5 Gy, respectively. A single dose of the hematopoietic growth factor peg-GCSF administered at 24 h post-TBI improved survival during H-ARS. Peg-GCSF treatment improved 30 d survival from 12.5% to 83% at 8 Gy and from 0% to 63% at 8.5 Gy. We then followed survivors of H-ARS through day 300. Rats exposed to TBI doses greater than 8 Gy had a 26% reduction in survival over days 30-300 compared to rats exposed to 7.75 Gy TBI. Concurrent with the reduction in long-term survival, a dose-dependent impairment of renal function as assessed by blood urea nitrogen (BUN) and urine protein to urine creatinine ratio (UP:UC) was observed.
Together, these data show survivors of H-ARS are at risk for the development of delayed renal toxicity and emphasize the need for the development of medical countermeasures for delayed renal injury.
涉及放射性或核制剂的大规模伤亡灾难仍然是公共卫生关注的问题，需要考虑暴露受害者的急性和迟发性组织毒性。随着减轻血液损伤的先进治疗选择的出现，全身照射 (TBI) 暴露高达 8-10Gy 的幸存者很可能会出现。这些幸存者有一系列迟发性多器官疾病的风险，包括进行性肾功能衰竭。
在这里，我们建立了 WAG/RijCmcr 大鼠作为评估急性血液辐射综合征 (H-ARS) 医疗对策 (MCM) 的有效模型。确定了成年和幼鼠 WAG/RijCmcr 大鼠的 LD 剂量。然后，我们证实了 FDA 批准的 MCM 培非格司亭（peg-GCSF，Neulasta®）可减轻成年雄性和雌性大鼠的 H-ARS。最后，我们评估了雄性和雌性成年大鼠 TBI 后 300 天内的生存和肾功能障碍。
在 WAG/RijCmcr 大鼠模型中，8Gy 和 8.5Gy 的 TBI 剂量分别使 87.5%和 100%的成年大鼠死于致命的造血急性辐射综合征 (H-ARS)。TBI 后 24 小时给予单次造血生长因子 peg-GCSF 可改善 H-ARS 期间的生存。Peg-GCSF 治疗可将 8Gy 时的 30d 存活率从 12.5%提高到 83%，将 8.5Gy 时的存活率从 0%提高到 63%。然后，我们通过第 300 天对 H-ARS 的幸存者进行了随访。与接受 7.75Gy TBI 的大鼠相比，接受大于 8Gy TBI 的大鼠在第 30-300 天的长期生存中降低了 26%。与长期生存率降低一致，观察到肾功能的剂量依赖性损害，如血尿素氮 (BUN) 和尿蛋白与尿肌酐比值 (UP:UC) 评估。
综上所述，这些数据表明 H-ARS 的幸存者有发生迟发性肾毒性的风险，并强调需要开发用于迟发性肾损伤的医疗对策。
