神经调节蛋白-1对脓毒症大鼠心肌血管内皮和心脏功能的影响

Effect of neuregulin-1 on myocardial vascular endothelium and cardiac function in septic rats

目的:研究神经调节蛋白-1(NRG-1)对脓毒症大鼠心肌血管内皮细胞及心功能的影响。方法:将雄性SD大鼠(220~280g)25只随机分为脓毒症组(n=10)、NRG组(n=10)、Sham组(n=5)。采用腹腔注射脂多糖(LPS)10mg/kg建立脓毒症模型,NRG组于术后4h和24h尾静脉注射重组人神经蛋白-1(rhNRG-1),0.01μg/g。术后48h检测各组大鼠血流动力学,心肌形态学及超微结构改变,检测血清一氧化氮(NO)含量和细胞间黏附分子-1(ICAM-1))水平,免疫荧光法检测心肌组织血管性血友病因子(vWF)表达情况。结果:与Sham组比较,脓毒症组大鼠光镜下可见心肌纤维排列紊乱和炎性细胞浸润,超微结构可见心肌细胞和线粒体肿胀,嵴断裂甚至消失,NRG组心肌纤维排列较整齐,少量炎性细胞浸润,心肌细胞和线粒体轻度肿胀;血流动力学参数Sham组为MAP(140.30±8.51)mmHg、LVSP(138.50±9.67)mmHg、LVEDP(9.37±0.65)mmHg、+dP/dt max(3418.21±226.10)mmHg/s、-dP/dt max(-3455.00±131.28)mmHg/s、HR(469.50±53.25)次,脓毒症组为MAP(46.97±4.06)mmHg、LVSP(97.17±5.38)mmHg、LVEDP(14.60±0.71)mmHg、+dP/dt max(2219.32±220.50)mmHg/s、-dP/dt max(-1345.05±170.20)mmHg/s、HR(444.50±86.67)次,NRG组为MAP(100.30±10.52)mmHg、LVSP(115.10±6.53)mmHg、LVEDP(4.41±1.25)mmHg、+dP/dt max(3009.49±106.41)mmHg/s、-dP/dt max(-2311.67±157.20)mmHg/s、HR(435.40±83.75)次,脓毒症组与Sham组相比,MAP、LVSP和±dP/dt max降低(P<0.05),LVEDP升高(P<0.05),HR无明显改变(P>0.05);NRG组与脓毒症组相比,MAP、LVSP和±dP/dt max升高(P<0.05),LVEDP降低(P<0.05),HR无明显改变(P>0.05);血清NO含量Sham组为(6.17±1.42)pg/ml,脓毒症组为(7.66±0.78)pg/ml,NRG组为(3.55±0.78)pg/ml,脓毒症组与Sham组间及NRG组与脓毒症组间差异均有统计学意义(P<0.05);血清ICAM-1含量Sham组为(338.593±14.701)pg/ml,脓毒症组为(959.597±55.206)pg/ml,NRG组为(605.010±23.646)pg/ml,脓毒症组与Sham组间及NRG组与脓毒症组间差异均有统计学意义(P<0.05);心肌血管管周vWF表达百分率Sham组为(76.42±6.36)%,脓毒症组为(40.58±4.33)%,NRG组为(64.41±6.13)%,脓毒症组与Sham组间及NRG组与脓毒症组间差异均有统计学意义(P<0.05)。结论:NRG-1能保护心肌血管内皮细胞功能,减弱氧化应激,改善心脏血流动力学从而减轻脓毒症引起的心脏功能障碍。

Objective:To study the effect of neuregulin-1(NRG-1)on myocardial vascular endothelial cells and cardiac function in septic rats.Method:Twenty-five male SD rats(220-280 g)were randomly divided into sepsis group(n=10),NRG group(n=10)and Sham group(n=5).A sepsis model was established by intraperitoneal injection of lipopolysaccharide(LPS)10 mg/kg.Recombinant human neuroprotein-1(rhNRG-1)0.01μg/g was injected into the NRG group at 4 hand 24 hafter surgery.The hemodynamics,myocardial morphology and ultrastructural changes of the rats in each group were detected 48 hafter operation.Serum nitric oxide(NO)content and intercellular adhesion molecule-1(ICAM-1)levels were detected.Myocardium was detected by immunofluorescence.Tissue von Willebrand Factor(vWF)expression.Result:Compared with the Sham group,the myocardial fiber arrangement disorder and inflammatory cell infiltration were observed under the light microscope in the sepsis group.The ultrastructure showed that the myocardial cells and mitochondria were swollen,the tendon was broken or even disappeared,and the myocardial fibers in the NRG group were arranged neatly.Inflammatory cell infiltration,mild swelling of cardiomyocytes and mitochondria;hemodynamic parameters in the Sham group were MAP(140.30±8.51)mmHg,LVSP(138.50±9.67)mmHg,LVEDP(9.37±0.65)mmHg,+dP/dt max(3418.21±226.10)mmHg/s,-dP/dt max(-3455.00±131.28)mmHg/s,HR(469.50±53.25)times,MAP(46.97±4.06)mmHg,LVSP(97.17±5.38)in the sepsis group)mmHg,LVEDP(14.60±0.71)mmHg,+dP/dt max(2219.32±220.50)mmHg/s,-dP/dt max(-1345.05±170.20)mmHg/s,HR(444.50±86.67)times,NRG group MAP(100.30±10.52)mmHg,LVSP(115.10±6.53)mmHg,LVEDP(4.41±1.25)mmHg,+dP/dt max(3009.49±106.41)mmHg/s,-dP/dt max(-2311.67±157.20)MMHg/s,HR(435.40±83.75)times,MAP,LVSP and±dP/dt max decreased(P<0.05),LVEDP increased(P<0.05),HR in the sepsis group compared with the Sham group.There was no significant change(P>0.05);MAP,LVSP and±dP/dt max were increased in the NRG group compared with the sepsis group(P<0.05),LVEDP was decreased(P<0.05),and HR was absent.Significant changes(P>0.05);serum NO levels were(6.17±1.42)pg/ml in the Sham group,(7.66±0.78)pg/ml in the sepsis group,(3.55±0.78)pg/ml in the NRG group There were significant differences between the sepsis group and the Sham group,and between the NRG group and the sepsis group(P<0.05).The serum ICAM-1 content in the Sham group was(338.593±14.701)pg/ml,sepsis.The group was(959.597±55.206)pg/ml,and the NRG group was(605.010±23.646)pg/ml.There were significant differences between the sepsis group and the Sham group,and between the NRG group and the sepsis group(P<0.05).The percentage of vWF expression in myocardial pericardial tube was(76.42±6.36)%in the Sham group,(40.58±4.33)%in the sepsis group,and(64.41±6.13)%in the NRG group,between the sepsis group and the Sham group.There were significant differences between the NRG group and the sepsis group(P<0.05).Conclusion:NRG-1 can protect myocardial vascular endothelial cells,attenuate oxidative stress,improve cardiac hemodynamics and alleviate cardiac dysfunction caused by sepsis.