Department of Radiation Oncology, University of Maryland, School of Medicine, MD, USA.
Health Phys. 2012 Oct;103(4):411-26. doi: 10.1097/HP.0b013e31826525f0.
The development of medical countermeasures against the acute gastrointestinal subsyndrome of the acute radiation syndrome in humans requires well characterized and validated animal models. These models must adhere to the criteria of the U.S. Food and Drug Administration's Animal Rule and consider the natural history and clinical context of the human radiation response and treatment in the nuclear terrorist scenario. The models must define the radiation dose- and time-dependent relationships for mortality and major signs of morbidity, including concurrent damage in other organs, such as the bone marrow, that may contribute to the overall mortality and morbidity. There are no such models of the gastrointestinal syndrome in response to total-body irradiation in the nonhuman primate. Herein, these parameters are defined for the rhesus macaque exposed to potentially lethal doses of radiation and administered medical management. Rhesus macaques (n = 69) were exposed bilaterally to 6 MV linear accelerator-derived photon total body irradiation to midline tissue (thorax) doses ranging from 10.0 to 14.0 Gy at 0.80 Gy min(-1). Following irradiation, all animals were administered supportive care consisting of fluids, anti-emetics, anti-diarrheal medication, antibiotics, blood transfusions, analgesics, and nutrition. The primary endpoint was survival at 15 d post-irradiation. Secondary endpoints included indices of dehydration, diarrhea, weight loss, hematological parameters, cellular histology of the small and large intestine, and mean survival time of decedents. Mortality within the 15-d in vivo study defined the acute gastrointestinal syndrome and provided an LD30/15 of 10.76 Gy, LD50/15 of 11.33 Gy, and an LD70/15 of 11.90 Gy. Intestinal crypt and villus loss were dose- and time-dependent with an apparent nadir 7 d post-irradiation and recovery noted thereafter. Severe myelosuppression and thrombocytopenia were noted in all animals, requiring the administration of antibiotics and blood transfusions. The model defines the dose response relationship and time course of acute gastrointestinal syndrome-induced morbidity and mortality in the rhesus macaque.
开发针对人类急性辐射综合征急性胃肠道综合征的医学对策需要经过良好特征描述和验证的动物模型。这些模型必须符合美国食品和药物管理局动物规则的标准，并考虑到核恐怖情景下人类辐射反应和治疗的自然史和临床背景。模型必须定义死亡率和主要发病迹象与辐射剂量和时间的关系，包括骨髓等其他器官的并发损伤，这些损伤可能导致整体死亡率和发病率。在非人类灵长类动物中，没有针对全身照射引起的胃肠道综合征的此类模型。在此，定义了接受潜在致死剂量辐射并接受医疗管理的恒河猴的这些参数。恒河猴（n = 69）接受双侧 6 MV 直线加速器衍生光子全身照射，中线组织（胸部）剂量范围为 10.0 至 14.0 Gy，剂量率为 0.80 Gy min(-1)。照射后，所有动物均接受支持性护理，包括液体、止吐药、止泻药、抗生素、输血、镇痛药和营养。主要终点是照射后 15 天的存活。次要终点包括脱水、腹泻、体重减轻、血液学参数、小肠和大肠的细胞组织学以及死者的平均存活时间。15 天体内研究中的死亡率定义了急性胃肠道综合征，并提供了 10.76 Gy 的急性胃肠道综合征 LD30/15、11.33 Gy 的 LD50/15 和 11.90 Gy 的 LD70/15。肠隐窝和绒毛损失与剂量和时间有关，在照射后 7 天达到明显的最低点，此后有所恢复。所有动物均出现严重的骨髓抑制和血小板减少，需要使用抗生素和输血。该模型定义了恒河猴急性胃肠道综合征诱导的发病率和死亡率的剂量反应关系和时间过程。
