高压氧对大鼠实验性脑损伤后脑组织ICAM-1和MCP-1表达的影响
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摘要
目的：
脑外伤(Traumatic Brain Injury，TBI)是临床常见的一种创伤性疾病，大量实验和临床研究证实，外伤造成的脑损伤并不仅仅是在伤后瞬时完成的，伤后逐渐发展演化形成的继发脑损伤才是主要病理过程。近年来国内外研究结果表明，外伤所导致的局部炎症反应在继发性脑损伤方面起着重要作用。局部神经组织变性坏死、血脑屏障(Blood Brain Barrier，BBB)的破坏和局部脑水肿都与炎症反应有着密切的关系。炎症反应的一个重要特点是白细胞浸润，而细胞间粘附分子-1(ICAM-1)和单核细胞趋化因子-1(MCP-1)是使白细胞游出血管壁并激活和引导白细胞向炎症区浸润的重要因子，其表达的程度与炎症反应的强弱有着密切关系。
高压氧(Hyperbaric Oxygen，HBO)治疗颅脑损伤，在促醒、促进神经功能的恢复和减少后遗症方面的效果已被多数学者所接受。但其确切的治疗机理目前尚不十分清楚。有学者在对肌瓣移植的缺血再灌注损伤进行实验研究时发现：HBO能够减少白细胞与血管内皮细胞粘附，并减少白细胞的浸润，减轻局部的炎症反应，从而减轻肌瓣的缺血再灌注损伤。但HBO对TBI后脑组织中白细胞浸润和ICAM-1、MCP-1的表达是否有影响，目前国内外尚未见报道。本实验研究目的在于通过对大鼠TBI后HBO的治疗，观察其对外伤脑组织内的ICAM-1和MCP-1表达的影响，进而了解HBO对TBI后脑组织中自细胞浸润的影响，为HBO治疗脑外伤提供理论依据。
娜州大拳2004月卜.士布呀，七息毕J七今全文
高压反对大双实脸性肺栩伤后肺姐旗1〔胡~1和峨P一]表达的影响
方法:
采用250一3009成年健康封闭群SD雄性大鼠，随机分为A、B两组，A、B
两组又分别分为6个亚组。所有大鼠均采用Freeney自由落体脑损伤模型的制
作方法，制造出中度的脑损伤模型。A组于外伤后不施加任何处理因素，B组于
外伤后30分钟内送入高压氧舱进行HBO治疗。将各亚组分别于伤后3小时，6
小时、12小时、24小时、72小时、7天断头处死，处死后立即采集标本，每个
标本的一部分送电镜中心进行透射电镜观察，另一部分进行ICAM一1、MCP一1免
疫组化染色，染色后阳性细胞用图像分析系统进行测定。测定结果在计算机上
用SPSS软件包(10.0版)进行统计学处理。计量资料均以x士s表示，采用成
组样本t检验，以。=0 .05为差异显著性的检验标准。
结果:
1.透射电镜下超微结构的变化
A组(对照组)于伤后3h即有明显的血管周围水肿、细胞内及线粒体肿胀。
伤后6h血管周围水肿达高峰，线粒体呈球形，有的线粒体空泡化甚至碎裂，线
粒体峭消失;有的神经细胞胞质内线粒体及其他细胞器已不存在。伤后12h血
管周围水肿及细胞内肿胀均减轻。B组(HBO组)于伤后3h和6h均亦出现血管
周围水肿，但明显较对照组为轻，无线粒体空泡化和破裂。伤后24h两组己无
明显差别。
2.ICAM一1的表达
A组在伤后3h即有ICAM一1的表达，伤后6h表达至高峰，伤后24h开始下
降，至伤后第7天仍有少量表达，B组在伤后3h、6h及伤后12h的ICAM一l的
表达与A组相比有明显降低(P<0 .05)，但两组在伤后24小时及以后，ICAM一1
的表达则无明显差异(P>0.05)。
3.MCP一1的表达
两组均于伤后3小时即有MCP一1的表达，伤后12小时达高峰，伤后24小
时仍有较高表达，但B组MCP一l表达于伤后3小时、6小时、12小时和24小
时明显低于
(P>0 .05)。
A组(P(0.
