脑缺血大鼠海马星形胶质纤维酸蛋白与高迁移率族蛋白表达变化及其意义
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摘要
目的
研究大鼠局灶性脑缺血再灌注后,星形胶质纤维酸蛋白(GFAP)与高迁移率族蛋白(HMGB1)在海马CA1区表达变化,探讨GFAP与HMGB1二者之间是否相关。
方法
1、实验动物:体重250~310g普通级成年雄性SD大鼠60只(安徽医科大学实验动物中心提供)。
2、实验动物分组:60只雄性SD大鼠随机分为假手术组及缺血组,两组再分为1 d,3 d,7 d,14 d,28 d ,5个亚组,每个亚组6只大鼠。
3、动物模型的制备:参照Longa[1]线栓法制作大鼠大脑中动脉阻塞再灌注(MCAO/R)模型。采用大脑中动脉栓塞2h制备SD大鼠脑缺血模型;假手术组不插入线栓,余手术过程同缺血组。
4、苏木素-伊红染色: HE染色观察海马CA1区的病理变化。
5、免疫组化:用免疫组化法观察在海马CA1区域GFAP和HMGB1在脑缺血1 d,3 d,7 d,14 d,28 d后表达情况。
6、免疫荧光双标:用免疫荧光双标结合激光共聚焦分析脑缺血后在海马CA1区域GFAP和HMGB1时程表达变化。
7、统计学分析:应用spss13.0统计软件进行数据处理,两组均数间比较采用t检验,多组均数比较采用单因素方差分析。以α=0.05作为检验标准,实验数据用均数±标准差( x±s)表示。
结果
1.对照组大部分细胞形态正常未发现明显病理变化,缺血再灌注组随着时间变化可见胶质细胞增生、肥大,间质水肿,细胞水肿,神经元细胞坏死、核萎缩,在阻塞区域,炎性细胞明显增加。
2.与假手术组比较,脑缺血组各时间点脑组织GFAP、HMGB1表达均显著增加(P<0.05)。
3.脑缺血组中再灌注7 d时GFAP表达最多,再灌注14 d时HMGB1表达最多(P<0.05)。
4.脑缺血组大鼠脑组织GFAP与HMGB1表达成正相关且在海马CA1区存有共定位细胞(r1=0.499, P<0.05; r2= 0.586 ,P<0.05)。
结论
脑缺血后,大鼠海马CA1区HMGB1表达主要与星形胶质细胞激活有关,过度激活的星形胶质细胞和过量表达的HMGB1促进脑缺血后神经元的迟发性损伤。
Objective To explore changes and significances of astrocytes glial fibrillary acidity protein and high mobility group protein expression in the hippocampus of rats following cerebral ischemic reperfusion and whether they are correlative
Methods
1. Animals Sixty healthy,male Sprague-Dawley rats weighing 250g-310g was used (Supplied by experimental of animal center of An Hui Medical University ,Hefei, China)
2. Animal Groups Sixty male Sprague Dawley(SD) rats were randomly divided into shamoperated group and ischeimia reperfusion(IR) group,The groups were divided into five subgroups:1 d ,3 d, 7 d ,14 d ,28 d,each subgroups had 6 rats.
3. Model Refering to longa[1] method, making rats underwent a 2 h middle cerebral artery occlusion (MCAO) followed by various reperfusion times (1 d, 3 d, 7 d, 14 d, 28 d); for shamoperated group, no suture was inserted into the artery,but the rest of operation were the same as above.
4. Hematoxylin-eosin(HE)staining HE was used to observe tissue pathological changes in the hippocampal CA1 subfield.
5. Immunohistochemistry The expressions of GFAP and HMGB1 in the hippocampal CA1 subfield were detected by using immunohistochemistry technique at 1 d ,3 d, 7 d ,14 d and 28 d after MCAO.
6. Fluorescent Double Staining Fluorescent double staining combined with confocal scanning were used to analyze the time course of expression of HMGB1 and GFAP in the hippocampl CA1 region after MCAO.
7. Statistical analysis The data was handled with spss13.0 statistic software, The difference of two groups was compared with t-test. The difference of many groups was compared with one-factor analysis of variance,significant level isα=0.05, The experimental data were described by means±standard deviation(x±s)
Result
1、The tissues of Sham-operated group was integrate,but that of ischemia-reperfusion group were changed with gliocyte hyperplasia and hypertrophia, interstitial edema, celluler edema, neuron necrosis,nucleus atrophy, the inflammory cells around the infarct area increasing remarkablely.
