肺炎链球菌溶血素致脑损伤细胞凋亡及凋亡诱导因子的表达及意义
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摘要
背景和目的
肺炎链球菌溶血素(pneumolysin, PLY)是肺炎链球菌(Streptococcus pneumoniae, S.pn)溶解释放的一个主要的毒素,是S.pn的一个主要毒力因子,具有多种功能,能够破坏血脑屏障的紧密连接、引起细胞溶解、刺激炎症因子释放、诱导细胞凋亡等,引起大脑严重损害。海马及大脑皮层神经元的凋亡使患儿学习、记忆能力下降,导致患儿智力低下,严重影响患儿生活质量。近年来PLY致脑损伤机制备受关注,但多局限在体外研究,缺乏直接客观的体内研究。
脑损伤后既有细胞坏死又有细胞凋亡。凋亡诱导因子(apoptosis inducing factor, AIF)是在研究细胞凋亡时发现的,Susin等在1996年发现存在广谱的胱天蛋白酶(caspase)抑制剂Z-VAD-FMK时,鼠肝细胞线粒体膜间J隙组分能够使分离的HeLa细胞核染色体以非依赖于caspases的方式发生异常凝集和DNA大片段的形成,遂将其命名为AIF°AIF在感染性脑损伤中扮演者重要角色,但对其具体作用机制及调控机制的了解较少。有研究表明PLY可以通过线粒体释放AIF途径诱导脑细胞凋亡,但却局限在体外研究。
本实验通过颈内动脉注射PLY制作感染性脑损伤动物模型,体内研究细胞凋亡及AIF在S.pn所致脑损伤中的作用,为肺炎链球菌脑膜炎的临床治疗拓展新思路。
材料与方法
将80只幼鼠随机分成溶血素组(PLY组,n=40),左颈内动脉注射0.2mL(7μg)PLY；生理盐水组(NS组,n=40),颈内动脉注射等体积生理盐水。两组按注射后不同时间点分为6h、12h、24h、48h4个亚组,每亚组均10只。于预定时间点处死动物,制备脑组织标本。干湿重法测脑含水量(brain watercontent, BWC),甲酰胺法测定伊文思兰(Evan's blue, EB)含量,免疫组织化学技术(SP法)测定脑内NSE、GFAP、AIF蛋白表达情况,原位末端标记法(TUNEL法)检测细胞凋亡。所有数据采用SPSS17.0软件进行统计分析,显著性水准为a<0.05。
结果
1形态学改变：PLY组左侧脑体积较右侧增大,脑组织肿胀发亮,脑膜紧张粘连,脑血管明显充血。HE染色光镜下观察PLY组脑血.管间隙增宽,神经元细胞、胶质细胞不同程度肿胀、空泡变性,NS组没有上述变化。
2 PLY组BWC、EB含量、NSE、GFAP(?)水平各时间点均明显高于对照组。差异有统计学意义(p<0.05)。
3 PLY组大脑皮层、海马区可见细胞凋亡,随时间逐渐增多,NS组可以见到少许凋亡细胞。PLY注射后6hAIF、凋亡细胞数均明显增加,AIF在24h达高峰,凋亡细胞数在48h仍有较高表达,各时间点与对照组比较均有显著性差异(p<0.05)。
4 AIF含量与TUNEL检测细胞凋亡结果呈正相关,r=0.879,p<0.05。
结论
1 PLY可以通过诱导神经细胞凋亡方式导致脑损伤。
2 PLY通过线粒体释放AIF途径诱导神经细胞凋亡。
Background and Objective
Streptococcus pneumoniae is the major pathogen of purulent meningitis in children. Pneumococcal meningitis has a high morbidity and high mortality. Pneumolysin(PLY) is the most important toxin that released during bacterial growth and lysis, and belongs to the family of thiol-activated, cholesterol-binding cytolysins. PLY has numerous functions,such as destroy the brain micro vascular endothelium cells, activate the host complement, induce proinflammatory reactions in immune cells, induce apoptosis of cells, cause widespread direct cellular and tissue damage by virtue of its membrane pore forming properties and so on, and ultimately cause the brain serious injury.The apoptosis causes permanent loss of neurons in the dentate gyrus of the hippocampus, which reduces the capability of learning and memory and seriously influence the life of children. Recently the mechanism of brain injury induced by PLY receives much concern,but these research more limited in vitro,lack of direct objective study in vivo.
Previous studies on brain injury focus on cell necrosis. But it is realized that brain injury contains both cell necrosis and cell apoptosis. Susin s experimental results showed that in the present of the broad-spectrum caspase inhibitor Z-VAD-FMK, rat liver cell mitochondrial intermembrane components were still have promoting apoptosis activity, can cause separate HeLa chromatin condensation and large-scale DNA fragmentation with approximately 50-kb fragments in the way of caspase- independent, and named the protein as apoptosis-inducing factors (apoptosis inducing factor,AIF).AIF plays important roles in the brain injury, but the understanding of the specific mechanism of brain injury is still less. Research has shown that PLY causes neuronal cell apoptosis through mitochondrial damage and releasing of AIF in vitro, and there is less experiment in vivo.