两组于伤后
05)。两组于伤后72小时毗P一1的表达即无明显差异
7天MCP一1均仍有表达。
娜州大学2004年硕士研免生早业论文
高压孰对大民实脸性肺扭伤后脸组织IC侧-1和式P一1表达的影响
结论:
1.炎症反应的一个重要特点是白细胞浸润，而白细胞浸润是TBI后的关
键事件，BSB的破坏、局部脑组织水肿与白细胞浸润密切相关;且ICAMeel和MCP一1
是使白细胞穿越血管内皮细胞向炎症部位游走和浸润的重要因子;本实验证实
了工CAMeel的表达高峰与脑水肿的高峰相一致，成P一1的表达的高峰与单核细胞、
淋巴细胞的迟发浸润相一致。
2.HBO能明显减轻大鼠脑外伤ICAM一l和MCP一1在伤后3h、6h和 12h的表
达，因而减少了白细胞向血管外游出和向外伤灶的游走和浸润，缓解了局部脑
组织的炎症反应和脑水肿，减轻了由炎症反应引起的继发性脑损伤，为HBO治
疗TBI提供理论依据。
3.本实验表明，TBI后3小时即有ICAMeel和MCP一l的表达，因此，HBO治
疗TBI应尽早进行，以有效降低工CAM一1和MCP一1的表达。
4.由于治疗组与对照组ICAM一1和MCP一1的表达分别于伤后24小时和72
小时已无明显差异，提示应最迟于TBI后24小时内行第二次HBO治疗，进一步
减少IcAM一1和MCP一1的迟发表达和白细胞的浸润，减轻迟发性炎症反应，改善
脑功能。
Objectives
Traumatic brain injury (TBI) is very common in neurosurgery. Many experimental and clinical researches have conformed that the secondary brain injury is an important pathological process after TBI. Recently, the results of oversea and domestic researches have indicated that inflammation after TBI play a critical role in the secondary brain injury. Inflammation contributes closely to brain tissue degeneration and necrosis, blood brain barrier (BBB) damage and local brain tissue edema after TBI. Leukocyte infiltration is a main characteristic of inflammation. Intercellular adhesion molecule-1 (1CAM-1) and
monocyte chemoattractant protein- 1 (MCP-1) are the key factors which activate and direct leukocytes moving out of capillary vessels and gathering in the inflammatory area. Therefore, ICAM-1 and MCP-1 are closely related to the inflammatory course after TBI.
Many researches indicate that hyperbaric oxygen(HBO) treatment can effectively alleviate TBI in recovering consciousness, improving nervous function and improving prognosis. But the accurate mechanisms are not known. In the course of experimental study on re-perfusion of ischemic skeletal-muscle graft, Zamboni found that HBO could reduce leukocyte adhering to endothelia and infiltrating. Whether HBO affects leukocyte infiltration and the expression of ICAM-1 and MCP-1 in brain tissue has been not reported. The objectives of present experimental research are to explore the HBO influence on the expression of ICAM-1 and MCP-1 after TBI, which may provide the theoretical evidences for the effect of HBO in treating TBI.
Methods
Adult healthy male SD rats are chosen. The range of their
-5-
weight was 250 - 300g. All rats were divided into two groups: group A and group B, then each group was divided into 6 sub-group at random. According to Freeney's experimental TBI model, moderate damage was done on all rats. No administration was done on group A and group B were sent to HBO treatment in 30 minutes after TBI. Then the rats of sub-group 1,2,3,4,5,6 were killed at 3h, 6h, 12h, 24h, 72h and on day 7 respectively after TBI. One part of each specimen was sent to electron microscope center, the rest was stained with immunohistochemical method of ICAM-1 and MCP-1. The positive cells were measured by map analysis system(MAS). The results were analysized by SPSS on computer. Data were expressed as x s with a =0.05 considered statistically significant.
