外周循环内皮祖细胞的数量对大鼠脑创伤后血脑屏障的通透性及学习记忆的影响
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摘要
目的观察大鼠脑创伤后血脑屏障通透性改变的规律,探讨外周循环内皮祖细胞的数量增加对大鼠脑创伤后血脑屏障通透性及学习记忆的影响。
方法健康成年Wistar大鼠随机分为对照组、假手术组、创伤组和治疗组。采用液压打击创伤性脑损伤模型。治疗组大鼠在打击前连续5天腹腔注射G-CSF(50ug·kg-1·d-1),停药后2d复制模型。EB定量采用检测大鼠皮质及海马光密度值,从标准曲线和方程上查得EB含量并计算结果；脑组织的EB示踪通过荧光显微镜观察。脑组织含水量的测定采用干湿重法。应用CD34／CD133双阳性标记方法标记内皮祖细胞,应用流式细胞仪进行测定。应用免疫组织化学的方法测定CD34+微血管密度。应用Morris水迷宫评价大鼠的学习记忆功能。
结果1、大鼠颅脑损伤后BBB通透性的改变：创伤组大鼠伤后2h损伤侧皮层及海马的EB浓度与对照组比较明显增高(P<0.05),于4h达高峰,6h有所下降,12h达峰底(仍明显高于正常组,P<0.05),24再次升高,于72h出现第二次高峰,皮层区明显低于4h(P<0.05),而海马区与4h相比无明显差异(P>0.05),于120h再次下降,168h均接近对照组(P>0.05)。2、粒细胞集落刺激因子(G-CSF)对大鼠TBI后皮层及海马BBB通透性的影响：治疗组大鼠TBI后2h、4h、6h和12h损伤侧皮层及海马的EB含量较创伤组无明显差异(P>0.05)；于伤后24h、72h、120h较创伤组明显下调(P<0.05)。3、EB示踪的脑组织荧光显微镜观察结果：创伤组大鼠脑损伤灶周围于TBI后2h红色荧光颗粒明显浓染,于4h为著,6h变浅,12h最浅,24h再次出现浓染,于72h出现第二次染色高峰,于120h再次下降,168h接近对照组；治疗组大鼠于伤后24h、72h、120h较创伤组荧光染色明显下降。4、大鼠脑组织含水量的变化：创伤组大鼠伤后2h脑组织含水量较对照组增加(P<0.05),4-24h逐渐呈上升趋势,于72小时达高峰,120h明显下降,168h基本恢复正常,对侧脑组织与对照组比较无明显差异(P>0.05)。治疗组大鼠伤后24-120h较创伤组明显下调(P<0.05)。5、大鼠外周循环EPCs的变化：创伤组大鼠伤后2h外周循环中EPCs较对照组明显下降(P<0.05),4h开始回升,于6-12 h较对照组明显增加(P<0.05),24 h有所下降,于72 h后接近正常水平；治疗组大鼠伤后2 h-72 h较创伤组明显增加(P<0.05),120 h后接近正常水平。6、CD34+微血管密度检测结果：创伤组大鼠损伤侧损伤灶周围皮层及海马齿状回区伤后72 h有所增加,与对照组相比有明显差异(P<0.05),一直持续至168 h；治疗组大鼠伤后24 h有所增加,72 h达高峰,与创伤组比较有明显差异(P<0.05),持续至168h。7、定位航行实验结果：创伤组大鼠1-5d的逃避潜伏期和游泳距离较对照组明显延长(P<0.05)。治疗组大鼠2-5d逃避潜伏期与游泳距离较创伤组明显缩短(P<0.05)。8、空间探索实验结果：创伤组大鼠目标象限百分比低于对照组(P<0.05)；治疗组大鼠目标象限百分比较创伤组明显增加(P<0.05)。
结论1、大鼠TBI后损伤灶周围皮质及海马存在BBB的开放,BBB的开放呈双相性；2、大鼠TBI后BBB破坏,脑组织的含水量增加,是导致继发性脑损伤的重要因素之一。3、EPCs参与了TBI后BBB的修复,增加外周循环的EPCs能够有效的修复BBB,降低脑水肿。4、大鼠TBI后BBB通透性增加,脑组织含水量增加导致继发性脑损伤是TBI后出现学习记忆功能障碍的重要原因。5、增加外周循环EPCs的数量,可以有效地减轻继发性脑损伤,从而改善学习记忆功能。
Objective:To observe the change of the permeability of blood-brain barrier after traumatic brain injury in rat and to investigate the impact of the permeability of blood-brain barrier and cognitive capacity after traumatic brain injury in rat by the increased number of endothelial progenitor cells in peripheral circulation.
