Abstract

Purpose

Animal models that accurately reflect human responses to radiation injury are needed for advanced mechanistic investigation and development of effective therapeutics. The rabbit is an established animal model accepted by the FDA for studies of cardiovascular disease, lipid metabolism, the development of anticoagulants, testing of bone implants, and the development of treatments for infectious diseases such as HIV. The purpose of this study was to investigate the New Zealand White (NZW) Rabbit model as a model of acute radiation exposure because of its established similarity to human vascular, immune, and coagulation responses.

Materials and methods

Two sequential studies were performed in a total of 81 male NZW rabbits, 16–20 weeks of age. All animals underwent clinical observations and peripheral blood analyses following a single dose of 0, 6, 7, 8, 8.5, 9, or 10 Gy of total body irradiation via a 6 MV Linear accelerator photon source on day 0. Animals were treated with timed release fentanyl patch (days 0–30), subcutaneous hydration (day 1, Study 2 only), and oral sulfamethoxazole/trimethoprim 30 mg/kg once daily (days 3–30) and were followed for 30 days or to time of mortality.

Results

Study 1 revealed the estimated LD30, −50, −70, and −90 with 95% confidence intervals (CI) at 30 days to be 6.7 (CI: 5.9–7.4), 7.3 (CI: 6.7–7.8), 7.9 (CI: 7.3–8.4), and 8.8 (CI: 7.9–9.7) Gy, respectively. In study 2, a survey of blood coagulation and biochemical parameters were performed over time and necropsy. Complete blood counts taken from animals exposed to 7, 8, or 10 Gy, demonstrated dose-dependent depletion of lymphocytes, neutrophils, and platelets. Platelet counts recovered to baseline levels in survivors by day 30, whereas lymphocyte and neutrophil counts did not. Decedent animals demonstrated grade 3 or 4 neutropenia and lymphopenia at time of death; 64% of the decedents experienced a 30% or greater drop in hematocrit. Decedent animals demonstrated more than 100% increases from serum baseline levels of blood urea nitrogen, creatinine, aspartate aminotransferase, and triglyceride levels at the time of death whereas survivors on average demonstrated modest or no elevation.

Conclusion

This NZW rabbit model demonstrates dose-dependent depletion of hematopoietic parameters. The LD_50/30 of 7.8 Gy (95% CI: 6.6–8.4) with supportive care appears to be close to the ranges reported for rhesus macaques (5.25–7.44 Gy) and humans (6–8 Gy) with supportive care. These findings support the utility of the NZW rabbit model for further mechanistic investigation of acute radiation exposure and medical countermeasure testing.

中文翻译：

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新西兰白兔急性辐射综合征动物模型：支持性护理后辐射剂量的造血和凝血参数

摘要

目的

需要能够准确反映人类对辐射损伤反应的动物模型来进行先进的机械研究和开发有效的治疗方法。兔子是 FDA 接受的已建立的动物模型，用于研究心血管疾病、脂质代谢、抗凝血剂的开发、骨植入物的测试以及艾滋病毒等传染病的治疗方法的开发。本研究的目的是研究新西兰白 (NZW) 兔模型作为急性辐射暴露模型，因为它与人体血管、免疫和凝血反应具有相似性。

材料和方法

在总共 81 只 16-20 周龄的雄性 NZW 兔中进行了两项连续研究。在第 0 天通过 6 MV 直线加速器光子源进行单剂量 0、6、7、8、8.5、9 或 10 Gy 全身照射后，所有动物都接受了临床观察和外周血分析。释放芬太尼贴剂（第 0-30 天）、皮下水化（第 1 天，仅限研究 2）和口服磺胺甲恶唑/甲氧苄啶 30 mg/kg，每天一次（第 3-30 天），并随访 30 天或直至死亡。

结果

研究 1 显示 30 天时估计的 LD30、-50、-70 和 -90 和 95% 置信区间 (CI) 分别为 6.7 (CI: 5.9–7.4)、7.3 (CI: 6.7–7.8)、7.9 (CI) : 7.3–8.4) 和 8.8 (CI: 7.9–9.7) Gy，分别。在研究 2 中，随着时间的推移和尸检对血液凝固和生化参数进行了调查。从暴露于 7、8 或 10 Gy 的动物身上采集的全血细胞计数显示淋巴细胞、中性粒细胞和血小板的剂量依赖性消耗。幸存者的血小板计数在第 30 天恢复到基线水平，而淋巴细胞和中性粒细胞计数没有。死亡动物在死亡时表现出 3 级或 4 级中性粒细胞减少症和淋巴细胞减少症；64% 的死者血细胞比容下降了 30% 或更多。死亡动物的血尿素氮、肌酐、

结论

这种 NZW 兔模型显示了造血参数的剂量依赖性消耗。支持治疗的 7.8 Gy (95% CI: 6.6-8.4)的 LD _50/30似乎接近报告的支持治疗恒河猴 (5.25-7.44 Gy) 和人类 (6-8 Gy) 的范围。这些发现支持 NZW 兔模型在急性辐射暴露和医学对策测试的进一步机械研究中的效用。