环磷酰胺心脏毒性小鼠模型的建立及其超声学评价

Establishment of cyclophosphamide-induced cardiotoxicity mouse model and ultrasound evaluation

目的分析环磷酰胺对小鼠心脏损伤的剂量依赖关系，建立环磷酰胺小鼠心脏损伤模型。方法选用30只7～8周龄的C57BL／6小鼠随机分为6组：单疗程对照组，双疗程对照组，单疗程低剂量环磷酰胺组，双疗程低剂量环磷酰胺组，单疗程高剂量环磷酰胺组，双疗程高剂量环磷酰胺组。于指定时间对小鼠进行心脏超声检查，第5周对小鼠心脏进行病理切片。结果与对照组相比，单疗程和双疗程的低剂量环磷酰胺及单疗程高剂量环磷酰胺处理后，小鼠毛色、活动度、体重及心脏功能变化略有降低，但差异无统计学意义（P〉0．05）。双疗程高剂量环磷酰胺组小鼠则活动度变差，毛发稀疏，体重增加受到抑制（P〈0．05），左室收缩功能减低（P〈0．05），舒张功能指标具有降低趋势。镜下显示双疗程高剂量环磷酰胺组小鼠心脏细胞肥大、排列紊乱，心肌组织纤维化。结论C57BL／6小鼠双疗程高剂量腹腔注射环磷酰胺能够引起心脏功能明显受损，是建立环磷酰胺致小鼠心脏损伤的理想方法，为后续机制研究提供了理想模型。

Objective To analyze the dose dependent cardiotoxicity of cyclophosphamide and thus establish the mouse models for understanding the underlying mechanisms. Methods Thirty mice （7 - 8 weeks old） were randomly divided into 6 groups ： control of one course group, control of two courses group, one course of low dose （50 mg/kg） group, two courses of low dose group, one course of high dose （100 mg/ kg） group, two courses of high dose group. The changes of cardiac function and morphology were analyzed at indicated times by ultrasound and histology respectively. Results Compared with the control groups, injection of low dose cyclophosphamide either with one course or two courses, and injection of high dose with only one course had no in statically significant changes in hair color, physical activity, body weight and cardiac function（ P 〈0.05）. Treatment of two courses with high dose resulted in significant decrease of physical activity and body weight （P 〈 0.05 ）. Meanwhile, cardiac systolic function was significantly decreased（ P〈0.05）. Histology study revealed robust cardiac hypertrophy and fibrosis. Conclusions Two courses of intraperitoneal injection of cyclophosphamide at high dose result in obvious cardiotoxicity, especially systolic dysfunction. Intraperitoneal injection of two courses of cyclophosphamide serves as a good strategy to induce cardiotoxicity in mice, which could be applied for future mechanism study.