Results
1, The change of brain tissue ultrastructure under electromicroscope
In group A, vascular periphery edema and mitochondria swollen were obviously observed at 3h after TBI. At 6h, vascular periphery edema was the most apparent and mitochondria was ball-like, even blebbing and fragmentary. Mitochondria matrixes vanished. At 12h, the conditions were alleviated. Vascular periphery edema in every sub-group of
group B was slighter than that of group A respectively. The blibbing and fragmentary of mitochondria wasn't exist in group B. At 24h, both group A and B showed no significant difference .
2, The expression of ICAM-1
In group A, the expression of ICAM-1 began to up-regulate at 3h and the expression reached the highest level at 6h and began to reduce after 24h. The expression of ICAM-1 became minor on 7th day after TBI. The expression of ICAM-1 in group B was dramatically lower than that in group A at 3h, 6h and 12h respectively (P<0.05). However, the conditions in both group A and B had not difference at 24h after TBI ( P>0.05 ) . 3, The expression of MCP-1
In both group A and B, the expression of MCP-1 began to be observed at 3h after TBI, and the expression reached the highest level at 12h, and the expression was high at 24h after TBI. But, the expression of MCP-1 in each sub-group of group B was lower than of group A at 3h, 6h, 12h and 24h respectively after TBI (P<0.05). The expression of MCP-1 in both group A and B showed no significant difference (P>0.05) . The expression of MCP-1 was faint on 7 day after TBI.
-7-
Conclusion
1, A critical characteris
脑外伤(Traumatic Brain Injury，TBI)是临床常见的一种创伤性疾病，大量实验和临床研究证实，外伤造成的脑损伤并不仅仅是在伤后瞬时完成的，伤后逐渐发展演化形成的继发脑损伤才是主要病理过程。近年来国内外研究结果表明，外伤所导致的局部炎症反应在继发性脑损伤方面起着重要作用。局部神经组织变性坏死、血脑屏障(Blood Brain Barrier，BBB)的破坏和局部脑水肿都与炎症反应有着密切的关系。炎症反应的一个重要特点是白细胞浸润，而细胞间粘附分子-1(ICAM-1)和单核细胞趋化因子-1(MCP-1)是使白细胞游出血管壁并激活和引导白细胞向炎症区浸润的重要因子，其表达的程度与炎症反应的强弱有着密切关系。
高压氧(Hyperbaric Oxygen，HBO)治疗颅脑损伤，在促醒、促进神经功能的恢复和减少后遗症方面的效果已被多数学者所接受。但其确切的治疗机理目前尚不十分清楚。有学者在对肌瓣移植的缺血再灌注损伤进行实验研究时发现：HBO能够减少白细胞与血管内皮细胞粘附，并减少白细胞的浸润，减轻局部的炎症反应，从而减轻肌瓣的缺血再灌注损伤。但HBO对TBI后脑组织中白细胞浸润和ICAM-1、MCP-1的表达是否有影响，目前国内外尚未见报道。本实验研究目的在于通过对大鼠TBI后HBO的治疗，观察其对外伤脑组织内的ICAM-1和MCP-1表达的影响，进而了解HBO对TBI后脑组织中自细胞浸润的影响，为HBO治疗脑外伤提供理论依据。
娜州大拳2004月卜.士布呀，七息毕J七今全文
高压反对大双实脸性肺栩伤后肺姐旗1〔胡~1和峨P一]表达的影响
