大鼠急性脊髓损伤后紧密连接与血管发生在血—脊髓屏障功能缺失中的机制研究
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摘要
研究背景与目的
脊髓损伤(spinal cord injury, SCI)是严重危害人类生存和生活质量的一类中枢性神经创伤。随着全民运动的日益普及和越来越频繁的交通运输活动,脊髓损伤的发生率近年来有了显著的增高。研究表明,脊髓损伤后微循环障碍导致的脊髓缺血-水肿-自由基变化-水肿-缺血加重的恶性循环是造成脊髓神经组织不可逆的变性、坏死和细胞凋亡的主要过程之一。在这一过程中,血-脊髓屏障(blood spinal cord barrier, BSCB)功能缺失导致的血管渗透性增加是该恶性循环中的关键事件。本研究定性定量评估SCI前后脊髓血管内皮细胞间紧密连接的超微结构变化和紧密连接蛋白Claudin-5、ZO-1以及新生血管的空间分布和表达,探讨紧密连接与血管发生在脊髓损伤后BSCB功能改变中的作用和相关机制。
方法
1.80只SD大鼠用于本实验。20只SD大鼠作为正常组,60只SD大鼠利用改良Allen's打击方法构建脊髓损伤模型后,随机分为损伤后1天组,3天组,7天组,每组20只。获取正常组和上述各时间点胸10(T10)段脊髓组织用于以下检测。
2.利用透射电子显微镜观察正常与脊髓损伤后1天、3天、7天SD大鼠T10段脊髓微血管紧密连接超微结构。各时间点样品数4只,共16只。
3.利用组织免疫荧光技术和Western Blotting技术,对正常与脊髓损伤后1天、3天、7天SD大鼠T10段脊髓紧密连接蛋白Claudin-5、ZO-1的空间分布与表达进行定性定量评估。蛋白荧光分析采用ImagePro Plus软件。各时间点样品数4只,共32只,其中16只用于组织免疫荧光分析,余16只用于Western Blotting分析。
4.利用组织免疫荧光技术,对正常与脊髓损伤后1天、3天、7天SD大鼠血管发生标记CD34+细胞的空间分布与表达进行2D评估。蛋白荧光分析采用ImagePro Plus软件。各时间点样品数4只,共16只。CD34分别与紧密连接蛋白Claudin-5、ZO-1荧光共标记。
5.通过活体注射EB染料,在荧光显微镜下观察正常与脊髓损伤后1天、3天、7天BSCB渗透性变化,定性分析正常组及脊髓损伤后各时间点BSCB功能。同时借助分光光度仪检测脊髓组织中EB含量,定量评估正常组及脊髓损伤后1天、3天、7天BSCB功能。各时间点样品数4只,共32只,其中16只用于定性分析,余16只用于定量评估。
6.以上实验数据统计均采用SPSS13.0软件,组间比较使用T检验,P<0.05具有统计学差异。
结果
1.紧密连接
透射电镜观察证实,正常组大鼠脊髓血管内皮细胞间紧密连接呈铆钉状结构,构成相对封闭的血管管腔。在急性脊髓损伤后,细胞间紧密连接开放,在3天时细胞间隙增宽最为显著,之后随时间延续逐渐恢复,但在7天时仍未达到正常水平。
2.紧密连接蛋白Claudin-5、ZO-1
组织免疫荧光结果发现,在正常组脊髓,紧密连接蛋白Claudin-5、ZO-1均与血管分布呈现高度一致性。在SCI后1天、3天、7天,上述蛋白均出现分布异常与不同程度的表达下降。其中在损伤后1天最为显著,之后随损伤时间延续逐渐恢复,但在SCI后7天,仍未恢复正常水平。Western Blotting结果同样发现,在SCI后1天,Claudin-5、ZO-1蛋白较正常组显著下降,并在SCI后3天、7天逐渐恢复,但7天时仍未达到正常水平。
3. CD34+细胞分布与表达
组织免疫荧光结果发现,在正常组脊髓,CD34+细胞分布于血管内皮。在SCI后,CD34+细胞在损伤中心区域分布缺失,同时出现不同程度表达下降,在脊髓损伤后1天最为显著,之后随损伤时间延续逐渐恢复,但在SCI后7天时仍未恢复正常水平。在脊髓损伤后3天,损伤中心区域出现少量CD34+细胞。在损伤后7天,损伤中心区域可见大量CD34+细胞表达。
4. BSCB渗透性
正常大鼠脊髓几乎无法观察到EB的渗出。在脊髓损伤后1、3、7天,出现了不同程度的EB渗出,其中损伤后3天时EB的渗出最为显著。定量结果显示脊髓损伤后1天即出现了组织EB含量的增加,在损伤后3天,组织EB含量最多,与定性观察结果一致。
结论
1.大鼠脊髓损伤后脊髓血管内皮细胞紧密连接蛋白Claudin-5、Z0-1出现分布异常与表达下降,在损伤后1天最为显著,之后逐渐恢复。
2.大鼠脊髓损伤后脊髓血管网络被破坏,在损伤后1天最为显著；在损伤后3天出现损伤中心区域血管发生。
3.大鼠脊髓损伤后BSCB功能改变可能与紧密连接开放、紧密连接蛋白Claudin-5、ZO-1表达下降、血管发生有关。
Background and Objective
Spinal cord injury is a central nerve trauma severely endangering survival and quality of human life. Along with the rising popularity of universal movement and increasing transportation, the incidence of SCI has significantly increased in recent years. Studies showed that the spinal cord suffered ischemia-edema-free radical-edema-ischemia. The vicious cycle caused by microcirculation dysfunction after SCI is one of the main processes that resulting in irreversible degeneration, necrosis and apoptosis of spinal cord. Blood spinal cord barrier plays an important role in this process. This study focuses on the ultrastructure of intercellular tight junctions and the expression of tight junctions proteins (Claudin-5and ZO-1) as well as the neovascularization, in order to investigate the probable mechanism between tight junctions and vasculogenesis in BSCB function after SCI.