2、Compared with shamoperated group,the expressions of GFAP and HMGB1 in ischemia-reperfusion groups were evidently upregulated at all time points(P<0.05).
3、The expressions of GFAP were approaching its peak value at 7 day of reperfusion(P<0.05); the expressions of HMGB1 were approaching its peak value at 14 day of reperfusion(P<0.05)
4、The expression of GFAP and HMGB1 were a positive correlative and HMGB1 siginficantly co-localized with GFAP in the hippocampl CA1 region in ischemia-reperfusion group(r1=0.499, P<0.05; r2= 0.586 ,P<0.05)
Conclusions
The expression of HMGB1 in the hippocampal CA1 region was significantly related with astrocytes activation after cerebral ischemia ,excessive HMGB1 and activated astocytes contributed to the pathophysiological processes of delaying neuronal injury.
研究大鼠局灶性脑缺血再灌注后,星形胶质纤维酸蛋白(GFAP)与高迁移率族蛋白(HMGB1)在海马CA1区表达变化,探讨GFAP与HMGB1二者之间是否相关。
方法
1、实验动物:体重250~310g普通级成年雄性SD大鼠60只(安徽医科大学实验动物中心提供)。
2、实验动物分组:60只雄性SD大鼠随机分为假手术组及缺血组,两组再分为1 d,3 d,7 d,14 d,28 d ,5个亚组,每个亚组6只大鼠。
3、动物模型的制备:参照Longa[1]线栓法制作大鼠大脑中动脉阻塞再灌注(MCAO/R)模型。采用大脑中动脉栓塞2h制备SD大鼠脑缺血模型;假手术组不插入线栓,余手术过程同缺血组。
4、苏木素-伊红染色: HE染色观察海马CA1区的病理变化。
5、免疫组化:用免疫组化法观察在海马CA1区域GFAP和HMGB1在脑缺血1 d,3 d,7 d,14 d,28 d后表达情况。
6、免疫荧光双标:用免疫荧光双标结合激光共聚焦分析脑缺血后在海马CA1区域GFAP和HMGB1时程表达变化。
7、统计学分析:应用spss13.0统计软件进行数据处理,两组均数间比较采用t检验,多组均数比较采用单因素方差分析。以α=0.05作为检验标准,实验数据用均数±标准差( x±s)表示。
结果
1.对照组大部分细胞形态正常未发现明显病理变化,缺血再灌注组随着时间变化可见胶质细胞增生、肥大,间质水肿,细胞水肿,神经元细胞坏死、核萎缩,在阻塞区域,炎性细胞明显增加。
2.与假手术组比较,脑缺血组各时间点脑组织GFAP、HMGB1表达均显著增加(P<0.05)。
3.脑缺血组中再灌注7 d时GFAP表达最多,再灌注14 d时HMGB1表达最多(P<0.05)。
4.脑缺血组大鼠脑组织GFAP与HMGB1表达成正相关且在海马CA1区存有共定位细胞(r1=0.499, P<0.05; r2= 0.586 ,P<0.05)。
结论
脑缺血后,大鼠海马CA1区HMGB1表达主要与星形胶质细胞激活有关,过度激活的星形胶质细胞和过量表达的HMGB1促进脑缺血后神经元的迟发性损伤。
Objective To explore changes and significances of astrocytes glial fibrillary acidity protein and high mobility group protein expression in the hippocampus of rats following cerebral ischemic reperfusion and whether they are correlative
Methods
1. Animals Sixty healthy,male Sprague-Dawley rats weighing 250g-310g was used (Supplied by experimental of animal center of An Hui Medical University ,Hefei, China)
2. Animal Groups Sixty male Sprague Dawley(SD) rats were randomly divided into shamoperated group and ischeimia reperfusion(IR) group,The groups were divided into five subgroups:1 d ,3 d, 7 d ,14 d ,28 d,each subgroups had 6 rats.
