Department of Surgery, University of Nebraska Medical Center, Omaha, NE, United States.
Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States.
Int J Radiat Oncol Biol Phys. 2014 Feb 1;88(2):404-411. doi: 10.1016/j.ijrobp.2013.10.037. Epub 2013 Dec 5.
Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease.
We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals.
At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis.
The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.
人类肝脏对辐射具有异常的敏感性，这限制了它在癌症治疗或肝细胞移植预处理中的应用。由于辐射性肝损伤的特征性静脉闭塞性病变不会在啮齿动物中发生，因此一直没有实验模型来研究安全放射治疗的极限或探索肝静脉闭塞性疾病的发病机制。
我们在 13 只灵长类动物（食蟹猴）中进行了一项剂量递增研究，使用分次立体定向体放射治疗。
在 40Gy 以上剂量时，动物会出现类似于人类辐射性肝损伤的全身综合征，表现为白蛋白减少、碱性磷酸酶升高、食欲不振、腹水和正常胆红素。更高的辐射剂量会导致致命的严重疾病，大约在辐射后 10 周需要安乐死。即使在辐射性肝损伤较轻或不存在的较低剂量下，通过半乳糖蛋白介导的功能成像也证明了肝细胞存在潜在的显著损伤。当这些猴子接受含有高浓度葡萄糖的肠外营养时，会发生肝衰竭伴脑病。组织学上，肝脏通过不常见的内膜肿胀导致中央阻塞，进而发展为中央纤维化。
食蟹猴作为首例人类静脉闭塞性辐射性肝损伤的动物模型，为研究静脉闭塞的早期变化和发病机制、确定非致死性治疗剂量以及研究减轻辐射损伤的实验治疗方法提供了资源。
