急性脑出血炎性细胞因子与周围脑组织水肿的相关性
摘要
目的:脑出血(intracerebral hemorrhage,ICH)是脑血管疾病中严重威胁人类健康的常见病、多发病,是最难治疗的脑卒中之一,在急性脑血管疾病中,脑出血约占10%至20%,是发生率、死亡率及致残率均较高的卒中类型,内科保守治疗无新的进展,其病死率高达70-80%以上。而脑出血后脑水肿是导致患者病情加重和死亡的主要原因之一,目前也是国内外研究的热点之一。脑出血除了产生急性占位作用外,血液成分(特别是凝血酶原)和继发脑缺血,是造成脑细胞死亡的重要原因。多数学者认为脑出血后血肿周围脑组织的继发性损伤是导致神经功能恶化的主要原因,其中最重要的病理变化是继发性脑水肿。脑水肿的形成原因极其复杂,血肿液中红细胞溶解后血红蛋白的释放,炎性因子的参与在脑出血后脑水肿的形成过程中起重要作用。目前细胞因子被认为是免疫反应中的基本介质,直接或间接参与炎症细胞的活化和浸润。细胞因子在体内的作用极其复杂,彼此之间相互影响,相互联系,够成一个关系复杂的细胞因子网络。
近几年来发现炎性细胞因子TNF-a、IL-1、IL-6、IL-8、是介导脑出血后脑水肿形成的重要因子。IL-10可抑制巨噬细胞和单核细胞对促炎因子TNF-a、IL-6、IL-8等的合成与释放。目前,动物实验证实炎性细胞因子在脑出血病情进展及脑水肿形成中有重要作用。国外研究证实脑出血患者的IL-8、IL-10明显升高。本研究测定脑出血患者脑血肿液和血清中IL-8、IL-10的水平,探索脑水肿的发生机制,明确脑出血患者血清和血肿液中IL-8、IL-10是否升高及其与脑水肿的关系,明确不同出血量患者血肿液和血清中IL-8、IL-10的水平是否有区别,进一步认识细胞因子与脑水肿的相关性,对有关细胞因子的基础研究应用于临床具有指导意义,为研发脑出血药物和手术治疗时机提供理论依据。
方法:排除标准:①近2周内有感染者或入院后合并感染者;②半年内有手术、外伤;③血管畸形、血管炎或凝血机制障碍所致脑出血者;④伴有严重心脏、肾脏、肝脏及肿瘤疾病;⑤糖尿病高血脂;⑥近期有TIA发作或有脑卒中的病史。
检测89例基底节区脑出血患者血清及颅内血肿液中IL-8、IL-10浓度,同时行头颅CT检查,观察血肿及其周围低密度的变化。按照不同时间段将患者分为五组(<6h,6-12h,12-24h,24-72h,3-7d)。收集脑出血患者的颅内血肿液和静脉血。对发病<6h者连续查第24h、72h、1w头颅CT,并根据多田氏公式计算出脑出血量和脑水肿量。17例健康体检者血清中IL-8、IL-10作为对照分析。抽取健康体检者晨空腹静脉血3ml。所有标本分离出血清后-20℃冰箱保存待检。用试剂盒进行IL-8、IL-10定量测定,采用ELISA方法。本实验数据用t检验,方差分析与相关分析,数据以均数±标准差(X±S)表示。
结果:患者血清与血肿液中IL-8、IL-10的含量明显高于对照组,且两者差别无统计学意义(P>0.05);IL-8含量在发病6h以内开始增高,在24-72h达到高峰,以后逐渐下降,但始终处于高水平。患者血清及血肿液中IL-10含量在发病第6-12h开始增高(与对照组比较P <0.05),以后逐渐升高。血肿周围的水肿体积24小时开始扩大,72小时达高峰,7d开始有下降趋势,但仍然高于对照组,期间IL-8的水平仍然很高。血清及血肿液中IL-8与IL-10的含量有相关关系,IL-8的峰值明显早于IL-10,且IL-8的水平与血肿周围水肿的扩大密切相关。
结论:1、急性脑出血患者血清及血肿液中IL-8、IL-10水平明显升高。IL-8、IL-10参与了脑出血脑水肿的病理生理过程,而脑出血后脑水肿又导致IL-8、IL-10浓度的异常变化,从而加重血肿周围脑组织的损害。2、脑出血后血清中IL-8含量呈动态变化,IL-8水平升高能加重血肿周围水肿量。3、基底节区脑出血后血清及血肿液中IL-10含量呈动态变化,IL-10对血肿周围水肿的具体作用尚没有定论。4、本研究初步探讨了脑出血后血清中炎性细胞因子与血肿周围水肿的动态变化,为临床的治疗和进一步研究提供了理论依据。
Objectives: ICH is one of commonly and frequently encountered diseases in cerebrovascular diseases ,significantly threatens human health。It accounts for 10%-20% of all acute cerebrovascular diseases,its morbidity mortality and disability rate are higher than others, stroke diseases。No definitely conservative treatment is available for ICH. ICH fatality is 70% to 80%。Brain edema after ICH is one of reasons which lead to disease aggravation and one of hot spots which is researched by domestic and foreign experts. Blood components (especial thrombinogen) and cerebral ischemia induced by ICH besides acute location effect are the important reasons. Most researchers believe that the secondary injury around hematoma is the main cause which leads to the deterioration of nerve function. The most important pathophysiologic change is the secondary brain edema following ICH. The reason of brain edema formation is very complex. Hemoglobin release after erythrocyte cytolysis in the hematoma and inflammatory cytokines participation may be important reasons in brain edema formation after ICH. Cytokines are basic mediators of immunity,and involved the inflammatory cells activation and infiltration. The functions of cytokines are greatly complicated in vivo, affect each other in their induction, regulation of receptor, and exertion of bioactivity. So a sophisticated cytokine network was formed.
