目的 探究芪参益气滴丸对阿霉素所致小鼠心脏毒性的影响及其作用机制。方法 将40只C57BL/6J小鼠按照随机数字表法分为对照组，模型组，芪参益气滴丸低、高剂量（150、600 mg/kg）组，每组10只。芪参益气滴丸低、高剂量组分别ig 150 mg/kg、600 mg/kg芪参益气滴丸，对照组和模型组均ig等量生理盐水，每日上午1次，连续14 d后开始造模。除对照组外，其余3组小鼠造模均采用尾iv 1 mg/mL多柔比星脂质体注射液，按照小鼠体质量每次给予5 mg/kg，每周1次，共3周，累积量为15 mg/kg建立心脏毒性损伤模型。对照组尾iv等体积生理盐水，期间密切观察并记录小鼠体质量变化及死亡情况。末次注射多柔比星脂质体1周后，完成所有存活小鼠超声心动观测并处死留取心脏及血液标本。观察小鼠超声心动图变化评估心功能情况，应用Millar压力–容积系统检测小鼠血流动力学改变。通过苏木精–伊红（HE）染色观察心肌细胞损伤，利用酶联免疫吸附测定法（ELISA）测定血清肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）水平，使用实时定量逆转录聚合酶链式反应（qRT-PCR）检测核因子-κB（NF-κB）及Toll样受体-4（TLR-4）表达。结果 小鼠存活率为100%；模型组小鼠体质量较对照组相比明显降低（P＜0.05），芪参益气滴丸150、600 mg/kg组较模型组有上升趋势，但未呈现统计学差异。与模型组相比，芪参益气滴丸150、600 mg/kg组左室射血分数（LVEF）、左室短轴缩短率（LVFS）明显增加（P＜0.05、0.01）；芪参益气滴丸600 mg/kg组干预后，小鼠左室收缩末期内径（LVIDs）、收缩末期左室后壁厚度（LVPWs）、左室容积（LV Vol）变化显著（P＜0.05、0.01）。与模型组比较，芪参益气滴丸150、600 mg/kg组小鼠心率（HR）均明显升高（P＜0.05、0.01）。与模型组相比，芪参益气滴丸150、600 mg/kg组＋dp/dt_max和−dp/dt_max均显著改善（P＜0.01）。与模型组比较，芪参益气滴丸150、600 mg/kg组小鼠血清TNF-α、IL-1β、IL-6水平明显降低（P＜0.01），且芪参益气滴丸600 mg/kg组下降趋势更显著。HE染色结果显示，芪参益气滴丸150、600 mg/kg组心肌损伤程度较模型组明显减轻。经芪参益气滴丸预干预后，小鼠心肌TLR-4和NF-κB mRNA表达水平显著降低（P＜0.05、0.01）。结论 芪参益气滴丸通过提高心功能，减轻心肌损伤，降低炎性因子水平，并通过调节TLR-4/NF-κB信号通路等多途径实现保护阿霉素所致的心脏毒性。

Objective To investigate the effect and mechanism of Qishen Yiqi Dropping Pills on adriamycin induced cardiotoxicity in mice. Methods Forty C57BL/6J mice were randomly divided into control group, model group, Qishen Yiqi Dropping Pills 150 mg/(kg∙d)group, and Qishen Yiqi Dropping Pills 600 mg/kg group, with 10 mice in each group. Qishen Yiqi Dropping Pills group were ig 150 mg/kg and 600 mg/kg Qishen Yiqi Dropping Pills, while control group and model group were ig the same amount of normal saline, once daily in the morning. The model was established after 14 consecutive days. After 14 days of Qishen Yiqi Dripping Pills intervention, except for the control group, the other 3 groups were injected with 1 mg/mL Doxorubicin Liposome Injection through tail vein, and the mice were given 5 mg/kg each time according to the body weight, once a week for 3 weeks, and the cumulative amount was 15 mg/kg to establish the cardiotoxic injury model. In the control group, the same volume of normal saline was injected into the tail vein. During the period, the changes of body weight and death of mice were closely observed and recorded. One week after the last injection of liposome doxorubicin, echocardiography was performed and all surviving mice were sacrificed for heart and blood samples. Echocardiography was used to evaluate the cardiac function, and Millar pressure-volume system was used to detect the hemodynamic changes of mice. Myocardial cell injury was observed by hematoxylin and eosin (HE) staining. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA). Reverse transcriptase polymerase chain reaction (qRT-PCR) was used to detect the expression of nuclear factor-κB (NF-κB) and Toll-like receptor-4 (TLR-4). The survival rate of mice was 100%. Compared with the control group, the body weight of the model group was significantly decreased (P < 0.05). Results Compared with the model group, the Qishen Yiqi Dripping Pills 150 and 600 mg/kg groups had an upward trend, but there was no statistical difference. Compared with model group, left ventricular ejection fraction (LVEF) and left ventricular short-axis shortening rate (LVFS) were significantly increased in Qishen Yiqi Dripping Pills 150 and 600 mg/kg groups (P < 0.05, 0.01). The left ventricular end-systolic diameter (LVIDs), left ventricular posterior wall thickness (LVPWs), and LV Vols of mice in Qishen Yiqi Dripping Pills 600 mg/kg group were significantly changed (P < 0.05, 0.01). Compared with model group, HR of mice in Qishen Yiqi Dropping Pills 150 and 600 mg/kg groups were significantly increased (P < 0.05, 0.01). Compared with the model group, the + dp/dt_max and −dp/dt_max of Qishen Yiqi Dripping Pills 150 and 600 mg/kg groups were significantly improved (P < 0.01). Compared with model group, the serum levels of TNF-α, IL-1β, and IL-6 in Qishen Yiqi Dropping Pills 150 and 600 mg/kg groups were significantly decreased (P < 0.01), and the decreasing trend was more significant in Qishen Yiqi Dropping Pills 600 mg/kg group. The results of HE staining showed that the myocardial injury of Qishen Yiqi Dripping Pills 150 and 600 mg/kg groups was significantly reduced compared with the model group. The mRNA expression levels of TLR-4 and NF-κB in myocardium of mice were significantly decreased after pre-intervention with Qishen Yiqi Dripping Pills (P < 0.05, 0.01). Conclusion Qishen Yiqi Dripping Pills can protect the cardiac toxicity caused by doxorubicin by improving cardiac function, reducing myocardial injury, reducing the level of inflammatory factors, and regulating TLR-4/NF-κB signaling pathway.

R914

天津市杰出青年科学基金(17JCJQJC46200);克拉玛依市人民医院院级科研项目(Ry2020011)