Method
1. A total of80SD rats were used in this experiment. Quarter was as normal group, others were as SCI group by using modified Allen's method,1day,3day,7day group after SCI were divided randomly, each group of20samples. T10section of spinal cord tissue was used for the following test.
2. Using transmission electron microscope to observe ultrastructure of tight junctions between spinal cord capillary at different point of time, i.e. normal,1day,3day and7day after SCI, each point of4samples, a total of16samples.
3. Using immunofluorescence and Western Blotting techniques to test the spatial distribution and expression of TJ proteins (Claudin-5and ZO-1) at different point of time (i.e. normal,1day,3day and7day after SCI), each point of4samples, a total of32samples. All the results of immunofluorescence were analyzed by ImagePro Plus software.
4. Using immunofluorescence techniques to make a two-dimensional evaluation on spatial distribution and expression of SD rats'CD34+cell. The samples were extracted on normal and1day,3day,7day after SCI, each point of4samples, a total of16samples. CD34was common with Claudin-5and ZO-1respectively. All data was analyzed by ImagePro Plus software.
5. Injecting Evans blue in vivo, the extravasation of Evans blue was observed after SCI by fluorescence microscope, and using spectrophotometer to detect the content of Evans blue at different point of time, i.e. normal,1day,3day and7day after SCI, each point of4samples, a total of32samples.
6. All statistical analysis was used SPSS13.0statistics software, The T test was applied in the group comparison. P<0.05was statistically significant.
Results
1. Tight junctions
Transmission electron microscopy (TEM) observation confirms that the spinal cord vascular endothelial cells connect closely in normal group. The tight junctions between endothelial cells open after acute SCI, the most significant of which occur in the third day after SCI, then gradually recover as time continues, but still have not reached normal levels in the7day after SCI.
2. Tight junctions proteins (Claudin-5and ZO-1)
Immunofluorescence assay observation confirms that the tight junctions proteins (Claduin-5and ZO-1) are consistent with spinal cord vascular distribution. The distribution and expression are abnormal at1day,3day,7day after SCI, significantly occurs in the first day after injury. Though the expression increases gradually after lday post SCI, have not reached to normal levels in7day after injury. The same results are found in Western Blotting test.
3. CD34+cell
Immunofluorescence assay observation confirms that the CD34+cells are consistent with blood vessel endothelium. After SCI, there are lacks of CD34+cells at the epicenter zone as well as the expression decreases, significantly occurs in the first day after injury. Though the expression increases gradually after1day post SCI, have not reached to normal levels in7day after injury. At the3day after SCI, there is a few of CD34+cells are observed at the epicenter zone. Until7day after SCI, the CD34+cells are obviously observed in the same region.
4. BSCB permeability
The extravasation of EB is hardly observed by fluorescence microscope in normal group, however, there is an overt extravasation of EB at1,3,7day after SCI, especially at3day post-SCI. The same outcome is obtained in quantitative analyze.
Conclusion
1. The distribution and expression of TJ proteins (Claudin-5and ZO-1) decline after SCI, especially at1day post-SCI and increase gradually.
2. The spinal cord vascular network is damaged after SCI, especially at1day post-SCI; Vasculogenesis can be observed at3day after SCI at epicenter zone.
3. The tight junctions, the decrease expression of tight junctions proteins (Claudin-5and ZO-1) and vasculogenesis may result in dysfunction of BSCB after SCI.