In recent years,inflammatory cytokines TNF-a、IL-1、IL-6、IL-8 are important reasons in the brain edema formation after ICH. Some experiments identify IL-10 can inhibit synthesis and releasing of TNF-a、IL-6、IL-8 of macrophage and mononuclear cells。Now inflammatory cytokines are important in TCH condition progression and cerebral edema, which are identified by animal tests. Some foreign research identified the levels of IL-8、IL-10 in ICH patients are significantly high. The levels of IL-8 and IL-10 were assayed in venous serum and hematoma fluid in patients with cerebral hemorrhage to approach the mechanism of cerebral edema and identify if the levels of IL-8 and IL-10 in venous serum and hematoma fluid if are high , the relation with cerebral edema. if the levels of IL-8 and IL-10 induced by different hemorrhage volume are different. We further know the correlation of cytokines and cerebral edema, which had directed significance about the foundation research of cytokines and can supply theory evidence to research ICH medicine and operation opportunity.
Methods: Eliminated standard:①infected or incorporated infection patients within 2w;②The patients were operated,injury within 6m;③The ICH patients induced by vascular malformation, vasculitis or clotting mechanism disorder;④The patients combining heart disease, nephrosis or tumor diseases;⑤DM and hyperlipemia;⑥The patients fell ill by TIA or stroke history in the near future.
Contents of IL-6、IL-10 in venous serum and hematoma fluid were detected in 89 basal ganglion ICH patients after intracerebral hemorrhage, respectively, brain hematoma and edema around hematoma volume were measured through CT at the same time. The 89 ICH patients are divided into five groups( < 6h,6-12h,12-24h,24-72h,3-7d). Venous serum and hematoma fluid are collected at the same time. Brain hematoma and edema around hematoma volume were measured through CT according to Duotian formula in<6h patients. The levels of IL-8、IL-10 were compared with 17 healthy people serum IL-8、IL-10 contents。The blood was drew in the control group, which was about 3ml.The serum which involved in all specimen were isolated and conserved in -20℃frig. The levels of IL-8、IL-10 were quantitatively detected with kits and by ELISA method. Data was analysed by statistic methods of t-testing and correlation-regression analysis. All data were expressed as mean±SEM.
Results:
1 The levels of IL-8、IL-10 in venous serum and hematoma fluid are higher in the ganglion ICH group than that of the control group(P<0.05), The levels of IL-8、IL-10 in venous serum and hematoma fluid are coincident(P>0.05).The level of IL-8 has tendency to decrease within 6h,and reaches to peak at 24-72h and tends to decrease thereafter. However, its level remains significantly higher compared with that of control group. The level of IL-10 in venous serum and hematoma fluid tends to rises at 6-12h(which is compared with in the control group P<0.05),progressively increases thereafter. Brain edema volume around hematoma enlarges at 24h, reaches to peak at 3d ,tends to decrease thereafter, its level remains significantly higher compared with that of control group. Meanwhile IL-8 content keeps on the high level during this time. There is a closely relationship between IL-10 and IL-8 in serum, the peak of IL-8 emerges earlier than that of IL-10, the level of IL-8 is correlate with brain edema enlargement around hematoma.
Conclusion:
1 the level of IL-8、IL-10 in serum and hematoma fluid are significantly higher . IL-8、IL-10 may be involved in the pathophysiologic process of brain edema after ICH, brain changes damage of concentrations of IL-8、edema after ICH leads to IL-10, and aggravate brain around the hematoma.
2 Serum IL-8 content shows serial changes in patients with ganglion intracerebral hemorrhage. High serum IL-6 content is harm to the brain edema around the hematoma.
3 Serum IL-10 intracerebral content shows serial changes in patients with ganglion hemorrhage. There is no final conclusion how IL-10 concretely effect on edema around hematoma now.
4 The study have observed the serial changes of serum and the volume of brain edema around hematoma with intracerebral hemorrhage, may offer some support for the treatment of ICH.