方法:
采用250一3009成年健康封闭群SD雄性大鼠，随机分为A、B两组，A、B
两组又分别分为6个亚组。所有大鼠均采用Freeney自由落体脑损伤模型的制
作方法，制造出中度的脑损伤模型。A组于外伤后不施加任何处理因素，B组于
外伤后30分钟内送入高压氧舱进行HBO治疗。将各亚组分别于伤后3小时，6
小时、12小时、24小时、72小时、7天断头处死，处死后立即采集标本，每个
标本的一部分送电镜中心进行透射电镜观察，另一部分进行ICAM一1、MCP一1免
疫组化染色，染色后阳性细胞用图像分析系统进行测定。测定结果在计算机上
用SPSS软件包(10.0版)进行统计学处理。计量资料均以x士s表示，采用成
组样本t检验，以。=0 .05为差异显著性的检验标准。
结果:
1.透射电镜下超微结构的变化
A组(对照组)于伤后3h即有明显的血管周围水肿、细胞内及线粒体肿胀。
伤后6h血管周围水肿达高峰，线粒体呈球形，有的线粒体空泡化甚至碎裂，线
粒体峭消失;有的神经细胞胞质内线粒体及其他细胞器已不存在。伤后12h血
管周围水肿及细胞内肿胀均减轻。B组(HBO组)于伤后3h和6h均亦出现血管
周围水肿，但明显较对照组为轻，无线粒体空泡化和破裂。伤后24h两组己无
明显差别。
2.ICAM一1的表达
A组在伤后3h即有ICAM一1的表达，伤后6h表达至高峰，伤后24h开始下
降，至伤后第7天仍有少量表达，B组在伤后3h、6h及伤后12h的ICAM一l的
表达与A组相比有明显降低(P<0 .05)，但两组在伤后24小时及以后，ICAM一1
的表达则无明显差异(P>0.05)。
3.MCP一1的表达
两组均于伤后3小时即有MCP一1的表达，伤后12小时达高峰，伤后24小
时仍有较高表达，但B组MCP一l表达于伤后3小时、6小时、12小时和24小
时明显低于
(P>0 .05)。
A组(P(0.
两组于伤后
05)。两组于伤后72小时毗P一1的表达即无明显差异
7天MCP一1均仍有表达。
娜州大学2004年硕士研免生早业论文
高压孰对大民实脸性肺扭伤后脸组织IC侧-1和式P一1表达的影响
结论:
1.炎症反应的一个重要特点是白细胞浸润，而白细胞浸润是TBI后的关
键事件，BSB的破坏、局部脑组织水肿与白细胞浸润密切相关;且ICAMeel和MCP一1
是使白细胞穿越血管内皮细胞向炎症部位游走和浸润的重要因子;本实验证实
了工CAMeel的表达高峰与脑水肿的高峰相一致，成P一1的表达的高峰与单核细胞、
淋巴细胞的迟发浸润相一致。
2.HBO能明显减轻大鼠脑外伤ICAM一l和MCP一1在伤后3h、6h和 12h的表
达，因而减少了白细胞向血管外游出和向外伤灶的游走和浸润，缓解了局部脑
组织的炎症反应和脑水肿，减轻了由炎症反应引起的继发性脑损伤，为HBO治
疗TBI提供理论依据。
3.本实验表明，TBI后3小时即有ICAMeel和MCP一l的表达，因此，HBO治
疗TBI应尽早进行，以有效降低工CAM一1和MCP一1的表达。
4.由于治疗组与对照组ICAM一1和MCP一1的表达分别于伤后24小时和72
小时已无明显差异，提示应最迟于TBI后24小时内行第二次HBO治疗，进一步
减少IcAM一1和MCP一1的迟发表达和白细胞的浸润，减轻迟发性炎症反应，改善
脑功能。
Objectives
Traumatic brain injury (TBI) is very common in neurosurgery. Many experimental and clinical researches have conformed that the secondary brain injury is an important pathological process after TBI. Recently, the results of oversea and domestic researches have indicated that inflammation after TBI play a critical role in the secondary brain injury. Inflammation contributes closely to brain tissue degeneration and necrosis, blood brain barrier (BBB) damage and local brain tissue edema after TBI. Leukocyte infiltration is a main characteristic of inflammation. Intercellular adhesion molecule-1 (1CAM-1) and
monocyte chemoattractant protein- 1 (MCP-1) are the key factors which activate and direct leukocytes moving out of capillary vessels and gathering in the inflammatory area. Therefore, ICAM-1 and MCP-1 are closely related to the inflammatory course after TBI.