脊髓损伤(spinal cord injury, SCI)是严重危害人类生存和生活质量的一类中枢性神经创伤。随着全民运动的日益普及和越来越频繁的交通运输活动,脊髓损伤的发生率近年来有了显著的增高。研究表明,脊髓损伤后微循环障碍导致的脊髓缺血-水肿-自由基变化-水肿-缺血加重的恶性循环是造成脊髓神经组织不可逆的变性、坏死和细胞凋亡的主要过程之一。在这一过程中,血-脊髓屏障(blood spinal cord barrier, BSCB)功能缺失导致的血管渗透性增加是该恶性循环中的关键事件。本研究定性定量评估SCI前后脊髓血管内皮细胞间紧密连接的超微结构变化和紧密连接蛋白Claudin-5、ZO-1以及新生血管的空间分布和表达,探讨紧密连接与血管发生在脊髓损伤后BSCB功能改变中的作用和相关机制。
方法
1.80只SD大鼠用于本实验。20只SD大鼠作为正常组,60只SD大鼠利用改良Allen's打击方法构建脊髓损伤模型后,随机分为损伤后1天组,3天组,7天组,每组20只。获取正常组和上述各时间点胸10(T10)段脊髓组织用于以下检测。
2.利用透射电子显微镜观察正常与脊髓损伤后1天、3天、7天SD大鼠T10段脊髓微血管紧密连接超微结构。各时间点样品数4只,共16只。
3.利用组织免疫荧光技术和Western Blotting技术,对正常与脊髓损伤后1天、3天、7天SD大鼠T10段脊髓紧密连接蛋白Claudin-5、ZO-1的空间分布与表达进行定性定量评估。蛋白荧光分析采用ImagePro Plus软件。各时间点样品数4只,共32只,其中16只用于组织免疫荧光分析,余16只用于Western Blotting分析。
4.利用组织免疫荧光技术,对正常与脊髓损伤后1天、3天、7天SD大鼠血管发生标记CD34+细胞的空间分布与表达进行2D评估。蛋白荧光分析采用ImagePro Plus软件。各时间点样品数4只,共16只。CD34分别与紧密连接蛋白Claudin-5、ZO-1荧光共标记。
5.通过活体注射EB染料,在荧光显微镜下观察正常与脊髓损伤后1天、3天、7天BSCB渗透性变化,定性分析正常组及脊髓损伤后各时间点BSCB功能。同时借助分光光度仪检测脊髓组织中EB含量,定量评估正常组及脊髓损伤后1天、3天、7天BSCB功能。各时间点样品数4只,共32只,其中16只用于定性分析,余16只用于定量评估。
6.以上实验数据统计均采用SPSS13.0软件,组间比较使用T检验,P<0.05具有统计学差异。
结果
1.紧密连接
透射电镜观察证实,正常组大鼠脊髓血管内皮细胞间紧密连接呈铆钉状结构,构成相对封闭的血管管腔。在急性脊髓损伤后,细胞间紧密连接开放,在3天时细胞间隙增宽最为显著,之后随时间延续逐渐恢复,但在7天时仍未达到正常水平。
2.紧密连接蛋白Claudin-5、ZO-1
组织免疫荧光结果发现,在正常组脊髓,紧密连接蛋白Claudin-5、ZO-1均与血管分布呈现高度一致性。在SCI后1天、3天、7天,上述蛋白均出现分布异常与不同程度的表达下降。其中在损伤后1天最为显著,之后随损伤时间延续逐渐恢复,但在SCI后7天,仍未恢复正常水平。Western Blotting结果同样发现,在SCI后1天,Claudin-5、ZO-1蛋白较正常组显著下降,并在SCI后3天、7天逐渐恢复,但7天时仍未达到正常水平。
3. CD34+细胞分布与表达
组织免疫荧光结果发现,在正常组脊髓,CD34+细胞分布于血管内皮。在SCI后,CD34+细胞在损伤中心区域分布缺失,同时出现不同程度表达下降,在脊髓损伤后1天最为显著,之后随损伤时间延续逐渐恢复,但在SCI后7天时仍未恢复正常水平。在脊髓损伤后3天,损伤中心区域出现少量CD34+细胞。在损伤后7天,损伤中心区域可见大量CD34+细胞表达。
4. BSCB渗透性
正常大鼠脊髓几乎无法观察到EB的渗出。在脊髓损伤后1、3、7天,出现了不同程度的EB渗出,其中损伤后3天时EB的渗出最为显著。定量结果显示脊髓损伤后1天即出现了组织EB含量的增加,在损伤后3天,组织EB含量最多,与定性观察结果一致。
结论
1.大鼠脊髓损伤后脊髓血管内皮细胞紧密连接蛋白Claudin-5、Z0-1出现分布异常与表达下降,在损伤后1天最为显著,之后逐渐恢复。
2.大鼠脊髓损伤后脊髓血管网络被破坏,在损伤后1天最为显著；在损伤后3天出现损伤中心区域血管发生。
3.大鼠脊髓损伤后BSCB功能改变可能与紧密连接开放、紧密连接蛋白Claudin-5、ZO-1表达下降、血管发生有关。
Background and Objective
Spinal cord injury is a central nerve trauma severely endangering survival and quality of human life. Along with the rising popularity of universal movement and increasing transportation, the incidence of SCI has significantly increased in recent years. Studies showed that the spinal cord suffered ischemia-edema-free radical-edema-ischemia. The vicious cycle caused by microcirculation dysfunction after SCI is one of the main processes that resulting in irreversible degeneration, necrosis and apoptosis of spinal cord. Blood spinal cord barrier plays an important role in this process. This study focuses on the ultrastructure of intercellular tight junctions and the expression of tight junctions proteins (Claudin-5and ZO-1) as well as the neovascularization, in order to investigate the probable mechanism between tight junctions and vasculogenesis in BSCB function after SCI.