近几年来发现炎性细胞因子TNF-a、IL-1、IL-6、IL-8、是介导脑出血后脑水肿形成的重要因子。IL-10可抑制巨噬细胞和单核细胞对促炎因子TNF-a、IL-6、IL-8等的合成与释放。目前,动物实验证实炎性细胞因子在脑出血病情进展及脑水肿形成中有重要作用。国外研究证实脑出血患者的IL-8、IL-10明显升高。本研究测定脑出血患者脑血肿液和血清中IL-8、IL-10的水平,探索脑水肿的发生机制,明确脑出血患者血清和血肿液中IL-8、IL-10是否升高及其与脑水肿的关系,明确不同出血量患者血肿液和血清中IL-8、IL-10的水平是否有区别,进一步认识细胞因子与脑水肿的相关性,对有关细胞因子的基础研究应用于临床具有指导意义,为研发脑出血药物和手术治疗时机提供理论依据。
方法:排除标准:①近2周内有感染者或入院后合并感染者;②半年内有手术、外伤;③血管畸形、血管炎或凝血机制障碍所致脑出血者;④伴有严重心脏、肾脏、肝脏及肿瘤疾病;⑤糖尿病高血脂;⑥近期有TIA发作或有脑卒中的病史。
检测89例基底节区脑出血患者血清及颅内血肿液中IL-8、IL-10浓度,同时行头颅CT检查,观察血肿及其周围低密度的变化。按照不同时间段将患者分为五组(<6h,6-12h,12-24h,24-72h,3-7d)。收集脑出血患者的颅内血肿液和静脉血。对发病<6h者连续查第24h、72h、1w头颅CT,并根据多田氏公式计算出脑出血量和脑水肿量。17例健康体检者血清中IL-8、IL-10作为对照分析。抽取健康体检者晨空腹静脉血3ml。所有标本分离出血清后-20℃冰箱保存待检。用试剂盒进行IL-8、IL-10定量测定,采用ELISA方法。本实验数据用t检验,方差分析与相关分析,数据以均数±标准差(X±S)表示。
结果:患者血清与血肿液中IL-8、IL-10的含量明显高于对照组,且两者差别无统计学意义(P>0.05);IL-8含量在发病6h以内开始增高,在24-72h达到高峰,以后逐渐下降,但始终处于高水平。患者血清及血肿液中IL-10含量在发病第6-12h开始增高(与对照组比较P <0.05),以后逐渐升高。血肿周围的水肿体积24小时开始扩大,72小时达高峰,7d开始有下降趋势,但仍然高于对照组,期间IL-8的水平仍然很高。血清及血肿液中IL-8与IL-10的含量有相关关系,IL-8的峰值明显早于IL-10,且IL-8的水平与血肿周围水肿的扩大密切相关。
结论:1、急性脑出血患者血清及血肿液中IL-8、IL-10水平明显升高。IL-8、IL-10参与了脑出血脑水肿的病理生理过程,而脑出血后脑水肿又导致IL-8、IL-10浓度的异常变化,从而加重血肿周围脑组织的损害。2、脑出血后血清中IL-8含量呈动态变化,IL-8水平升高能加重血肿周围水肿量。3、基底节区脑出血后血清及血肿液中IL-10含量呈动态变化,IL-10对血肿周围水肿的具体作用尚没有定论。4、本研究初步探讨了脑出血后血清中炎性细胞因子与血肿周围水肿的动态变化,为临床的治疗和进一步研究提供了理论依据。
Objectives: ICH is one of commonly and frequently encountered diseases in cerebrovascular diseases ,significantly threatens human health。It accounts for 10%-20% of all acute cerebrovascular diseases,its morbidity mortality and disability rate are higher than others, stroke diseases。No definitely conservative treatment is available for ICH. ICH fatality is 70% to 80%。Brain edema after ICH is one of reasons which lead to disease aggravation and one of hot spots which is researched by domestic and foreign experts. Blood components (especial thrombinogen) and cerebral ischemia induced by ICH besides acute location effect are the important reasons. Most researchers believe that the secondary injury around hematoma is the main cause which leads to the deterioration of nerve function. The most important pathophysiologic change is the secondary brain edema following ICH. The reason of brain edema formation is very complex. Hemoglobin release after erythrocyte cytolysis in the hematoma and inflammatory cytokines participation may be important reasons in brain edema formation after ICH. Cytokines are basic mediators of immunity,and involved the inflammatory cells activation and infiltration. The functions of cytokines are greatly complicated in vivo, affect each other in their induction, regulation of receptor, and exertion of bioactivity. So a sophisticated cytokine network was formed.
In recent years,inflammatory cytokines TNF-a、IL-1、IL-6、IL-8 are important reasons in the brain edema formation after ICH. Some experiments identify IL-10 can inhibit synthesis and releasing of TNF-a、IL-6、IL-8 of macrophage and mononuclear cells。Now inflammatory cytokines are important in TCH condition progression and cerebral edema, which are identified by animal tests. Some foreign research identified the levels of IL-8、IL-10 in ICH patients are significantly high. The levels of IL-8 and IL-10 were assayed in venous serum and hematoma fluid in patients with cerebral hemorrhage to approach the mechanism of cerebral edema and identify if the levels of IL-8 and IL-10 in venous serum and hematoma fluid if are high , the relation with cerebral edema. if the levels of IL-8 and IL-10 induced by different hemorrhage volume are different. We further know the correlation of cytokines and cerebral edema, which had directed significance about the foundation research of cytokines and can supply theory evidence to research ICH medicine and operation opportunity.
Methods: Eliminated standard:①infected or incorporated infection patients within 2w;②The patients were operated,injury within 6m;③The ICH patients induced by vascular malformation, vasculitis or clotting mechanism disorder;④The patients combining heart disease, nephrosis or tumor diseases;⑤DM and hyperlipemia;⑥The patients fell ill by TIA or stroke history in the near future.
Contents of IL-6、IL-10 in venous serum and hematoma fluid were detected in 89 basal ganglion ICH patients after intracerebral hemorrhage, respectively, brain hematoma and edema around hematoma volume were measured through CT at the same time. The 89 ICH patients are divided into five groups( < 6h,6-12h,12-24h,24-72h,3-7d). Venous serum and hematoma fluid are collected at the same time. Brain hematoma and edema around hematoma volume were measured through CT according to Duotian formula in<6h patients. The levels of IL-8、IL-10 were compared with 17 healthy people serum IL-8、IL-10 contents。The blood was drew in the control group, which was about 3ml.The serum which involved in all specimen were isolated and conserved in -20℃frig. The levels of IL-8、IL-10 were quantitatively detected with kits and by ELISA method. Data was analysed by statistic methods of t-testing and correlation-regression analysis. All data were expressed as mean±SEM.