Many researches indicate that hyperbaric oxygen(HBO) treatment can effectively alleviate TBI in recovering consciousness, improving nervous function and improving prognosis. But the accurate mechanisms are not known. In the course of experimental study on re-perfusion of ischemic skeletal-muscle graft, Zamboni found that HBO could reduce leukocyte adhering to endothelia and infiltrating. Whether HBO affects leukocyte infiltration and the expression of ICAM-1 and MCP-1 in brain tissue has been not reported. The objectives of present experimental research are to explore the HBO influence on the expression of ICAM-1 and MCP-1 after TBI, which may provide the theoretical evidences for the effect of HBO in treating TBI.
Methods
Adult healthy male SD rats are chosen. The range of their
-5-
weight was 250 - 300g. All rats were divided into two groups: group A and group B, then each group was divided into 6 sub-group at random. According to Freeney's experimental TBI model, moderate damage was done on all rats. No administration was done on group A and group B were sent to HBO treatment in 30 minutes after TBI. Then the rats of sub-group 1,2,3,4,5,6 were killed at 3h, 6h, 12h, 24h, 72h and on day 7 respectively after TBI. One part of each specimen was sent to electron microscope center, the rest was stained with immunohistochemical method of ICAM-1 and MCP-1. The positive cells were measured by map analysis system(MAS). The results were analysized by SPSS on computer. Data were expressed as x s with a =0.05 considered statistically significant.
Results
1, The change of brain tissue ultrastructure under electromicroscope
In group A, vascular periphery edema and mitochondria swollen were obviously observed at 3h after TBI. At 6h, vascular periphery edema was the most apparent and mitochondria was ball-like, even blebbing and fragmentary. Mitochondria matrixes vanished. At 12h, the conditions were alleviated. Vascular periphery edema in every sub-group of
group B was slighter than that of group A respectively. The blibbing and fragmentary of mitochondria wasn't exist in group B. At 24h, both group A and B showed no significant difference .
2, The expression of ICAM-1
In group A, the expression of ICAM-1 began to up-regulate at 3h and the expression reached the highest level at 6h and began to reduce after 24h. The expression of ICAM-1 became minor on 7th day after TBI. The expression of ICAM-1 in group B was dramatically lower than that in group A at 3h, 6h and 12h respectively (P<0.05). However, the conditions in both group A and B had not difference at 24h after TBI ( P>0.05 ) . 3, The expression of MCP-1
In both group A and B, the expression of MCP-1 began to be observed at 3h after TBI, and the expression reached the highest level at 12h, and the expression was high at 24h after TBI. But, the expression of MCP-1 in each sub-group of group B was lower than of group A at 3h, 6h, 12h and 24h respectively after TBI (P<0.05). The expression of MCP-1 in both group A and B showed no significant difference (P>0.05) . The expression of MCP-1 was faint on 7 day after TBI.
-7-
Conclusion
1, A critical characteris
引文
(1) 蔺世龙、刘景昌、辛佩珠等。高压氧医学理论与新技术人民卫生出版社58-63， 1998．
(2) Zamboni WA,Roth AC ,Russell RC ,et al ,Morphologic analysis of the microcirculation during reperfusion of ischemic skeletal muscle and the effect of HBO .Plast Reconstr surg 91,1110-1123.1993
(3) Carlos TM, Clark RS, Franicola-Higgin D, et al Expression of endothelial adhesion molecular and recruitment of neutrophils after TBI in rat. J Leukoc Biol. 61(3)279-285 1997
