青蒿琥酯对猪心肺复苏后心脑损伤的保护作用

Protective effect of artesunate on cardiocerebral injury after cardiopulmonary resuscitation in a swine model

目的探讨青蒿琥酯(ART)对猪心肺复苏(CPR)后心脑损伤的保护作用。方法国产健康白猪24头,体质量(36.63±2.55)kg,应用随机数字表法分为三组:假手术组(Sham组,n=6)、CPR组(n=10)、ART组(n=8)。CPR组和ART组采用电刺激诱发室颤9 min、CPR 6 min的方法制作心脏骤停复苏模型。Sham组不经历心脏骤停。在制作模型后5 min时,ART组静脉注射青蒿琥酯4.8 mg/kg,维持2 h。另外两组输注等量溶媒。分别于基线及复苏后1、2、4、24 h检测血心肌肌钙蛋白I(cTnI)、肌酸激酶同工酶(CK-MB)、神经元特异性烯醇化酶(NSE)、钙结合蛋白S100 B(S100B)水平。复苏后24 h实验猪安乐死,获取心脏及大脑组织,检测肿瘤坏死因子α(TNF-α)、白细胞介素1β(IL-1β)及细胞凋亡指数。结果与Sham组比较,CPR组血cTnI、CK-MB、NSE、S100B在复苏后1、2、4、24 h均明显升高(P<0.05);ART组血cTnI仅在复苏后4、24 h明显升高(P<0.05),CK-MB仅在复苏后1、2 h明显升高(P<0.05),NSE和S100B仅在复苏后2、4、24 h明显升高(P<0.05)。与CPR组比较,ART组血cTnI在复苏后4、24 h明显降低,CK-MB在复苏后2 h明显降低,NSE在复苏后2、4、24 h明显降低,S100B在复苏后2、4 h明显降低[cTnI(pg/mL):4 h为469.10±55.29 vs.291.15±17.68,24 h为566.35±31.34 vs.333.50±22.50;CK-MB(ng/mL):66.78±5.93 vs.58.65±5.84;NSE(ng/mL):2 h为21.44±1.61 vs.15.91±1.26,4 h为26.08±1.03 vs.19.47±1.22,24 h为31.70±0.87 vs.23.46±1.09;S100B(pg/mL):2 h为2643.10±215.90 vs.2041.46±107.37,4 h为3132.82±178.64 vs.2337.77±112.85,均P<0.05]。与Sham组比较,CPR组心肌及大脑皮层TNF-α、IL-1β均明显升高(P<0.05)。与CPR组比较,ART组心肌TNF-α、IL-1β及皮层IL-1β均明显降低[TNF-α(pg/mL):心肌632.68±33.19 vs.348.69±27.12;IL-1β(pg/mL):心肌1627.29±53.94 vs.982.88±52.79,皮层1606.54±49.56 vs.976.45±44.84,均P<0.05]。与Sham组比较,CPR组心肌及皮层的凋亡指数均明显升高(P<0.05)。与CPR组比较,ART组心肌及皮层的凋亡指数均有所降低,但差异无统计学意义[心肌(%):52.78±10.53 vs.14.33±4.01,皮层(%):59.00±7.76 vs.19.11±5.56,均P>0.05]。结论青蒿琥酯能通过抑制炎症反应、抗细胞凋亡途径,减轻猪心脏骤停复苏后的心脑损伤。

Objective To investigate the protective effect of artesunate(ART)on cardiocerebral injury after cardiopulmonary resuscitation(CPR)in a swine model.Methods Twenty-four healthy domestic pigs,weighing(36.63±2.55)kg,were randomized(random number)to 3 groups:sham operation group(Sham group,n=6),CPR group(n=10)and artesunate intervention group(ART group,n=8).In the CPR group and ART group,the experimental model was established by electrically induced ventricular fibrillation for 9 min and then cardiopulmonary resuscitation for 6 min.Animals in the Sham group did not experience cardiac arrest.At 5 min after resuscitation,the ART group received continuous infusion of 4.8 mg/kg artesunate for 2 h.The same amount of menstruum was administered in the Sham and CPR groups.At baseline,1,2,4 and 24 h after resuscitation,the levels of serum cardiac troponin I(cTnI),creatine kinase isoenzyme(CK-MB),neuron-specific enolase(NSE)and S100B protein(S100B)were measured.At 24 h after resuscitation,the animals were sacrificed,cerebral cortex and myocardium were obtained for the determination of tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β)and cell apoptosis.Results Compared with the Sham group,serum cTnI,CK-MB,NSE and S100B in CPR group were significantly increased at 1,2,4 and 24 h after resuscitation(P<0.05);in ART group,serum cTnI was significantly increased only at 4 h and 24 h after resuscitation(P<0.05),serum CK-MB was significantly increased only at 1 h and 2 h after resuscitation(P<0.05),and serum NSE and S100B were significantly increased only at 2,4 and 24 h after resuscitation(P<0.05).Serum cTnI was significantly decreased at 4 h and 24 h after resuscitation,serum CK-MB was significantly decreased at 2 h after resuscitation,serum NSE was significantly decreased at 2,4 and 24 h after resuscitation,and serum S100B was significantly decreased at 2 h and 4 h after resuscitation in the ART group compared with the CPR group[cTnI(pg/mL):469.10±55.29 vs.291.15±17.68 at 4 h,566.35±31.34 vs.333.50±22.50 at 24 h;CK-MB(ng/mL):66.78±5.93 vs.58.65±5.84 at 2 h;NSE(ng/mL):21.44±1.61 vs.15.91±1.26 at 2 h,26.08±1.03 vs.19.47±1.22 at 4 h,31.70±0.87 vs.23.46±1.09 at 24 h;S100B(pg/mL):2643.10±215.90 vs.2041.46±107.37 at 2 h,3132.82±178.64 vs.2337.77±112.85 at 4 h,all P<0.05].Compared with the Sham group,the contents of TNF-αand IL-1βof cerebral cortex and myocardium in CPR group were significantly increased(P<0.05).The contents of TNF-αand IL-1βin myocardium and IL-1βin cerebral cortex were significantly decreased in ART group compared with the CPR group[TNF-α(pg/mL):632.68±33.19 vs.348.69±27.12 in myocardium;IL-1β(pg/mL):1627.29±53.94 vs.982.88±52.79 in myocardium,1606.54±49.56 vs.976.45±44.84 in cerebral cortex,all P<0.05].Compared with the Sham group,the apoptosis index of myocardium and cerebral cortex in CPR group were significantly increased(P<0.05).The apoptosis index of myocardium and cerebral cortex in ART group were decreased,but the difference was not statistically significant compared with the CPR group[the apoptosis index(%):52.78±10.53 vs.14.33±4.01 in myocardium,59.00±7.76 vs.19.11±5.56 in cerebral cortex,all P>0.05].Conclusions Artesunate can reduce cardiocerebral injury after the resuscitation of cardiac arrest in swines by inhibiting inflammatory response and anti-apoptotic pathways.