Results:
1 The levels of IL-8、IL-10 in venous serum and hematoma fluid are higher in the ganglion ICH group than that of the control group(P<0.05), The levels of IL-8、IL-10 in venous serum and hematoma fluid are coincident(P>0.05).The level of IL-8 has tendency to decrease within 6h,and reaches to peak at 24-72h and tends to decrease thereafter. However, its level remains significantly higher compared with that of control group. The level of IL-10 in venous serum and hematoma fluid tends to rises at 6-12h(which is compared with in the control group P<0.05),progressively increases thereafter. Brain edema volume around hematoma enlarges at 24h, reaches to peak at 3d ,tends to decrease thereafter, its level remains significantly higher compared with that of control group. Meanwhile IL-8 content keeps on the high level during this time. There is a closely relationship between IL-10 and IL-8 in serum, the peak of IL-8 emerges earlier than that of IL-10, the level of IL-8 is correlate with brain edema enlargement around hematoma.
Conclusion:
1 the level of IL-8、IL-10 in serum and hematoma fluid are significantly higher . IL-8、IL-10 may be involved in the pathophysiologic process of brain edema after ICH, brain changes damage of concentrations of IL-8、edema after ICH leads to IL-10, and aggravate brain around the hematoma.
2 Serum IL-8 content shows serial changes in patients with ganglion intracerebral hemorrhage. High serum IL-6 content is harm to the brain edema around the hematoma.
3 Serum IL-10 intracerebral content shows serial changes in patients with ganglion hemorrhage. There is no final conclusion how IL-10 concretely effect on edema around hematoma now.
4 The study have observed the serial changes of serum and the volume of brain edema around hematoma with intracerebral hemorrhage, may offer some support for the treatment of ICH.
引文
1 Carhuapoma JR, Wang PY, Beauchamp NJ, et al. Diffusion weighted MRI and proton MR spectroscopic imaging in the study of secondary neuronal injury after intracerebral hemorrhage.Stroke,2000,31(3):726～732
2 Barber M, Roditi G, Stott DJ, et al. Poor outcome in primary intracerebral hemorrhage:results of a matched comparison. Postgrad Med J, 2004;80:89～92
3 Qureshi AI, Tuhrim S, Broderick JP, et al. Spontaneous intracerebral hemorrhage. N.Engl.J.Med, 2001:344(19): 1450～1460
4 Fernandes HM, Gregson B, Siddique S, et al. Surgery in intracerebral hemorrhage:the uncertainty continues. stroke, 2000;31:2511～2516
5 Hanley DF. Review of critical care and emergency approaches to stroke. Stroke, 2003;34(2):362～364
6 Wagner KR, Xi C,Hua Y, et al. Early metabolic alterations in edematous perihematomal brain regions following experimental intracerebral hemorrhage. J Nerosurg, 1998,88 (6):1058～1065
7 Xue M, Del Bigio MR. Intracortical hemorrhage injury in rats: relationship between blood fractions and brain cell death.Stroke,2000,31(7):1721～1727
8 陈秀,陈忠伦,李作孝.细胞因子与脑出血.国外医学(脑血管疾病分册),2004,12(5)345～347
9 Zhang WJ,Shi ZX,Wang BB. Auitridum mimics effect of ischemic preconditioning by activation of protein kinase C. Act Pharmacol Sin,2001,22(2):132～136
10 Dziedic T,Slowik A,Klimkowicz A, et al .Asymmetrical modulation of interleukin-10 release in patients with intracerebral hemorrhage. Brain behave immune,2003,17(6): 438～441
11 Dziedzic T, Bartus S, Klimkowicz A, et al. Intracerebral hemorrhage triggers interleukin-6 and interleukin-10 release in Blood. Stroke.2002;33(9):2334～2335
12 Spera PA, Ellison JA, Feuerstein GZ, et al. IL-10 reduce sratbrain injury following focalstroke. NeurosciLett,1998, 251 (3):189～192
13 van Exel E , Gussekloo J , Craen AJ , et al. Inflammatory and troke: the Leiden 852Plus Study. Stroke ,2002,33: 1135～1138.