(4) Shibayama M, Kuchwaki H, Inao S, et al . ICAM-1 expression on glia flollowing brain injury . J Neurotrauma 13(12)801-808 1996
(5) Balabanov R, Goldman H, Murphy S, et al. Endothelial cell activation following moderate TBI. Neurol Res. 23(23)175-182 2001
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(7) Carlos TM , Clark RS, Franico-Higgin D, et al Expression of endothelial adhesion molecular and recruitment of neutrophils after TBI in rat. J Leukoc Biol. 61(3)279-285 1997
(8) Kupatt C, Habazettl H, Goedecke A, et al TNF-a contributes to ischemia-and reperfusion -indused endothelial activation in isolated hearts . Circ Res , 84(4):392-404 1999
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(18)Kim J .S. Gautam S.C. Chopp M. et al. Expression of monocyte chemoattractant protein-1 and macrophage inftammatory protein-1 after flcal cerebral ischemia in the rat. J.Neuroimmun.56,127-134. 1995
(19)GaassoJ. Miller M. J. Cowell R.M et al. Acute excitotoxic injury ineuces expression of monocyte chemoattractant protein-1 and its receptor CCR2.in neonatal rat brain .Expl Neurol 165,295-300. 2000
(20)Wand X. Yue T. Barone F.Cet al. Monocyte chemoattractant protein-1 messenger RNA expression in rat ischemic area. Stroke26,661-666. 1995
(21)Bermant J .W. Guida .M P .Warren J.et al. localization of monocyte chemoattractant pretein-1 expression in the central nervous system in experimental autoimmune encephalomyelitis and trauma in the rat J. immun156,3017-3023.1996
(22)Glabinski A. R Balasingam.V. Tani M. Kunkel S.L et. al .Chenmokine MCP-1 is expressed by astrocytes after mechanical injury to the brain .J Immun. 156,4363-4368.1996
(23) Galasso J.M .Miller M.J .Cowell R.M et.al Acute excitotoxic injury induces expression of MCP-1 and its receptor CCR2.in neonatal rat brain Expl N eurol, 165,295-300. 2000
(24) Szafiarski J. Ivacko J. Liu X .et al Excitotoxic injury induces monocyte chemoattractant protein-1 expression neonatoal rat brain. Brain Res.55,306-314. 1998
(25) Ghirnikar R.S. Lee Y.L. Li .J.D. et al. Chemokine in rat stab wound brain injury using antisense oligodeoxynucheotion Neurosci.Lett.247,21-24. 1998
(26) Ghimikar R.S. Lee Y . L . and Eng L.F. Chemokine antagonist infusion attenuates cellular infitration following spinal cord contusion injury in rat . J. Neurosci. Res .59,63-73.2000
(27) Kennedy K.J. Stfieter R.M. Kunkel S. L. et al. Acute and relapsing experimental autoimmune encephalomyelitis is regulated by differential expression of the CCr2 chemokines macrophage inflammatory protein- alpha and MCP-1.J .Neuro immun.92,98-108. 1998
(28) Ghirnikar RS, Lee YL, Eng LF, et al Iflammation in traumatic brain injury :role of cytokines and chemokines. Neurochem Res 23(3)329-340 1998
(29) Hausmann EH, Berman NE, Wang YY, et al. Slective chemokines mRNA expression following brain injury. Brain Res, 788(1-2):49-59 1998
(30) Galasso J.M, Hamson J.K, Silverstein F.S: MCP-lis a mediator of acute excitotoxic injury in neonatal rat brain .J Neurosci. 101(3):737-744, 2000
(31) Ghirnikar RS, Lee YL, Eng LF, et al Iflammation in traumatic brain injury :role of cytokines and chemokines. Neurochem Res 23(3)329-340 1998
(32) Bell M .D, Taub D.D, Perry V.H. Overriding the brain intrinsic resistance to leukocyte recruitment with intraparenchymal injection of accombinant chemokines. J. Neurosci 74:283-292 1996
(33) Giulian D, Corpuz M, Chapman S, et al. Reactive mononuclear phagocytes release neurotoxins after ischemic and traumatic injury to the CNS J Neurosci Res 36:681-693,1995