Methods:450 healthy adult Wistar rats were randomly divided into control group, sham group, TBI group and treatment group. The model of traumatic brain injury used by hydraulic blow. The rats of treatment group were gotten intraperitoneal injection of G-CSF (50 ug·kg-1·d-1) for 5 days before injury, and the models were replicated in 2 days after stopping injection. EB quantitative detection of cortex and hippocampus was gotten through detecting the optical density of sample, and Evans blue content was inquired from standard curve and equation, then the results were worked out. EB tracing of brains was observed under fluorescence microscope. Brain water content was determinated in wet and drying weight way. Endothelial progenitor cells were marked by CD34/CD133 double positive cells and measured by flow cytometry. CD34+ micro vessel density was detected by immunohistochemical method. Morris water maze was applicated to evaluate cognitive function.
Results:1 The changs of BBB permeability after traumatic brain injury in rats:The EB content of cortex and hippocampus in injury side in TBI group was significantly higher compared with the control group at 2h after injury (P<0.05), and reached the peak at 4h, and begained to decline at 6h and to the lowest at 12h (still significantly higher than the control group, P<0.05), and increased again at 24h and reached the second peak at 72h, and significantly was lower in cortex than 4h(P<0.05), but was not significantly different in hippocampus at 4h, and declined again at 120h, and approached to the control group at 168h (P>0.05).2 The influence of Granulocyte colony stimulating factor on BBB permeability of cortex and hippocampus after brain injury in rat:Compared with TBI group, the EB content of cortex and hippocampus in treatment group was no significant difference at 2h,4h,6h and 12h after TBI (P> 0.05), and lower than the TBI group at 24h,72h and 120h after TBI (P<0.05); 3 The regults of EB tracer of rat brain tissue slices observed under fluorescence microscopy: The red fluorescent granules was obvious in TBI group at 2h after TBI, and deepened at 4h, and thin at 6h, and thinest at 12h, and deepened again at 24h, and the second peak occurred at 72h, and thin again at 120h, and approached to the control group at 168h. Compared with TBI group, the red fluorescence of treatment group was decreased significantly at 24h,72h,120h after TBI.4 Changes of brain water content: Compared with the control group, the brain water content in treatment group increased at 2h after injury (P<0.05), and gradually rised at 4-24h, and peaked at 72 h, and decreased at 120h, and returned to normal at 168h. Compared with TBI group, the brain water content in treatment group was lower at 24-120h group (P<0.05).5 The changes of EPCs in peripheral circulation in rats:Compared with the control group, EPCs in peripheral circulation in TBI group decreased significantly at 2 h after injury (P<0.05), and began to rise at 4h, and increased significantly at 6～12 h compared with the control group (P<0.05),24 h decreased, and closed to the normal level at 72 h. EPCs in peripheral circulation in treatment group was significantly increased compared with TBI group at 2 h～72 h after injury (P<0.05), and closed to the normal level at 120 h after in injury.6 CD34+microvessel density test results: CD34+ microvessel density of cortex and hippocampal dentate gyrus increased in TBI group at 72 h after injury, and were significantly different compared with the control group (P<0.05), and continued to 168 h. CD34+ microvessel density increased in treatment group at 24 h after injury, reached the peak at 72 h, and increased significantly compared with the TBI group (P<0.05), and continued to 168h.7 The results of oriented navigation test:Compared with control group, the escape latency and swimming distance extented significantly in the training of 1-5 day in TBI group (P<0.05). Compared with TBI group, the escape latency and swimming distance in the training of 1-5 day in treatment group shortened significantly (P<0.05).8 The results of space exploration test:Compared with the control group, the percentage of target quadrant if TBI group decreased (P<0.05) significantly. Compared with TBI group the percentage of target quadrant of treatment group was increased significantly (P<0.05).
Conclusion:1 BBB opening exists in the injury cortex and hippocampus in rats after TBI, and BBB opening was biphasic.2 The destruction of BBB and increased brain water content in rats is one of the important factors leading to secondary brain injury after TBI.3 EPCs involve in BBB repair after TBI. the increased EPCs in peripheral circulation can repair the BBB and reduce brain edema.4 The increased permeability of BBB and brain water content after TBI result in secondary brain injury which is an important reason of cognitive dysfunction.5 Increasing the number of EPCs in peripheral circulation can repair BBB and decrease brain edema in rats after TBI, then reduce secondary brain injury, thereby improve the cognitive dysfunction.