14 傅春景,张建芳.阿魏酸钠对离体大鼠缺血心肌再灌注损伤的影响.河南医科大学学报,1994,29(4):344
15 中华神经科学会,中华神经外科学会.各类脑血管疾病诊 断要点.中华神经科杂志 1996,9(6):379～380
16 Ford ES, Giles WH. Serum C-reactive protein and selfreported stroke:findings from the Third National Health and Nutrition Examination Survey. Arterioscler Thromb Vasc Biol,2000;20(4):1052～1056
17 Gussekloo J, Schaap MC, Frolich M, et al. C-reactive protein is a strong but nonspecific risk factor of fatal stroke inelderly persons. Arterioscler Thromb Vasc Biol,2000 ;20:1047～1051
18 Ridker PM, Cushman M, Stampfer MJ, et al. Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation,1998;97(5):425～428
19 Vila N, Castilto J, Davalos A, et al. Proinflammatory cytokines and early neurological worsening in ischemicstroke. Stroke,2000;31(10):2325～2329
20 Yamasaki Y, Itoyama Y, Kogure K. Involvement of production in pathogenesis of transient cerebral ischemic damage. Keio J Med, 1996,45(3):225～229
21 Xue M, Del Bigio MR. Intracerebral injection of whole blood in rats:time course of inflammation death. Neurosci Lett, 2000,283(3):230～232
22 Holmin S,Mathiesen T. Intracerebral administration of interleukin-lβ and induction ofinflammation, apoptosis, and vasogenic edema. Neurosurg,2000,92(1):108～120
23 Lee KR, Kawai M, Kim S,et al . Mechanisims of edema formation after intracerebral hemorrhage:effects of thrombinon cerebral blood flow, blood-brain barrier permeability and cell survival in ratmodel. J Neurosurg,1997,86(2):272～278
24 陈秀,陈忠伦,李作孝.细胞因子与脑出血.国外医学(脑血管疾病分册)2004,12(5):345～347
25 Luscinskas FW, Kiely JM ,Ding H, et al. In vitro inhibitoryeffect of IL-8 and other chemoattractants on neutrophil endothelial adhesive interactions. J Immunol, 1992,149:2163～2171
26 Matsumoto T, Ikeda K, Mukaida N, et al. Prevention of cerebral e2dema and infarct in cerebralre perfusion injury by an antibody to interleukin-8. Lab Invest,1997,77:119～125
27 王怀立,高东培,芦军萍,等.TNF-α、IL-8 在脂多糖致大鼠脑水肿中的表达.免疫学杂志,2002,18(6):440～446
28 Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell. IV. clones secrete a factor that inhibits cytokine production by Thl clones. j Exp Med,1989,170(6):2081～2095
29 Stordeur P, Goldman M. Interleukin-10 as regulatory cytokine induced by cellular stress molecular aspects. Int Rev Immunol.1998;16(5-6):501～522
30 Pelidow SH, Kostulas N, Matusevicius D,et al. High levels of IL-10 secreting cells are present in blood in cerebrovascular diseases. Eur J Neurol,1999:437～442
31 Kurabayashi H,Machida I,Handa H, et al. Effects of physical therapy on immunological parameters in patients with cerebrovascular diseases. J Med. 1996; 27(3-4): 171 ～ 175
32 左红霞,干超士,闻树群等.急性脑出血患者血清炎性因子及抗炎因子含量变化.浙江临床医学,2004, 6(6):466～467
33 李凯丽,王百迢,鞠躬,等.出血性卒中与免疫.国外医学(脑血管分册),2000, 8 (5):281～282
34 Knoblach SM, Faden AI.Interleukin-10 improves out come and alters proinflammatory cytokine expression after experimental traumatic brain injury. Exp Neurol. 1998, 153 (1):143～151
35 Hess PJ,Seeger JM, Huber TS, et al. Exogenously administered interleukin-10 decreases pulmonary neutrophil infiltration in a tumor necrosis factordependent murine model of acute visceral ischemia. J Vasc Surg.1997 ,26(l):113～118
36 Koedel U, Bernatowicz A, Frei K, etal. Systemically (but not intrathecally)administered IL-10 attenuates pathophysilologic alterations in experimental pneumococcal meningitis. J . Immunol,1996,157:5185～5191
37 Deckert M, Soltek S, Geginat G, et al. Endogenous interleukin-10 is Required for prevention of a Hyperinflammatory intracerebral immune response in Listeria monocytogenes meningoencephalitis. Infect.Immun, 2001;69:4561～4571
38 Piani D, Spranger M, Frei K, et al. Macrophage induced cytotoxicity of N-methyl-D-aspartate receptor positive neurons involves excitatory amino acids rather than reactive oxygen intermediates and cytokines. Eur J Immunol,1992,22(9): 2429～2436
39 Xi G, Keep RF, Hoff JT. Erythrocytes and delayed brain edema formation following intracerebral hemorrhage in rats. J Neurosurg,1998,89(6): 991～996
1 Jong S. Kim, Yoon SS, Kim YH, et al. Serial Measurement of Interleukin-6, Transforming Growth Factor-?, and S-100 Protein in Patients With Acute Stroke. 1996;27:1553～1557
2 Mayne M, Johnston B, Bigio MR, et al. Antisense Oligodeoxynucleotide Inhibition of Tumor Necrosis Factor-α Expression Is Neuroprotective After Intracerebral Hemorrhage .Editorial Comment. Stroke,2001;32:240～248
3 Jin X, Zhao H, Wang JF,et al. Influence of beta endorphin on function of immune system of patients with cerebral hemorrhage.Zhonghua Yi Xue Za Zhi.2003;83(16):1409～1412
4 Mengzhou X, Bigio D, and Muizelaar JP. Intracortical Hemorrhage Injury in Rats:Relationship Between blood Fractions and Brain Cell Death Editorial Comment:Relationship Between Blood Fractions and Brain Cell Death.Stroke.2000;31:1721～1727