(34) Holmin S, Mathiesen T Shetye Jet al:Biphasic edema development after experimental brain contusion in rat. Neursci Lett 194:97-100 ,1995
(35) Staffan Holmin M.D, Johan MS, Peter Biberfeld MD, et al Intracerebral inflammation after human brain contusion Neurosurgery 42:291-299 1998
(36) Soares HD ,Hicks RR, Smith D, et al. Inflammatory leukocytic recruitment and diffuse neuronal degeneration result from traumatic brain injury. J Neurosci 15:8223-8233,1995
(37) Holmin S . Schalling M, Hojeberg B , et al . Intracerebral inflammatory response to experimental brain contusion. Acta Neurochir 132 : 110-119 1995
(38) Carlos TM ,Clark RS , Franco-Higgin D, et al. Expression endothelial adhesion molecule and recruitment neutrophils after traumatic brain injury in rat. J Leukoc Biol,61(3):279-285 1997
(39) Sukoff MH ,Houin SA, Espinosa OE, et al. The protecture effect of hyper bade oxyenation in experimental cerebral edema. J Neurosurg, 1986, 29:236
(40) Sukoff MH ,Ragayz RE. Hyperbric oxygenation for the treatment of acute cerebral edema. Neurosurgery, 1982,10:29
(41) Contreres FL , Kade Raro M, Eisenberg HM, et al Effection of hyperbaric oxygen on glucose utlization in a freeze-traumatized rat brain. J Neurosurg, 1988, 68:137
(42) 李静，万积成，吴建中，等。高压氧对实验性脑损伤和脑水肿的影响。中华神经外科杂志，1994，10(5)：266-268．
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(3) Carlos TM, Clark RS, Franicola-Higgin D, et al Expression of endothelial adhesion molecular and recruitment of neutrophils after TBI in rat. J Leukoc Biol. 61(3)279-285 1997
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(7) Carlos TM , Clark RS, Franico-Higgin D, et al Expression of endothelial adhesion molecular and recruitment of neutrophils after TBI in rat. J Leukoc Biol. 61(3)279-285 1997
(8) Kupatt C, Habazettl H, Goedecke A, et al TNF-a contributes to ischemia-and reperfusion -indused endothelial activation in isolated hearts . Circ Res , 84(4):392-404 1999
(9) Whalen MJ, Carlos TM, Dixon CE, et al. redused brain edema after TBI in mouse deficient in P-selectin and ICAM-1. J Leukoc Biol, 67(2): 160-168 2000
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after TBI. Anesth Analg, 86(4):759-765 1998
(12)Whalen MJ, Carlos TM, Kochanek PM, et al. SICAM in CNS are increased in children with severity head injury. J Neurotrauma 15(10):777-787, 1998
(13)Pleines UF, Stover JF, Kossmann T, et al. Soluble ICAM-1 in CSF coincides with the extent of cerebral damage in patient with severe traumatic brain injury.J Neurotrauma 15(6):399-409 1998
(14)Luster AD, Chemokines-chemotactic cytokines that mediate inflammation. N Engl J Med 338(7):436-445 1998
(15)Martinery JA, Cuff C, Litwak M, et al. Cytokine-indused inflammation in the CNS revisited. Neurochem Res, 23(3):349-359 1998
(16)Bell M. D D. and Pery V. H. Overriding the brain,s intrinsic reststance to leukacyte with intraparenchymal injectons of recombinent chemokines. Neuroscience74,283-292. 1996
(17)Frade j .M .Mellado M. edl Real G, et al characterization of the CCR2 chemokine receptor:CCR2 Expression in B cells. J .Immun. 159-5576-5584. 1997
(18)Kim J .S. Gautam S.C. Chopp M. et al. Expression of monocyte chemoattractant protein-1 and macrophage inftammatory protein-1 after flcal cerebral ischemia in the rat. J.Neuroimmun.56,127-134. 1995
(19)GaassoJ. Miller M. J. Cowell R.M et al. Acute excitotoxic injury ineuces expression of monocyte chemoattractant protein-1 and its receptor CCR2.in neonatal rat brain .Expl Neurol 165,295-300. 2000
(20)Wand X. Yue T. Barone F.Cet al. Monocyte chemoattractant protein-1 messenger RNA expression in rat ischemic area. Stroke26,661-666. 1995
