阿糖胞苷诱发C57BL/6小鼠骨髓抑制的模型建立及其机制研究  

Animal Model Establishment and Its Mechanism of Cytarabine-Iduced Myelosuppression

作　　者：李亚玲 楚薇[1] 李俊杰 董娟娟 李高勤 靳晓杰 姚娟 刘永琦 LI Ya-ling;CHU Wei;Jun-Jie;DONG Juan-Juan;LI Gao-Qin;JIN Xiao-Jie;YAO Juan;LIU Yong-Qi(Provincial-Level Key Laboratory of Molecular Medicine of Major Diseases and Study on Prevention and Treatment of Traditional Chinese Medicine,Gansu University of Chinese Medicine;Key Laboratory of Dunhuang Medicine and Transformation Constructed by Chinese Ministry of Education and Gansu Province;Gansu Cancer Clinical Medical Research Center of Integated Traditional Chinese and Western Medicine,Lanzhou730000,GansuProvince,China)

机构地区：[1]甘肃中医药大学,甘肃省高校重大疾病分子医学与中医药防治研究省级重点实验室,甘肃兰州730000 [2]敦煌医学与转化省部共建教育部重点实验室,甘肃兰州730000 [3]甘肃省中西医结合肿瘤临床医学研究中心,甘肃兰州730000

出　　处：《中国实验血液学杂志》2022年第5期1376-1383,共8页Journal of Experimental Hematology

基　　金：2021年陇原青年创新创业人才项目(LYQN2021-2);甘肃省科技计划项目(18JR2FA001);甘肃省青年科技计划(21JR11RA149)。

摘　　要：目的:建立阿糖胞苷(Ara-C)诱发C57BL/6小鼠骨髓抑制的优化模型,并从细胞周期和凋亡角度初步探讨Ara-C诱发骨髓抑制的机制。方法:C57BL/6小鼠分别用Ara-C 50、100和200 mg/kg连续腹腔注射7 d后,监测小鼠生存率和体重变化,于实验7、14和21 d分别检测外周血象、骨髓有核细胞(BMNC)数量,HE染色观察骨髓、胸腺和脾形态,同时采用流式细胞术检测BMNC周期和凋亡。结果:Ara-C 200 mg/kg造成小鼠的死亡率为46.7%,其他剂量对小鼠死亡率无明显影响。3个不同剂量的Ara-C均可诱发小鼠出现骨髓抑制,表现为外周血细胞(WBC、Neu、RBC、PLT)数下降和BMNC数量减少(P<0.05),骨髓增生下降,伴随脾脏代偿造血和免疫抑制,以上表现与持续时间呈剂量依赖性,其中Ara-C 50 mg/kg组骨髓抑制恢复较快,200 mg/kg组骨髓抑制严重且恢复慢。流式细胞术检测结果显示,Ara-C可造成BMNC的S期和G_(2)/M期阻滞及凋亡增加。结论:Ara-C可诱发小鼠出现骨髓抑制,严重程度与持续时间呈剂量依赖性,以Ara-C 100 mg/kg造成骨髓抑制的模型更为优化,其机制与Ara-C抑制BMNC增殖和促进凋亡相关。Objective:To establish an optimized model of bone marrow suppression induced by cytarabine(Ara-C)in C57BL/6mice and preliminarily explore the mechanism of myelosuppression based on the cycle and apoptosis of BMNC. Methods:C57BL/6mice were intraperitoneally injected with Ara-C50, 100and200mg/kg for7days,respectively. The survival rate and body weight of C57BL/6mice were monitored. The number of peripheral blood cells and bone marrow nucleated cells(BMNC)was detected,and the morphology of bone marrow,thymus and spleen were measured on the7th, 14th and21st day of the experiment. The cycle and apoptosis of BMNC were also detected by flow cytometry. Results:Ara-C200mg/kg caused46.7% mortality in mice,and other doses had no significant effect on mortality. All doses of Ara-C induced bone marrow suppression in mice,as shown by a decrease in the number of peripheral blood cells(WBC,Neu,RBC,PLT)and BMNC(P< 0.05),decrease in bone marrow hyperplasia,accompanied by immunosuppression and compensatory hematopoiesis of the spleen,and the above manifestations and duration were dose-dependent. Among them,the myelosuppression caused by Ara-C50mg/kg recovered quickly,and caused by Ara-C200mg/kg was too severe. The result of flow cytometry showed that Ara-C could cause S and G_(2)/M arrest and increased apoptosis in BMNC. Conclusion:Ara-C can induce myelosuppression in mice with a dosedependent severity and duration,and the model of myelosuppression with Ara-C100mg/kg is more optimized. The mechanism is related to the inhibition of BMNC proliferation and the promotion of apoptosis.

关 键 词：阿糖胞苷 骨髓抑制 小鼠模型 

分 类 号：R329[医药卫生—人体解剖和组织胚胎学]