方法健康成年Wistar大鼠随机分为对照组、假手术组、创伤组和治疗组。采用液压打击创伤性脑损伤模型。治疗组大鼠在打击前连续5天腹腔注射G-CSF(50ug·kg-1·d-1),停药后2d复制模型。EB定量采用检测大鼠皮质及海马光密度值,从标准曲线和方程上查得EB含量并计算结果；脑组织的EB示踪通过荧光显微镜观察。脑组织含水量的测定采用干湿重法。应用CD34／CD133双阳性标记方法标记内皮祖细胞,应用流式细胞仪进行测定。应用免疫组织化学的方法测定CD34+微血管密度。应用Morris水迷宫评价大鼠的学习记忆功能。
结果1、大鼠颅脑损伤后BBB通透性的改变：创伤组大鼠伤后2h损伤侧皮层及海马的EB浓度与对照组比较明显增高(P<0.05),于4h达高峰,6h有所下降,12h达峰底(仍明显高于正常组,P<0.05),24再次升高,于72h出现第二次高峰,皮层区明显低于4h(P<0.05),而海马区与4h相比无明显差异(P>0.05),于120h再次下降,168h均接近对照组(P>0.05)。2、粒细胞集落刺激因子(G-CSF)对大鼠TBI后皮层及海马BBB通透性的影响：治疗组大鼠TBI后2h、4h、6h和12h损伤侧皮层及海马的EB含量较创伤组无明显差异(P>0.05)；于伤后24h、72h、120h较创伤组明显下调(P<0.05)。3、EB示踪的脑组织荧光显微镜观察结果：创伤组大鼠脑损伤灶周围于TBI后2h红色荧光颗粒明显浓染,于4h为著,6h变浅,12h最浅,24h再次出现浓染,于72h出现第二次染色高峰,于120h再次下降,168h接近对照组；治疗组大鼠于伤后24h、72h、120h较创伤组荧光染色明显下降。4、大鼠脑组织含水量的变化：创伤组大鼠伤后2h脑组织含水量较对照组增加(P<0.05),4-24h逐渐呈上升趋势,于72小时达高峰,120h明显下降,168h基本恢复正常,对侧脑组织与对照组比较无明显差异(P>0.05)。治疗组大鼠伤后24-120h较创伤组明显下调(P<0.05)。5、大鼠外周循环EPCs的变化：创伤组大鼠伤后2h外周循环中EPCs较对照组明显下降(P<0.05),4h开始回升,于6-12 h较对照组明显增加(P<0.05),24 h有所下降,于72 h后接近正常水平；治疗组大鼠伤后2 h-72 h较创伤组明显增加(P<0.05),120 h后接近正常水平。6、CD34+微血管密度检测结果：创伤组大鼠损伤侧损伤灶周围皮层及海马齿状回区伤后72 h有所增加,与对照组相比有明显差异(P<0.05),一直持续至168 h；治疗组大鼠伤后24 h有所增加,72 h达高峰,与创伤组比较有明显差异(P<0.05),持续至168h。7、定位航行实验结果：创伤组大鼠1-5d的逃避潜伏期和游泳距离较对照组明显延长(P<0.05)。治疗组大鼠2-5d逃避潜伏期与游泳距离较创伤组明显缩短(P<0.05)。8、空间探索实验结果：创伤组大鼠目标象限百分比低于对照组(P<0.05)；治疗组大鼠目标象限百分比较创伤组明显增加(P<0.05)。
结论1、大鼠TBI后损伤灶周围皮质及海马存在BBB的开放,BBB的开放呈双相性；2、大鼠TBI后BBB破坏,脑组织的含水量增加,是导致继发性脑损伤的重要因素之一。3、EPCs参与了TBI后BBB的修复,增加外周循环的EPCs能够有效的修复BBB,降低脑水肿。4、大鼠TBI后BBB通透性增加,脑组织含水量增加导致继发性脑损伤是TBI后出现学习记忆功能障碍的重要原因。5、增加外周循环EPCs的数量,可以有效地减轻继发性脑损伤,从而改善学习记忆功能。
Objective:To observe the change of the permeability of blood-brain barrier after traumatic brain injury in rat and to investigate the impact of the permeability of blood-brain barrier and cognitive capacity after traumatic brain injury in rat by the increased number of endothelial progenitor cells in peripheral circulation.