(21)Bermant J .W. Guida .M P .Warren J.et al. localization of monocyte chemoattractant pretein-1 expression in the central nervous system in experimental autoimmune encephalomyelitis and trauma in the rat J. immun156,3017-3023.1996
(22)Glabinski A. R Balasingam.V. Tani M. Kunkel S.L et. al .Chenmokine MCP-1 is expressed by astrocytes after mechanical injury to the brain .J Immun. 156,4363-4368.1996
(23) Galasso J.M .Miller M.J .Cowell R.M et.al Acute excitotoxic injury induces expression of MCP-1 and its receptor CCR2.in neonatal rat brain Expl N eurol, 165,295-300. 2000
(24) Szafiarski J. Ivacko J. Liu X .et al Excitotoxic injury induces monocyte chemoattractant protein-1 expression neonatoal rat brain. Brain Res.55,306-314. 1998
(25) Ghirnikar R.S. Lee Y.L. Li .J.D. et al. Chemokine in rat stab wound brain injury using antisense oligodeoxynucheotion Neurosci.Lett.247,21-24. 1998
(26) Ghimikar R.S. Lee Y . L . and Eng L.F. Chemokine antagonist infusion attenuates cellular infitration following spinal cord contusion injury in rat . J. Neurosci. Res .59,63-73.2000
(27) Kennedy K.J. Stfieter R.M. Kunkel S. L. et al. Acute and relapsing experimental autoimmune encephalomyelitis is regulated by differential expression of the CCr2 chemokines macrophage inflammatory protein- alpha and MCP-1.J .Neuro immun.92,98-108. 1998
(28) Ghirnikar RS, Lee YL, Eng LF, et al Iflammation in traumatic brain injury :role of cytokines and chemokines. Neurochem Res 23(3)329-340 1998
(29) Hausmann EH, Berman NE, Wang YY, et al. Slective chemokines mRNA expression following brain injury. Brain Res, 788(1-2):49-59 1998
(30) Galasso J.M, Hamson J.K, Silverstein F.S: MCP-lis a mediator of acute excitotoxic injury in neonatal rat brain .J Neurosci. 101(3):737-744, 2000
(31) Ghirnikar RS, Lee YL, Eng LF, et al Iflammation in traumatic brain injury :role of cytokines and chemokines. Neurochem Res 23(3)329-340 1998
(32) Bell M .D, Taub D.D, Perry V.H. Overriding the brain intrinsic resistance to leukocyte recruitment with intraparenchymal injection of accombinant chemokines. J. Neurosci 74:283-292 1996
(33) Giulian D, Corpuz M, Chapman S, et al. Reactive mononuclear phagocytes release neurotoxins after ischemic and traumatic injury to the CNS J Neurosci Res 36:681-693,1995
(34) Holmin S, Mathiesen T Shetye Jet al:Biphasic edema development after experimental brain contusion in rat. Neursci Lett 194:97-100 ,1995
(35) Staffan Holmin M.D, Johan MS, Peter Biberfeld MD, et al Intracerebral inflammation after human brain contusion Neurosurgery 42:291-299 1998
(36) Soares HD ,Hicks RR, Smith D, et al. Inflammatory leukocytic recruitment and diffuse neuronal degeneration result from traumatic brain injury. J Neurosci 15:8223-8233,1995
(37) Holmin S . Schalling M, Hojeberg B , et al . Intracerebral inflammatory response to experimental brain contusion. Acta Neurochir 132 : 110-119 1995
(38) Carlos TM ,Clark RS , Franco-Higgin D, et al. Expression endothelial adhesion molecule and recruitment neutrophils after traumatic brain injury in rat. J Leukoc Biol,61(3):279-285 1997
(39) Sukoff MH ,Houin SA, Espinosa OE, et al. The protecture effect of hyper bade oxyenation in experimental cerebral edema. J Neurosurg, 1986, 29:236
(40) Sukoff MH ,Ragayz RE. Hyperbric oxygenation for the treatment of acute cerebral edema. Neurosurgery, 1982,10:29
(41) Contreres FL , Kade Raro M, Eisenberg HM, et al Effection of hyperbaric oxygen on glucose utlization in a freeze-traumatized rat brain. J Neurosurg, 1988, 68:137
(42) 李静，万积成，吴建中，等。高压氧对实验性脑损伤和脑水肿的影响。中华神经外科杂志，1994，10(5)：266-268．