5 Katsuno M, Yokota H, Yamamoto Y, et al. Increased regional interleukin-4 during the acute stage of severe intracranial disorders. Neurol Med Chir (Tokyo),2006;46(10):471～474;discussion474～475
6 Fang HY, Ko WJ, and Lin CY. Plasma interleukin-11 levels correlate with outcome of spontaneous intracerebral hemorrhage. Surg Neurol. 2005 ; 64(6): 511 ～ 517,discussion 517～518
7 Fang HY, Ko WJ, and Lin CY. Inducible heat shock protein 70, interleukin-18, and tumor necrosis factor alpha correlate with outcomes in spontaneous intracerebral hemorrhage. J Clin Neurosci.2007; 14(5):435～441
8 Dinarello CA. Biologic basis for interleukin-1 in disease.Blood. 1996;87:2095～2147
9 Holmin S and Mathiesen T. Intracerebral administration of interleukin-1 beta and induction of inflammation, apoptosis, and vasogenic edema. J Neurosurg.2000;92(1):108～120
10 Yasundo Y, Naosuke M, Hidetaka S,et al.Interleukin-1 as a Pathogenetic Mediator of Ischemic Brain Damage in Rats.Stroke.1995;26:676～681
11 Melissa J.B, Asmaa E, Mahmud H, et al. IL-1 and TNF independent pathways mediate ICAM-1/VCAM-1 up-regulation in ischemia reperfusion injury. Leukoc. Biol. 2001;70:192
12 Awatsuji H, Furukawa Y, Nakajima M, et al.Interleukin-2 as a neurotrophic factor for supporting the survival of neurons cultured from various regions of fetal rat brain. J Neurosci Res.1993;35(3):305～311
13 Mukaida N, Matsumoto T, Yokoi K, et al. Inhibition of neutrophil-mediated acute inflammation injury by an antibody against interleukin-8(IL-8). Inflamm Res.1998;47.Suppl.3:151～157
14 张越林, 刘王宣, 师蔚.高血压脑出血患者细胞免疫及 IL 2 、 Sil-R 表 达 的 意 义 . 西 安 交 通 大 学 学 报 ( 医 学版),2002,23(6):555～557
15 肖岚,黎杏群. 白介素-6 与脑缺血损伤.国外医学神经 病 学神经外科学分册,2000,27(4):258
16 Penkowa M, Giralt M, Lago N,et al. Astrocytetargeted expression of IL-6 protects the CNS against a focal brain injury. Exp Neurol.2003;181(2):130～148
17 Tilg H, Dinarello CA, and Mier JW.IL-6 and APPs: anti-inflammatory and immunosuppressive media tors.Immunol Today.1997;18(9):428～432
18 Ferrarese C, Mascarucci P, Zoia C, et al. Increased cytokine release from peripheral blood cells after acute stroke. J Cereb Blood Flow Metab.1999;19(9):1004～1009
19 张越林,刘王宣,师蔚.高血压脑出血患者细胞免疫 IL-2、Sil-2R 表 达 的 意 义 . 西 安 交 通 大 学 学 报 ( 医 学版),2002,23(6):555～557
20 陈秀, 陈忠伦,李作孝.细胞因子与 ICH。国外医学脑血管疾病分册,2004,12:345～347
21 张凯,何志义.白介素-10 与急性脑血管病.国外医学脑血管疾病分册,2001,9:302～304
22 Woiciechowsky C, Asadullah K, Nestler D, et al. Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury. Nat Med.1998;4(7):808～813
23 Van Beek J, Bernaudin M, Petit E, et al. Expression of receptors for complement anaphylatoxins C3a and C5a following permanent focal cerebral ischemia in themouse.Exp eurol.2000;161(1):373～382
24 Zaremba J, Losy J. Adhesion molecules of immunoglobul in gene superfamily in stroke. Folia Morphol (Warsz), 2002,61:1～6
25 Kraus J, Oschmann P, Leis S, et al. High concentrations of sVCAM-1 and sICAM-1 in the cerebrospinal fluid of patients with intracerebral haemorrhage are associated with poor outcome. J Neurol Neurosurg Psychiatry,2002,73:346～347
26 Kanemoto Y, Nakase H, Akita N, et al. Effects of anti-intercellular adhesion molecule-1 antibody on reperfusion injury induced by late reperfusion in the rat middle cerebral artery occlusion model. Neurosurgery, 2002,51:1041～1042
2 Barber M, Roditi G, Stott DJ, et al. Poor outcome in primary intracerebral hemorrhage:results of a matched comparison. Postgrad Med J, 2004;80:89～92
3 Qureshi AI, Tuhrim S, Broderick JP, et al. Spontaneous intracerebral hemorrhage. N.Engl.J.Med, 2001:344(19): 1450～1460
4 Fernandes HM, Gregson B, Siddique S, et al. Surgery in intracerebral hemorrhage:the uncertainty continues. stroke, 2000;31:2511～2516
5 Hanley DF. Review of critical care and emergency approaches to stroke. Stroke, 2003;34(2):362～364
6 Wagner KR, Xi C,Hua Y, et al. Early metabolic alterations in edematous perihematomal brain regions following experimental intracerebral hemorrhage. J Nerosurg, 1998,88 (6):1058～1065
7 Xue M, Del Bigio MR. Intracortical hemorrhage injury in rats: relationship between blood fractions and brain cell death.Stroke,2000,31(7):1721～1727
8 陈秀,陈忠伦,李作孝.细胞因子与脑出血.国外医学(脑血管疾病分册),2004,12(5)345～347
9 Zhang WJ,Shi ZX,Wang BB. Auitridum mimics effect of ischemic preconditioning by activation of protein kinase C. Act Pharmacol Sin,2001,22(2):132～136
10 Dziedic T,Slowik A,Klimkowicz A, et al .Asymmetrical modulation of interleukin-10 release in patients with intracerebral hemorrhage. Brain behave immune,2003,17(6): 438～441
11 Dziedzic T, Bartus S, Klimkowicz A, et al. Intracerebral hemorrhage triggers interleukin-6 and interleukin-10 release in Blood. Stroke.2002;33(9):2334～2335
12 Spera PA, Ellison JA, Feuerstein GZ, et al. IL-10 reduce sratbrain injury following focalstroke. NeurosciLett,1998, 251 (3):189～192
13 van Exel E , Gussekloo J , Craen AJ , et al. Inflammatory and troke: the Leiden 852Plus Study. Stroke ,2002,33: 1135～1138.