Methods:450 healthy adult Wistar rats were randomly divided into control group, sham group, TBI group and treatment group. The model of traumatic brain injury used by hydraulic blow. The rats of treatment group were gotten intraperitoneal injection of G-CSF (50 ug·kg-1·d-1) for 5 days before injury, and the models were replicated in 2 days after stopping injection. EB quantitative detection of cortex and hippocampus was gotten through detecting the optical density of sample, and Evans blue content was inquired from standard curve and equation, then the results were worked out. EB tracing of brains was observed under fluorescence microscope. Brain water content was determinated in wet and drying weight way. Endothelial progenitor cells were marked by CD34/CD133 double positive cells and measured by flow cytometry. CD34+ micro vessel density was detected by immunohistochemical method. Morris water maze was applicated to evaluate cognitive function.
Results:1 The changs of BBB permeability after traumatic brain injury in rats:The EB content of cortex and hippocampus in injury side in TBI group was significantly higher compared with the control group at 2h after injury (P<0.05), and reached the peak at 4h, and begained to decline at 6h and to the lowest at 12h (still significantly higher than the control group, P<0.05), and increased again at 24h and reached the second peak at 72h, and significantly was lower in cortex than 4h(P<0.05), but was not significantly different in hippocampus at 4h, and declined again at 120h, and approached to the control group at 168h (P>0.05).2 The influence of Granulocyte colony stimulating factor on BBB permeability of cortex and hippocampus after brain injury in rat:Compared with TBI group, the EB content of cortex and hippocampus in treatment group was no significant difference at 2h,4h,6h and 12h after TBI (P> 0.05), and lower than the TBI group at 24h,72h and 120h after TBI (P<0.05); 3 The regults of EB tracer of rat brain tissue slices observed under fluorescence microscopy: The red fluorescent granules was obvious in TBI group at 2h after TBI, and deepened at 4h, and thin at 6h, and thinest at 12h, and deepened again at 24h, and the second peak occurred at 72h, and thin again at 120h, and approached to the control group at 168h. Compared with TBI group, the red fluorescence of treatment group was decreased significantly at 24h,72h,120h after TBI.4 Changes of brain water content: Compared with the control group, the brain water content in treatment group increased at 2h after injury (P<0.05), and gradually rised at 4-24h, and peaked at 72 h, and decreased at 120h, and returned to normal at 168h. Compared with TBI group, the brain water content in treatment group was lower at 24-120h group (P<0.05).5 The changes of EPCs in peripheral circulation in rats:Compared with the control group, EPCs in peripheral circulation in TBI group decreased significantly at 2 h after injury (P<0.05), and began to rise at 4h, and increased significantly at 6～12 h compared with the control group (P<0.05),24 h decreased, and closed to the normal level at 72 h. EPCs in peripheral circulation in treatment group was significantly increased compared with TBI group at 2 h～72 h after injury (P<0.05), and closed to the normal level at 120 h after in injury.6 CD34+microvessel density test results: CD34+ microvessel density of cortex and hippocampal dentate gyrus increased in TBI group at 72 h after injury, and were significantly different compared with the control group (P<0.05), and continued to 168 h. CD34+ microvessel density increased in treatment group at 24 h after injury, reached the peak at 72 h, and increased significantly compared with the TBI group (P<0.05), and continued to 168h.7 The results of oriented navigation test:Compared with control group, the escape latency and swimming distance extented significantly in the training of 1-5 day in TBI group (P<0.05). Compared with TBI group, the escape latency and swimming distance in the training of 1-5 day in treatment group shortened significantly (P<0.05).8 The results of space exploration test:Compared with the control group, the percentage of target quadrant if TBI group decreased (P<0.05) significantly. Compared with TBI group the percentage of target quadrant of treatment group was increased significantly (P<0.05).
Conclusion:1 BBB opening exists in the injury cortex and hippocampus in rats after TBI, and BBB opening was biphasic.2 The destruction of BBB and increased brain water content in rats is one of the important factors leading to secondary brain injury after TBI.3 EPCs involve in BBB repair after TBI. the increased EPCs in peripheral circulation can repair the BBB and reduce brain edema.4 The increased permeability of BBB and brain water content after TBI result in secondary brain injury which is an important reason of cognitive dysfunction.5 Increasing the number of EPCs in peripheral circulation can repair BBB and decrease brain edema in rats after TBI, then reduce secondary brain injury, thereby improve the cognitive dysfunction.
引文
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