3. Model Refering to longa[1] method, making rats underwent a 2 h middle cerebral artery occlusion (MCAO) followed by various reperfusion times (1 d, 3 d, 7 d, 14 d, 28 d); for shamoperated group, no suture was inserted into the artery,but the rest of operation were the same as above.
4. Hematoxylin-eosin(HE)staining HE was used to observe tissue pathological changes in the hippocampal CA1 subfield.
5. Immunohistochemistry The expressions of GFAP and HMGB1 in the hippocampal CA1 subfield were detected by using immunohistochemistry technique at 1 d ,3 d, 7 d ,14 d and 28 d after MCAO.
6. Fluorescent Double Staining Fluorescent double staining combined with confocal scanning were used to analyze the time course of expression of HMGB1 and GFAP in the hippocampl CA1 region after MCAO.
7. Statistical analysis The data was handled with spss13.0 statistic software, The difference of two groups was compared with t-test. The difference of many groups was compared with one-factor analysis of variance,significant level isα=0.05, The experimental data were described by means±standard deviation(x±s)
Result
1、The tissues of Sham-operated group was integrate,but that of ischemia-reperfusion group were changed with gliocyte hyperplasia and hypertrophia, interstitial edema, celluler edema, neuron necrosis,nucleus atrophy, the inflammory cells around the infarct area increasing remarkablely.
2、Compared with shamoperated group,the expressions of GFAP and HMGB1 in ischemia-reperfusion groups were evidently upregulated at all time points(P<0.05).
3、The expressions of GFAP were approaching its peak value at 7 day of reperfusion(P<0.05); the expressions of HMGB1 were approaching its peak value at 14 day of reperfusion(P<0.05)
4、The expression of GFAP and HMGB1 were a positive correlative and HMGB1 siginficantly co-localized with GFAP in the hippocampl CA1 region in ischemia-reperfusion group(r1=0.499, P<0.05; r2= 0.586 ,P<0.05)
Conclusions
The expression of HMGB1 in the hippocampal CA1 region was significantly related with astrocytes activation after cerebral ischemia ,excessive HMGB1 and activated astocytes contributed to the pathophysiological processes of delaying neuronal injury.
引文
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1唐道林,康睿,肖献忠.晚期炎症介质HMGB1的病理生理作用.中国病理生理杂志,2005,21:1426-1430
2 Hayakawa K,Mishima K,Nozako M,et al. Delayed treatment with minocycline ameliorates neurologic impairment through activated microglia expressing high-mobility group box1-inhibiting mechanism. Stroke,2008,39:951-958.
3 Huttunen HJ,Rauvala H. Amphoterin as an extracellular regulator of cellmotility:from discovery to disease. J Intern Med,2004,255:351-366.
4 Li J,Kokkola R,Tabibzadeh S,et al. Structural basis for the proinflammatory cytokine activity of high mobility group box 1. Mol Med,2003,9:37-45.
5 Kim JB,Lim CM,Yu YM,et al. Induction and subcellurlar localization of high-mobihity group box-1 in the postischemic rat brain. J Neurosci Res,2008,86:1125-1131.
6 Scaffidi P,Misteli T,Bianchi ME. Release of chromatin protein HMGB1 by necrotic cell triggers inflammation. Nature, 2002,418:191-195.
7 Bonaldi T,Talamo F,Scaffidi P,et al. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J,2003,22:5551-5560.
8 Gardella S,Andrei C,Ferrera D,et al. The nuclear protein HMGB1 is secreted by monocytes via a non-classical vesicle-mediated secretory pathway. EMBO Rep,2002,3:995-1001.
9 Guazzi S,Strangio A,Franzi AT,et al. HMGB1,an architectural chromatin protein and extracellular signalling factor,has a spatially and temporally restricted expression pattern in morse brain. Gene Expression Patterns,2003,3:29-33.
10 Kim JB,Yu YM,Piao CS,et al. HMGB1,a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain. J Neurosci,2006,26:6413-6421.
11 Nishibori M,Zhang J,Liu K,et al. Early translocation and release of HMGB1 in ischemic brain in rats. Neuroscience Research,2009,65:S150.
12 Hayakawa K,Mishima K,Irie K,et al. Cannabidiol prevents a post-ischemic injury progressively induced by cerebral ischemia via a high-mobility group box1-inbibiting mechamism. Neuropharmacology,2008,55:1280-1286.
