线粒体分裂抑制剂对脓毒症大鼠器官功能的保护作用

Protective effect of mitochondrial fission inhibitor on organ function in septic rat

目的观察线粒体分裂抑制剂(Mdivi-1)对脓毒症大鼠器官功能的保护作用。方法采用盲肠结扎穿孔术(CLP)复制大鼠脓毒症模型,将120只体重为200~220g的SD大鼠,随机分成假手术组、脓毒症组、常规治疗组、常规治疗+Mdivi-1(1mg/kg)治疗组(M1)、常规治疗+Mdivi-1(3mg/kg)治疗组(M3),其中常规治疗组在CLP12h后从股静脉给予乳酸林格液输注,同时给予抗生素头孢呋辛钠(100mg/kg)和血管活性药物多巴胺;M1组和M3组是在常规治疗液体中给予Mdivi-11mg/kg和3mg/kg从股静脉输注;脓毒症组在CLP12h后,股动静脉插管后放置;假手术组大鼠除不结扎盲肠和穿孔外,其余操作同模型组。观察各组对脓毒症大鼠肝脏、肾脏、肠道和心脏功能及动物存活时间、存活率的影响。结果与假手术组比较,脓毒症后大鼠的器官功能明显受损,表现为谷草转氨酶(AST)、谷丙转氨酶(ALT)、尿素氮(BUN)和肌酐(Cr)、肌钙蛋白T以及D-乳酸在脓毒症后均升高,与假手术组比较,差异有统计学意义;采用输液、抗感染以及血管活性药物常规治疗并不能明显改善大鼠的器官功能;不同浓度(1、3mg/kg)的线粒体分裂抑制剂Mdivi-1联合常规治疗可明显改善肝脏、肾脏、肠道和心脏功能,其中3mg/kg效果更好,与常规治疗组比较,AST为(152.2±11.8比216.5±14.7,P=0.000),ALT为(49.0±3.8比66.3±2.3,P=0.000)、BUN分别为(11.2±1.6比16.1±2.8,P=0.001),Cr为(23.6±2.5比35.7±2.7,P=0.000)、D-乳酸(D-lac)为(1.3±0.1比2.8±0.3,P=0.000);同时可提高组织氧供和氧耗,延长动物存活时间[(60.30±30.82)h比(11.28±20.77)h,P=0.000],提高存活率(8/16比1/16)。结论线粒体分裂抑制剂Mdivi-1对脓毒症大鼠多器官功能有保护作用。

Objective To investigate the protective effect of mitochondrial fission inhibitor-1 (Mdivi-1) on organ functions in septic rats. Methods with cecal ligation and puncture (CLP) imitated sepsis model, 120 SD rats were divided into 5 groups randomly: sham, sepsis, conventional treatment, Mdivi-1 (1 mg/kg) and Mdivi-1 (3 mg/kg), the effects of different concentrations of Mdivi-1 on vital organ function of liver, kidney, intestines, cardiac, and animal survival were observed. Results As compared with the sham, the organ function was damaged after sepsis. After conventional treatment with LR, anti-infection and vasoactive drugs, organ functions were no significant improvement. The different concentration of Mdivi-1 (1 mg/kg and 3 mg/kg) in combination with conventional treatment significantly improved organ functions, 3 mg/kg Mdivi-1 had best effect. As compared with conventional treatment, aspartate aminotransferase (AST) (152.2±11.8 vs. 216.5±14.7, P=0.000), alanine aminotransferase (ALT) (49.0±3.8 vs. 66.3±2.3, P=0.000), blood urea nitrogen (BUN) (11.2±1.6 vs. 16.1±2.8, P=0.001), creatinine (Cr) (23.6±2.5 vs. 35.7±2.7, P=0.000), D-lac (1.3±0.1 vs. 2.8±0.3, P=0.000) the animal survival time was (60.30±30.82) h vs. (11.28±20.77) h (P=0.000), the survival rate was 8/16 vs. 1/16. Conclusion Mitochondrial fission inhibitor Mdivi-1 was beneficial to sepsis via improving multiple organ functions.