14 傅春景,张建芳.阿魏酸钠对离体大鼠缺血心肌再灌注损伤的影响.河南医科大学学报,1994,29(4):344
15 中华神经科学会,中华神经外科学会.各类脑血管疾病诊 断要点.中华神经科杂志 1996,9(6):379～380
16 Ford ES, Giles WH. Serum C-reactive protein and selfreported stroke:findings from the Third National Health and Nutrition Examination Survey. Arterioscler Thromb Vasc Biol,2000;20(4):1052～1056
17 Gussekloo J, Schaap MC, Frolich M, et al. C-reactive protein is a strong but nonspecific risk factor of fatal stroke inelderly persons. Arterioscler Thromb Vasc Biol,2000 ;20:1047～1051
18 Ridker PM, Cushman M, Stampfer MJ, et al. Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation,1998;97(5):425～428
19 Vila N, Castilto J, Davalos A, et al. Proinflammatory cytokines and early neurological worsening in ischemicstroke. Stroke,2000;31(10):2325～2329
20 Yamasaki Y, Itoyama Y, Kogure K. Involvement of production in pathogenesis of transient cerebral ischemic damage. Keio J Med, 1996,45(3):225～229
21 Xue M, Del Bigio MR. Intracerebral injection of whole blood in rats:time course of inflammation death. Neurosci Lett, 2000,283(3):230～232
22 Holmin S,Mathiesen T. Intracerebral administration of interleukin-lβ and induction ofinflammation, apoptosis, and vasogenic edema. Neurosurg,2000,92(1):108～120
23 Lee KR, Kawai M, Kim S,et al . Mechanisims of edema formation after intracerebral hemorrhage:effects of thrombinon cerebral blood flow, blood-brain barrier permeability and cell survival in ratmodel. J Neurosurg,1997,86(2):272～278
24 陈秀,陈忠伦,李作孝.细胞因子与脑出血.国外医学(脑血管疾病分册)2004,12(5):345～347
25 Luscinskas FW, Kiely JM ,Ding H, et al. In vitro inhibitoryeffect of IL-8 and other chemoattractants on neutrophil endothelial adhesive interactions. J Immunol, 1992,149:2163～2171
26 Matsumoto T, Ikeda K, Mukaida N, et al. Prevention of cerebral e2dema and infarct in cerebralre perfusion injury by an antibody to interleukin-8. Lab Invest,1997,77:119～125
27 王怀立,高东培,芦军萍,等.TNF-α、IL-8 在脂多糖致大鼠脑水肿中的表达.免疫学杂志,2002,18(6):440～446
28 Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell. IV. clones secrete a factor that inhibits cytokine production by Thl clones. j Exp Med,1989,170(6):2081～2095
29 Stordeur P, Goldman M. Interleukin-10 as regulatory cytokine induced by cellular stress molecular aspects. Int Rev Immunol.1998;16(5-6):501～522
30 Pelidow SH, Kostulas N, Matusevicius D,et al. High levels of IL-10 secreting cells are present in blood in cerebrovascular diseases. Eur J Neurol,1999:437～442
31 Kurabayashi H,Machida I,Handa H, et al. Effects of physical therapy on immunological parameters in patients with cerebrovascular diseases. J Med. 1996; 27(3-4): 171 ～ 175
32 左红霞,干超士,闻树群等.急性脑出血患者血清炎性因子及抗炎因子含量变化.浙江临床医学,2004, 6(6):466～467
33 李凯丽,王百迢,鞠躬,等.出血性卒中与免疫.国外医学(脑血管分册),2000, 8 (5):281～282
34 Knoblach SM, Faden AI.Interleukin-10 improves out come and alters proinflammatory cytokine expression after experimental traumatic brain injury. Exp Neurol. 1998, 153 (1):143～151
35 Hess PJ,Seeger JM, Huber TS, et al. Exogenously administered interleukin-10 decreases pulmonary neutrophil infiltration in a tumor necrosis factordependent murine model of acute visceral ischemia. J Vasc Surg.1997 ,26(l):113～118
36 Koedel U, Bernatowicz A, Frei K, etal. Systemically (but not intrathecally)administered IL-10 attenuates pathophysilologic alterations in experimental pneumococcal meningitis. J . Immunol,1996,157:5185～5191
37 Deckert M, Soltek S, Geginat G, et al. Endogenous interleukin-10 is Required for prevention of a Hyperinflammatory intracerebral immune response in Listeria monocytogenes meningoencephalitis. Infect.Immun, 2001;69:4561～4571
38 Piani D, Spranger M, Frei K, et al. Macrophage induced cytotoxicity of N-methyl-D-aspartate receptor positive neurons involves excitatory amino acids rather than reactive oxygen intermediates and cytokines. Eur J Immunol,1992,22(9): 2429～2436
39 Xi G, Keep RF, Hoff JT. Erythrocytes and delayed brain edema formation following intracerebral hemorrhage in rats. J Neurosurg,1998,89(6): 991～996
