乌司他丁改善顺铂致心肌损伤的作用及机制  

Improvement effects and mechanism of ulinastatin on cisplatin-induced myocardial injury

作　　者：任家孚 陈鹏飞 阿荣[1] 李婧[1] REN Jiafu;CHEN Pengfei;A Rong;LI Jing(Dept.of Cardiovascular Medicine,the Affiliated Hospital of Inner Mongolia Medical University,Hohhot 010050,China)

机构地区：[1]内蒙古医科大学附属医院心血管内科,呼和浩特010050

出　　处：《中国药房》2025年第8期920-925,共6页China Pharmacy

基　　金：国家自然科学基金地区科学基金项目(No.82260075);内蒙古自治区自然科学基金项目(No.2024QN08043);内蒙古自治区高等学校科学研究项目(No.NJZY23143);内蒙古医科大学附属医院科研项目(No.2023NYFYGG020);内蒙古医科大学附属医院高层次人才项目“航行系列”。

摘　　要：目的探讨乌司他丁(UTI)对顺铂(CP)诱导心肌损伤的改善作用及潜在机制。方法将家兔随机分为空白组(blank组,生理盐水2mL/d,连续7d),CP组(150mg/m^(2),第1、4天)、乌司他丁低/高剂量组(UTIL组/UTIH组,UTL2.5万单位/kg或5.0万单位/kg,每天1次,连续7 d+CP 150 mg/m^(2),第1、4天)、c-Jun氨基端激酶(JNK)抑制剂组(JNKi组,SP60012515 mg/kg,第1、4天+CP 150 mg/m^(2),第1、4天+生理盐水2 mL/d,其余5 d)。除blank组外,其余各组家兔经一侧耳缘静脉注射相应药液和(或)生理盐水。检测实验第1天和第8天各组家兔血清中肌钙蛋白Ⅰ(cTnⅠ)水平以及实验第8天其心肌组织中超氧化物歧化酶(SOD)、谷胱甘肽(GSH)、丙二醛(MDA)水平,观察其心肌组织病理学改变和心肌细胞凋亡情况,检测其心肌组织中B细胞淋巴瘤2(Bcl-2)、Bcl-2相关X蛋白(Bax)、JNK、磷酸化JNK(p-JNK)、线粒体裂解因子(Mff)、动力相关蛋白1(Drp1)的表达情况。结果与blank组比较,CP组家兔第8天的心肌组织损伤明显,细胞凋亡指数、血清中cTnⅠ水平和心肌组织中MDA水平以及Bax、JNK、p-JNK、Mff、Drp1蛋白的表达均显著升高或上调,SOD水平和Bcl-2蛋白的表达均显著降低或下调(P<0.05)。与CP组比较,各药物组家兔心肌组织损伤均有所好转,细胞凋亡指数、血清中cTnⅠ水平和心肌组织中MDA以及Bax、JNK、p-JNK、Mff(UTIL组除外)、Drp1蛋白的表达均显著降低或下调,SOD、GSH水平和Bcl-2蛋白的表达均显著升高或上调(P<0.05),且UTIH组、JNKi组部分指标的改善显著优于UTIL组(P<0.05)。结论UTI可改善CP诱导的心肌损伤,其潜在机制可能与拮抗氧化应激和抑制JNK/Mff信号通路有关。OBJECTIVE To investigate the improvement effects and potential mechanism of ulinastatin(UTI)on cisplatin(CP)-induced myocardial injury.METHODS Rabbits were used as study subjects and randomly divided into blank group(normal saline 2 mL/d,for consecutive 7 d),CP group(150 mg/m^(2),on the 1st and 4th day),UTI low-dose/high-dose group(UTIL/UTIH group,UTL 25000 or 50000 IU/kg,once a day,for consecutive 7 d),c-Jun N-terminal kinase(JNK)inhibitor group(JNKi group,SP60012515 mg/kg,on the 1st and 4th day+CP 150 mg/m^(2),on the 1st and 4th day+normal saline 2 mL/d,on the other 5 days).Except for the blank group,rabbits in the other groups were injected with relevant medicine and/or normal saline via a marginal ear vein on one side.The serum level of cardiac troponinⅠ(cTnⅠ)in rabbits on the 1st and 8th days of the detection experiment,as well as the levels of superoxide dismutase(SOD),glutathione(GSH)and malondialdehyde(MDA)in myocardial tissue on the 8th day of the experiment,were all measured in each group.The pathological changes and myocardial cell apoptosis in myocardial tissue were observed,and the protein expressions of B-cell lymphoma-2(Bcl-2),Bcl-2 associated X protein(Bax),JNK,phosphorylated JNK(P-JNK),mitochondrial fission factor(Mff),and dynamin-related protein 1(Drp1)in myocardial tissue were all determined.RESULTS Compared with the blank group,the CP group showed significant myocardial injury.The cell apoptotic rate,the levels of cTnⅠin serum and MDA in myocardial tissue,as well as protein expressions of Bax,JNK,p-JNK,Mff,and Drp1,were all significantly increased or up-regulated,SOD level and protein expression of Bcl-2 significantly reduced or down+regulated(P<0.05).Compared with the CP group,the myocardial injury in rabbits from each drug treatment group showed improvement.The cell apoptosis index,the levels of cTnⅠin serum and MDA in myocardial tissue,as well as protein expressions of Bax,JNK,p-JNK,Mff(except for UTIL group),and Drp1,were all significantly reduced or down-regulated,while SOD,GSH le

关 键 词：乌司他丁 顺铂 心肌损伤 JNK/Mff信号通路 

分 类 号：R965[医药卫生—药理学] R541.9[医药卫生—药学]