Method
1. A total of80SD rats were used in this experiment. Quarter was as normal group, others were as SCI group by using modified Allen's method,1day,3day,7day group after SCI were divided randomly, each group of20samples. T10section of spinal cord tissue was used for the following test.
2. Using transmission electron microscope to observe ultrastructure of tight junctions between spinal cord capillary at different point of time, i.e. normal,1day,3day and7day after SCI, each point of4samples, a total of16samples.
3. Using immunofluorescence and Western Blotting techniques to test the spatial distribution and expression of TJ proteins (Claudin-5and ZO-1) at different point of time (i.e. normal,1day,3day and7day after SCI), each point of4samples, a total of32samples. All the results of immunofluorescence were analyzed by ImagePro Plus software.
4. Using immunofluorescence techniques to make a two-dimensional evaluation on spatial distribution and expression of SD rats'CD34+cell. The samples were extracted on normal and1day,3day,7day after SCI, each point of4samples, a total of16samples. CD34was common with Claudin-5and ZO-1respectively. All data was analyzed by ImagePro Plus software.
5. Injecting Evans blue in vivo, the extravasation of Evans blue was observed after SCI by fluorescence microscope, and using spectrophotometer to detect the content of Evans blue at different point of time, i.e. normal,1day,3day and7day after SCI, each point of4samples, a total of32samples.
6. All statistical analysis was used SPSS13.0statistics software, The T test was applied in the group comparison. P<0.05was statistically significant.
Results
1. Tight junctions
Transmission electron microscopy (TEM) observation confirms that the spinal cord vascular endothelial cells connect closely in normal group. The tight junctions between endothelial cells open after acute SCI, the most significant of which occur in the third day after SCI, then gradually recover as time continues, but still have not reached normal levels in the7day after SCI.
2. Tight junctions proteins (Claudin-5and ZO-1)
Immunofluorescence assay observation confirms that the tight junctions proteins (Claduin-5and ZO-1) are consistent with spinal cord vascular distribution. The distribution and expression are abnormal at1day,3day,7day after SCI, significantly occurs in the first day after injury. Though the expression increases gradually after lday post SCI, have not reached to normal levels in7day after injury. The same results are found in Western Blotting test.
3. CD34+cell
Immunofluorescence assay observation confirms that the CD34+cells are consistent with blood vessel endothelium. After SCI, there are lacks of CD34+cells at the epicenter zone as well as the expression decreases, significantly occurs in the first day after injury. Though the expression increases gradually after1day post SCI, have not reached to normal levels in7day after injury. At the3day after SCI, there is a few of CD34+cells are observed at the epicenter zone. Until7day after SCI, the CD34+cells are obviously observed in the same region.
4. BSCB permeability
The extravasation of EB is hardly observed by fluorescence microscope in normal group, however, there is an overt extravasation of EB at1,3,7day after SCI, especially at3day post-SCI. The same outcome is obtained in quantitative analyze.
Conclusion
1. The distribution and expression of TJ proteins (Claudin-5and ZO-1) decline after SCI, especially at1day post-SCI and increase gradually.
2. The spinal cord vascular network is damaged after SCI, especially at1day post-SCI; Vasculogenesis can be observed at3day after SCI at epicenter zone.
3. The tight junctions, the decrease expression of tight junctions proteins (Claudin-5and ZO-1) and vasculogenesis may result in dysfunction of BSCB after SCI.
引文
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