The purpose of this study was to determine the role and mechanisms of brain cell apoptosis and AIF in the brain injury induced by Streptococcus pneumoniae in animal models of infectious brain damage which were established by injecting PLY through internal carotid artery in vivo, and provide better therapeutic strategy of Pneumococcal meningitis.
Materials and Methods
A total of 80 infant rats were randomly divided into 2 groups:pneumolysin group (PLY groups, n=40),0.2mL(7μg)PLY was injected via the left internal carotid. nomal saline group(NS group, n=40), isopyknic nomal saline was given to each rat by the same methods as PLY group. Each group was devided into 4 subgroups:6h、12 h、24 h and 48 h,10 infant rats were prepared in every subgroup. Rats were decapitated at different time point and brain tissue samples were prepared. By measuring both wet and dry weight, the water content of brain tissue were recorded. The Evan's blue(EB) content of brain tissue was measured by the formamide method,the expression of NSE protein,GFAP protein and AIF were studied by immunohistochemistry. And apoptosis was examined by TUNEL technique. All the data were analyzed with SPSS 17.0 software, the significant level was assigned at a< 0.05.
Results
1 morphology: In PLY group, the left side of the brain was larger than the right side, the brain was swelling and the cerebral pia mater was adhesive, cerebrovascular hyperemia was clearly revealed. After the HE dyeing and observation by light-microscopy, the clearance around vessels became broader and inflammatory cells infiltrated out of vessels. Neurons and gliacytes became swelled, vacuolar degenerated and their cubage augmented than before. These changes did not discovered in NS group.
2 The BWC, brain EB content and the expression levels of NSE protein and GFAP protein were higher in PLY group at each time point comparing with those in corresponding NS group, the difference was significant(p<0.05).
3 After injection of PLY, cell apoptosis can be found in the cerebral cortex and the hippocamp.The differences of AIF and the number of apoptosis between in PLY group and the control group had statistic significance at every time point (P<0.05).
4 Relative correlation analysis: positive correlation was got between AIF protein and the number of apoptosis, and the r value was 0.879, P<0.05.
Conclusions
1 PLY can induce brain injury by the way of neurocyte apoptosis.
2 PLY can induce neurocyte apoptosis through the releasing of AIF by the mitochondria.
肺炎链球菌溶血素(pneumolysin, PLY)是肺炎链球菌(Streptococcus pneumoniae, S.pn)溶解释放的一个主要的毒素,是S.pn的一个主要毒力因子,具有多种功能,能够破坏血脑屏障的紧密连接、引起细胞溶解、刺激炎症因子释放、诱导细胞凋亡等,引起大脑严重损害。海马及大脑皮层神经元的凋亡使患儿学习、记忆能力下降,导致患儿智力低下,严重影响患儿生活质量。近年来PLY致脑损伤机制备受关注,但多局限在体外研究,缺乏直接客观的体内研究。
脑损伤后既有细胞坏死又有细胞凋亡。凋亡诱导因子(apoptosis inducing factor, AIF)是在研究细胞凋亡时发现的,Susin等在1996年发现存在广谱的胱天蛋白酶(caspase)抑制剂Z-VAD-FMK时,鼠肝细胞线粒体膜间J隙组分能够使分离的HeLa细胞核染色体以非依赖于caspases的方式发生异常凝集和DNA大片段的形成,遂将其命名为AIF°AIF在感染性脑损伤中扮演者重要角色,但对其具体作用机制及调控机制的了解较少。有研究表明PLY可以通过线粒体释放AIF途径诱导脑细胞凋亡,但却局限在体外研究。
本实验通过颈内动脉注射PLY制作感染性脑损伤动物模型,体内研究细胞凋亡及AIF在S.pn所致脑损伤中的作用,为肺炎链球菌脑膜炎的临床治疗拓展新思路。
材料与方法
将80只幼鼠随机分成溶血素组(PLY组,n=40),左颈内动脉注射0.2mL(7μg)PLY；生理盐水组(NS组,n=40),颈内动脉注射等体积生理盐水。两组按注射后不同时间点分为6h、12h、24h、48h4个亚组,每亚组均10只。于预定时间点处死动物,制备脑组织标本。干湿重法测脑含水量(brain watercontent, BWC),甲酰胺法测定伊文思兰(Evan's blue, EB)含量,免疫组织化学技术(SP法)测定脑内NSE、GFAP、AIF蛋白表达情况,原位末端标记法(TUNEL法)检测细胞凋亡。所有数据采用SPSS17.0软件进行统计分析,显著性水准为a<0.05。
结果
1形态学改变：PLY组左侧脑体积较右侧增大,脑组织肿胀发亮,脑膜紧张粘连,脑血管明显充血。HE染色光镜下观察PLY组脑血.管间隙增宽,神经元细胞、胶质细胞不同程度肿胀、空泡变性,NS组没有上述变化。
2 PLY组BWC、EB含量、NSE、GFAP(?)水平各时间点均明显高于对照组。差异有统计学意义(p<0.05)。
3 PLY组大脑皮层、海马区可见细胞凋亡,随时间逐渐增多,NS组可以见到少许凋亡细胞。PLY注射后6hAIF、凋亡细胞数均明显增加,AIF在24h达高峰,凋亡细胞数在48h仍有较高表达,各时间点与对照组比较均有显著性差异(p<0.05)。
4 AIF含量与TUNEL检测细胞凋亡结果呈正相关,r=0.879,p<0.05。
结论
1 PLY可以通过诱导神经细胞凋亡方式导致脑损伤。
2 PLY通过线粒体释放AIF途径诱导神经细胞凋亡。
Background and Objective