13吴林青.高迁移率族蛋白B1:从核蛋白到新的细胞因子.国际免疫学杂志,2007,30:96-101.
14 van Beijnum JR,Buurman WA,Griffioen AW. Convergence and amplification oftoll-like receptor (TLR) and receptor advanced glycation end products (RAGE) signaling pathway via high mobility group B1(HMGB1). Angiogensis,2008,11:91-99.
15 Mullins GE,Sunden-Cullberg J,Johansson AS,et al. Activation of human umbilical vein endothelial cells leads to relocation and release of high-mobility group box chromosomal protein 1. Scand J Immunol,2004,60:566-573.
16 Huttunen HJ,Rauvala H. Amphoterin as an extracellular regulator of cell motility:from discovery to disease. J Intern Med,2004,255:351-366.
17 Orlova VV,Choi EY,Xie C,et al. A novel pathway of HMGB1-mediated inflammatory cell recruitment that requires Mac-1-intergrin. EMBO J,2007,26:1129-1139.
18 Ridder DA,Schwaninger M. NF-κB Signaling in cerebral ischemia. Neuroscience, 2009,158:995-1006.
19 Fiuza C,Bustin M,Talwar S,et al. Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood,2003,101:2652-2660.
20王力娜,刘玲玲,李敏,等.高迁移率族蛋白B1与中枢神经系统疾病.国际脑血管病杂志,2009,17:797-800.
21 Qiu J,Nishimura M,Wang Y,et al. Early release of HMGB1 from neurons after the onset of brain ischemia. J Cereb Blood Flow Metab,2008,28:927-938.
22 Pedrazzi M,Patrone M,Passalacqua M,et al. Selective Proinflammatory Activation of Astrocytes by HMGB1 Protein Signaling. J Immunol,2007,179:8525-8532
23 Svedin P,Hagberg H,Savman K,et al. Matrix metalloproteinase-9 gene knock-out protects the immature brain after cerebral hypoxia-ischemia. J Neurosci,2007,27:1511-1518.
24 Svedin P,Hagberg H,Savman K,et al. Matrix metalloproteinase-9 gene knock-out protects the immature brain after cerebral hypoxia-ischemia. J Neuroscience,2007,27:1511-1518.
25 Liu K,Mori S,Takahashi HK,et al. Anti-high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats. FASEB J,2007,21:3904-3916.
26 Hayakawa K, Nakano T,Irie K,et al. Inhibition of reactive astrocytes with fluorocitrate retards neurovascular remodeling and recovery after focal cerebral ischemia in mice. J Cereb Blood Flow Metab,2009,[Epub ahead of print].
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29 Degryse B,Bonaldi T,Scaffidi P,et al. The high mobilty group(HMG) boxes of the nclear protein HMG1 induce chemotaxis and cytoskeleton reorganization in rat smooth muscle cells. J Cell biol,2001,152:1197-1206.
30 Hennon M,Fan L,Tzeng E. The endogenous danger signal HMGB1 mediates vascular smooth muscle cell proliferation and intimal hyperplasia. Journal of Surgical Research,2006,130:181-182.
31 Bianchi ME,Manfredi AA. High-mobility group box1(HMGB1)protein at the crossroads between innate and adaptive immunity. Immunol Rev,2007,220:35-46.
32 Hassid BG,Nair MN,Ducruet AF,et al. Neuronal RAGE expression modulates severity of injury following transient focal Cerebral isehemia. J Clin Neurosci,2009,16:302-306.
33 Pedrazzi M,Raiteri L,Bonanno G,et al. Stimulation of excitatory amino acid release from adult mouse brain glia subcellular particles by high mobility group box 1 protein. J Neurochem,2006,99:827-838.
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1唐道林,康睿,肖献忠.晚期炎症介质HMGB1的病理生理作用.中国病理生理杂志,2005,21:1426-1430
2 Hayakawa K,Mishima K,Nozako M,et al. Delayed treatment with minocycline ameliorates neurologic impairment through activated microglia expressing high-mobility group box1-inhibiting mechanism. Stroke,2008,39:951-958.
3 Huttunen HJ,Rauvala H. Amphoterin as an extracellular regulator of cellmotility:from discovery to disease. J Intern Med,2004,255:351-366.