1 Jong S. Kim, Yoon SS, Kim YH, et al. Serial Measurement of Interleukin-6, Transforming Growth Factor-?, and S-100 Protein in Patients With Acute Stroke. 1996;27:1553～1557
2 Mayne M, Johnston B, Bigio MR, et al. Antisense Oligodeoxynucleotide Inhibition of Tumor Necrosis Factor-α Expression Is Neuroprotective After Intracerebral Hemorrhage .Editorial Comment. Stroke,2001;32:240～248
3 Jin X, Zhao H, Wang JF,et al. Influence of beta endorphin on function of immune system of patients with cerebral hemorrhage.Zhonghua Yi Xue Za Zhi.2003;83(16):1409～1412
4 Mengzhou X, Bigio D, and Muizelaar JP. Intracortical Hemorrhage Injury in Rats:Relationship Between blood Fractions and Brain Cell Death Editorial Comment:Relationship Between Blood Fractions and Brain Cell Death.Stroke.2000;31:1721～1727
5 Katsuno M, Yokota H, Yamamoto Y, et al. Increased regional interleukin-4 during the acute stage of severe intracranial disorders. Neurol Med Chir (Tokyo),2006;46(10):471～474;discussion474～475
6 Fang HY, Ko WJ, and Lin CY. Plasma interleukin-11 levels correlate with outcome of spontaneous intracerebral hemorrhage. Surg Neurol. 2005 ; 64(6): 511 ～ 517,discussion 517～518
7 Fang HY, Ko WJ, and Lin CY. Inducible heat shock protein 70, interleukin-18, and tumor necrosis factor alpha correlate with outcomes in spontaneous intracerebral hemorrhage. J Clin Neurosci.2007; 14(5):435～441
8 Dinarello CA. Biologic basis for interleukin-1 in disease.Blood. 1996;87:2095～2147
9 Holmin S and Mathiesen T. Intracerebral administration of interleukin-1 beta and induction of inflammation, apoptosis, and vasogenic edema. J Neurosurg.2000;92(1):108～120
10 Yasundo Y, Naosuke M, Hidetaka S,et al.Interleukin-1 as a Pathogenetic Mediator of Ischemic Brain Damage in Rats.Stroke.1995;26:676～681
11 Melissa J.B, Asmaa E, Mahmud H, et al. IL-1 and TNF independent pathways mediate ICAM-1/VCAM-1 up-regulation in ischemia reperfusion injury. Leukoc. Biol. 2001;70:192
12 Awatsuji H, Furukawa Y, Nakajima M, et al.Interleukin-2 as a neurotrophic factor for supporting the survival of neurons cultured from various regions of fetal rat brain. J Neurosci Res.1993;35(3):305～311
13 Mukaida N, Matsumoto T, Yokoi K, et al. Inhibition of neutrophil-mediated acute inflammation injury by an antibody against interleukin-8(IL-8). Inflamm Res.1998;47.Suppl.3:151～157
14 张越林, 刘王宣, 师蔚.高血压脑出血患者细胞免疫及 IL 2 、 Sil-R 表 达 的 意 义 . 西 安 交 通 大 学 学 报 ( 医 学版),2002,23(6):555～557
15 肖岚,黎杏群. 白介素-6 与脑缺血损伤.国外医学神经 病 学神经外科学分册,2000,27(4):258
16 Penkowa M, Giralt M, Lago N,et al. Astrocytetargeted expression of IL-6 protects the CNS against a focal brain injury. Exp Neurol.2003;181(2):130～148
17 Tilg H, Dinarello CA, and Mier JW.IL-6 and APPs: anti-inflammatory and immunosuppressive media tors.Immunol Today.1997;18(9):428～432
18 Ferrarese C, Mascarucci P, Zoia C, et al. Increased cytokine release from peripheral blood cells after acute stroke. J Cereb Blood Flow Metab.1999;19(9):1004～1009
19 张越林,刘王宣,师蔚.高血压脑出血患者细胞免疫 IL-2、Sil-2R 表 达 的 意 义 . 西 安 交 通 大 学 学 报 ( 医 学版),2002,23(6):555～557
20 陈秀, 陈忠伦,李作孝.细胞因子与 ICH。国外医学脑血管疾病分册,2004,12:345～347
21 张凯,何志义.白介素-10 与急性脑血管病.国外医学脑血管疾病分册,2001,9:302～304
22 Woiciechowsky C, Asadullah K, Nestler D, et al. Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury. Nat Med.1998;4(7):808～813
23 Van Beek J, Bernaudin M, Petit E, et al. Expression of receptors for complement anaphylatoxins C3a and C5a following permanent focal cerebral ischemia in themouse.Exp eurol.2000;161(1):373～382
24 Zaremba J, Losy J. Adhesion molecules of immunoglobul in gene superfamily in stroke. Folia Morphol (Warsz), 2002,61:1～6
25 Kraus J, Oschmann P, Leis S, et al. High concentrations of sVCAM-1 and sICAM-1 in the cerebrospinal fluid of patients with intracerebral haemorrhage are associated with poor outcome. J Neurol Neurosurg Psychiatry,2002,73:346～347
26 Kanemoto Y, Nakase H, Akita N, et al. Effects of anti-intercellular adhesion molecule-1 antibody on reperfusion injury induced by late reperfusion in the rat middle cerebral artery occlusion model. Neurosurgery, 2002,51:1041～1042