Streptococcus pneumoniae is the major pathogen of purulent meningitis in children. Pneumococcal meningitis has a high morbidity and high mortality. Pneumolysin(PLY) is the most important toxin that released during bacterial growth and lysis, and belongs to the family of thiol-activated, cholesterol-binding cytolysins. PLY has numerous functions,such as destroy the brain micro vascular endothelium cells, activate the host complement, induce proinflammatory reactions in immune cells, induce apoptosis of cells, cause widespread direct cellular and tissue damage by virtue of its membrane pore forming properties and so on, and ultimately cause the brain serious injury.The apoptosis causes permanent loss of neurons in the dentate gyrus of the hippocampus, which reduces the capability of learning and memory and seriously influence the life of children. Recently the mechanism of brain injury induced by PLY receives much concern,but these research more limited in vitro,lack of direct objective study in vivo.
Previous studies on brain injury focus on cell necrosis. But it is realized that brain injury contains both cell necrosis and cell apoptosis. Susin s experimental results showed that in the present of the broad-spectrum caspase inhibitor Z-VAD-FMK, rat liver cell mitochondrial intermembrane components were still have promoting apoptosis activity, can cause separate HeLa chromatin condensation and large-scale DNA fragmentation with approximately 50-kb fragments in the way of caspase- independent, and named the protein as apoptosis-inducing factors (apoptosis inducing factor,AIF).AIF plays important roles in the brain injury, but the understanding of the specific mechanism of brain injury is still less. Research has shown that PLY causes neuronal cell apoptosis through mitochondrial damage and releasing of AIF in vitro, and there is less experiment in vivo.
The purpose of this study was to determine the role and mechanisms of brain cell apoptosis and AIF in the brain injury induced by Streptococcus pneumoniae in animal models of infectious brain damage which were established by injecting PLY through internal carotid artery in vivo, and provide better therapeutic strategy of Pneumococcal meningitis.
Materials and Methods
A total of 80 infant rats were randomly divided into 2 groups:pneumolysin group (PLY groups, n=40),0.2mL(7μg)PLY was injected via the left internal carotid. nomal saline group(NS group, n=40), isopyknic nomal saline was given to each rat by the same methods as PLY group. Each group was devided into 4 subgroups:6h、12 h、24 h and 48 h,10 infant rats were prepared in every subgroup. Rats were decapitated at different time point and brain tissue samples were prepared. By measuring both wet and dry weight, the water content of brain tissue were recorded. The Evan's blue(EB) content of brain tissue was measured by the formamide method,the expression of NSE protein,GFAP protein and AIF were studied by immunohistochemistry. And apoptosis was examined by TUNEL technique. All the data were analyzed with SPSS 17.0 software, the significant level was assigned at a< 0.05.
Results
1 morphology: In PLY group, the left side of the brain was larger than the right side, the brain was swelling and the cerebral pia mater was adhesive, cerebrovascular hyperemia was clearly revealed. After the HE dyeing and observation by light-microscopy, the clearance around vessels became broader and inflammatory cells infiltrated out of vessels. Neurons and gliacytes became swelled, vacuolar degenerated and their cubage augmented than before. These changes did not discovered in NS group.
2 The BWC, brain EB content and the expression levels of NSE protein and GFAP protein were higher in PLY group at each time point comparing with those in corresponding NS group, the difference was significant(p<0.05).
3 After injection of PLY, cell apoptosis can be found in the cerebral cortex and the hippocamp.The differences of AIF and the number of apoptosis between in PLY group and the control group had statistic significance at every time point (P<0.05).
4 Relative correlation analysis: positive correlation was got between AIF protein and the number of apoptosis, and the r value was 0.879, P<0.05.
Conclusions
1 PLY can induce brain injury by the way of neurocyte apoptosis.
2 PLY can induce neurocyte apoptosis through the releasing of AIF by the mitochondria.
引文
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