Wu Dijiong, Wen Xiaowen, Liu Wenbin, Xu Linlong, Ye Baodong, Zhou Yuhong
Department of Hematology, First Affiliated Hospital of Zhejiang Chinese Medical University, National Clinical Research Base of Traditional Chinese Medicine, Hangzhou, Zhejiang 310006, P.R. China.
Department of Internal Medicine, Central Hospital of Jinhua Affiliated to Zhejiang University, Jinhua, Zhejiang 321001, P.R. China.
Exp Ther Med. 2018 Feb;15(2):1449-1455. doi: 10.3892/etm.2017.5523. Epub 2017 Nov 17.
Iron overload is commonly encountered during the course of aplastic anemia (AA), but no composite animal model has been developed yet, which hinders drug research. In the present study, the optimal dosage and duration of intraperitoneal iron dextran injection for the development of an iron overload model in mice were explored. A composite model of AA was successfully established on the principle of immune-mediated bone marrow failure. Liver volume, peripheral hemogram, bone marrow pathology, serum iron, serum ferritin, pathological iron deposition in multiple organs (liver, bone marrow, spleen), liver hepcidin, and bone morphogenetic protein 6 (BMP6), SMAD family member 4 (SMAD4) and transferrin receptor 2 (TfR2) mRNA expression levels were compared among the normal control, AA, iron overload and composite model groups to validate the composite model, and explore the pathogenesis and features of iron overload in this model. The results indicated marked increases in iron deposits, with significantly increased liver/body weight ratios as well as serum iron and ferritin in the iron overload and composite model groups as compared with the normal control and AA groups (P<0.05). There were marked abnormalities in iron regulation gene expression between the AA and composite model groups, as seen by the significant decrease of hepcidin expression in the liver (P<0.01) that paralleled the changes in BMP6, SMAD4, and TfR2. In summary, a composite mouse model with iron overload and AA was successfully established, and AA was indicated to possibly have a critical role in abnormal iron metabolism, which promoted the development of iron deposits.
铁过载在再生障碍性贫血（AA）病程中较为常见，但尚未建立复合动物模型，这阻碍了药物研究。在本研究中，探索了腹腔注射右旋糖酐铁建立小鼠铁过载模型的最佳剂量和持续时间。基于免疫介导的骨髓衰竭原理成功建立了AA复合模型。比较正常对照组、AA组、铁过载组和复合模型组的肝脏体积、外周血象、骨髓病理、血清铁、血清铁蛋白、多器官（肝脏、骨髓、脾脏）的病理性铁沉积、肝脏铁调素、骨形态发生蛋白6（BMP6）、SMAD家族成员4（SMAD4）和转铁蛋白受体2（TfR2）mRNA表达水平，以验证复合模型，并探讨该模型中铁过载的发病机制和特征。结果表明，与正常对照组和AA组相比，铁过载组和复合模型组的铁沉积显著增加，肝/体重比、血清铁和铁蛋白也显著升高（P<0.05）。AA组和复合模型组之间铁调节基因表达存在明显异常，肝脏中铁调素表达显著降低（P<0.01），与BMP6、SMAD4和TfR2的变化一致。综上所述，成功建立了铁过载和AA复合小鼠模型，提示AA可能在铁代谢异常中起关键作用，促进了铁沉积的发展。
