目的 探究芪參益氣滴丸對阿霉素所致小鼠心臟毒性的影響及其作用機制。方法 將40只C57BL/6J小鼠按照隨機數(shù)字表法分為對照組，模型組，芪參益氣滴丸低、高劑量（150、600 mg/kg）組，每組10只。芪參益氣滴丸低、高劑量組分別ig 150 mg/kg、600 mg/kg芪參益氣滴丸，對照組和模型組均ig等量生理鹽水，每日上午1次，連續(xù)14 d后開始造模。除對照組外，其余3組小鼠造模均采用尾iv 1 mg/mL多柔比星脂質(zhì)體注射液，按照小鼠體質(zhì)量每次給予5 mg/kg，每周1次，共3周，累積量為15 mg/kg建立心臟毒性損傷模型。對照組尾iv等體積生理鹽水，期間密切觀察并記錄小鼠體質(zhì)量變化及死亡情況。末次注射多柔比星脂質(zhì)體1周后，完成所有存活小鼠超聲心動觀測并處死留取心臟及血液標本。觀察小鼠超聲心動圖變化評估心功能情況，應(yīng)用Millar壓力–容積系統(tǒng)檢測小鼠血流動力學(xué)改變。通過蘇木精–伊紅（HE）染色觀察心肌細胞損傷，利用酶聯(lián)免疫吸附測定法（ELISA）測定血清腫瘤壞死因子-α（TNF-α）、白細胞介素-1β（IL-1β）、白細胞介素-6（IL-6）水平，使用實時定量逆轉(zhuǎn)錄聚合酶鏈式反應(yīng)（qRT-PCR）檢測核因子-κB（NF-κB）及Toll樣受體-4（TLR-4）表達。結(jié)果 小鼠存活率為100%；模型組小鼠體質(zhì)量較對照組相比明顯降低（P＜0.05），芪參益氣滴丸150、600 mg/kg組較模型組有上升趨勢，但未呈現(xiàn)統(tǒng)計學(xué)差異。與模型組相比，芪參益氣滴丸150、600 mg/kg組左室射血分數(shù)（LVEF）、左室短軸縮短率（LVFS）明顯增加（P＜0.05、0.01）；芪參益氣滴丸600 mg/kg組干預(yù)后，小鼠左室收縮末期內(nèi)徑（LVIDs）、收縮末期左室后壁厚度（LVPWs）、左室容積（LV Vol）變化顯著（P＜0.05、0.01）。與模型組比較，芪參益氣滴丸150、600 mg/kg組小鼠心率（HR）均明顯升高（P＜0.05、0.01）。與模型組相比，芪參益氣滴丸150、600 mg/kg組＋dp/dt_max和−dp/dt_max均顯著改善（P＜0.01）。與模型組比較，芪參益氣滴丸150、600 mg/kg組小鼠血清TNF-α、IL-1β、IL-6水平明顯降低（P＜0.01），且芪參益氣滴丸600 mg/kg組下降趨勢更顯著。HE染色結(jié)果顯示，芪參益氣滴丸150、600 mg/kg組心肌損傷程度較模型組明顯減輕。經(jīng)芪參益氣滴丸預(yù)干預(yù)后，小鼠心肌TLR-4和NF-κB mRNA表達水平顯著降低（P＜0.05、0.01）。結(jié)論 芪參益氣滴丸通過提高心功能，減輕心肌損傷，降低炎性因子水平，并通過調(diào)節(jié)TLR-4/NF-κB信號通路等多途徑實現(xiàn)保護阿霉素所致的心臟毒性。

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

天津市杰出青年科學(xué)基金(17JCJQJC46200);克拉瑪依市人民醫(yī)院院級科研項目(Ry2020011)