4 Li J,Kokkola R,Tabibzadeh S,et al. Structural basis for the proinflammatory cytokine activity of high mobility group box 1. Mol Med,2003,9:37-45.
5 Kim JB,Lim CM,Yu YM,et al. Induction and subcellurlar localization of high-mobihity group box-1 in the postischemic rat brain. J Neurosci Res,2008,86:1125-1131.
6 Scaffidi P,Misteli T,Bianchi ME. Release of chromatin protein HMGB1 by necrotic cell triggers inflammation. Nature, 2002,418:191-195.
7 Bonaldi T,Talamo F,Scaffidi P,et al. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J,2003,22:5551-5560.
8 Gardella S,Andrei C,Ferrera D,et al. The nuclear protein HMGB1 is secreted by monocytes via a non-classical vesicle-mediated secretory pathway. EMBO Rep,2002,3:995-1001.
9 Guazzi S,Strangio A,Franzi AT,et al. HMGB1,an architectural chromatin protein and extracellular signalling factor,has a spatially and temporally restricted expression pattern in morse brain. Gene Expression Patterns,2003,3:29-33.
10 Kim JB,Yu YM,Piao CS,et al. HMGB1,a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain. J Neurosci,2006,26:6413-6421.
11 Nishibori M,Zhang J,Liu K,et al. Early translocation and release of HMGB1 in ischemic brain in rats. Neuroscience Research,2009,65:S150.
12 Hayakawa K,Mishima K,Irie K,et al. Cannabidiol prevents a post-ischemic injury progressively induced by cerebral ischemia via a high-mobility group box1-inbibiting mechamism. Neuropharmacology,2008,55:1280-1286.
13吴林青.高迁移率族蛋白B1:从核蛋白到新的细胞因子.国际免疫学杂志,2007,30:96-101.
14 van Beijnum JR,Buurman WA,Griffioen AW. Convergence and amplification oftoll-like receptor (TLR) and receptor advanced glycation end products (RAGE) signaling pathway via high mobility group B1(HMGB1). Angiogensis,2008,11:91-99.
15 Mullins GE,Sunden-Cullberg J,Johansson AS,et al. Activation of human umbilical vein endothelial cells leads to relocation and release of high-mobility group box chromosomal protein 1. Scand J Immunol,2004,60:566-573.
16 Huttunen HJ,Rauvala H. Amphoterin as an extracellular regulator of cell motility:from discovery to disease. J Intern Med,2004,255:351-366.
17 Orlova VV,Choi EY,Xie C,et al. A novel pathway of HMGB1-mediated inflammatory cell recruitment that requires Mac-1-intergrin. EMBO J,2007,26:1129-1139.
18 Ridder DA,Schwaninger M. NF-κB Signaling in cerebral ischemia. Neuroscience, 2009,158:995-1006.
19 Fiuza C,Bustin M,Talwar S,et al. Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood,2003,101:2652-2660.
20王力娜,刘玲玲,李敏,等.高迁移率族蛋白B1与中枢神经系统疾病.国际脑血管病杂志,2009,17:797-800.
21 Qiu J,Nishimura M,Wang Y,et al. Early release of HMGB1 from neurons after the onset of brain ischemia. J Cereb Blood Flow Metab,2008,28:927-938.
22 Pedrazzi M,Patrone M,Passalacqua M,et al. Selective Proinflammatory Activation of Astrocytes by HMGB1 Protein Signaling. J Immunol,2007,179:8525-8532
23 Svedin P,Hagberg H,Savman K,et al. Matrix metalloproteinase-9 gene knock-out protects the immature brain after cerebral hypoxia-ischemia. J Neurosci,2007,27:1511-1518.
24 Svedin P,Hagberg H,Savman K,et al. Matrix metalloproteinase-9 gene knock-out protects the immature brain after cerebral hypoxia-ischemia. J Neuroscience,2007,27:1511-1518.
25 Liu K,Mori S,Takahashi HK,et al. Anti-high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats. FASEB J,2007,21:3904-3916.
26 Hayakawa K, Nakano T,Irie K,et al. Inhibition of reactive astrocytes with fluorocitrate retards neurovascular remodeling and recovery after focal cerebral ischemia in mice. J Cereb Blood Flow Metab,2009,[Epub ahead of print].
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