尿毒症大鼠脑缺血再灌注损伤机制的实验研究
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摘要
近年来,尿毒症的发病人数逐渐增多。尿毒症,是各种原发或继发的慢性肾脏疾病不断恶化、进展的最终阶段,也称终末期肾病(ESRD),此时由于肾脏功能受损,大量代谢产物在体内蓄积、钠水潴留,引起水、电解质、酸碱平衡紊乱及全身各系统功能失调,其中心脑血管系统受累最重,也是影响尿毒症患者预后的主要因素。尿毒症对心血管系统的影响研究得较多,近年有关尿毒症对神经系统的影响逐渐引起学者们的重视。然而,有关尿毒症病人发生脑缺血再灌注损伤后的病理生理变化尚未见报道。本文以尿毒症大鼠为研究对象,从多个角度探讨尿毒症合并脑缺血再灌注损伤后脑组织的病理变化、抗氧化能力的变化、炎症因子的影响及神经细胞凋亡的情况,其中运用了RT-PCR技术、免疫组化技术等多种方法,最终发现尿毒症合并脑缺血再灌注损伤的大鼠除神经细胞凋亡与单纯脑缺血再灌注无显著不同外,其余几方面的改变均重于单纯脑缺血再灌注大鼠,提示尿毒症患者体内长期存在的大量毒素使机体免疫功能下降,机体长期处于过度氧化应激水平及微炎症状态之下,当机体合并其他系统疾病特别是脑血管病时,预后极差。通过这一研究,使我们再次认识到对尿毒症病人进行抗氧化治疗、纠正微炎症状态的必要性,这是和血液净化治疗同等重要的治疗手段,是改善尿毒症病人预后的必要手段。
The incidence of chronic kidney disease (CKD) and cerebrovascular disease was increased with obesity, hypertension, diabetes and the growing elderly population in recent years. It has become the serious public health problem for humanity. Uremia is the final stage of deterioration of primary or secondary chronic kidney disease. The kidney function is damaged seriously, a large number of metabolites accumulate in the body, combined with sodium and water retention, resulting in acid-base balance disorders and dysfunction of various systems in uremic patients. Cardiovascular system is the most severely affected and is the important factor influencing uremia prognosis. Higher incidence rate of cerebrovascular disease was found in Uremic patients, its mortality rate even in dialysis patients also occupy a large proportion. At present, there are a lot of researches about the impact of uremia on the cardiovascular system, and the impact of uremia on the nervous system has been in favor of scholars gradually. However, the pathological changes and mechanisms after cerebral ischemia-reperfusion injury of uremic patients have not been reported. Experimental studies of the feature and mechanism of the cerebral ischemia reperfusion in uremic rats in the level of whole animal, cellular, molecular, genetic were made in this paper in order to find the appropriate treatment to reduce the incidence of uremic patients with cerebral ischemia and reduce morbidity and mortality and improve the prognosis.
Methods:
(1) Experimental animals and groups:
90 clean grade healthy male Wistar rats were divided into uremic group (18), uremia with cerebral ischemia-reperfusion group (72) randomly, uremia models were made. The other 90 rats were divided into normal control group (18) and ischemia-reperfusion group (72) randomly. Rats of the uremia with cerebral ischemia-reperfusion group and cerebral ischemia and reperfusion group were made into middle cerebral artery occlusion models. Reperfusion after 2 hours cerebral ischemia. according to different time points after reperfusion (Oh，2h，12h,24h), each group was divided into four sub-groups(18 each sub-group). Rats of normal control group and uremic group were also divided into four sub-groups according to different time points after reperfusion.
(2) Animal Model:
1) Methods of uremic rat model:The classic 5/6 nephrectomy
2) Methods of focal cerebral ischemia-reperfusion injury model:
the classic filament induced by reversible middle cerebral artery occlusion method (MCAO).
(3) Observe indicators and detecting methods:
1) The research of pathological changes in brain tissue
Histopathological examination:6 rats were taken from each sub-group, whole body perfusion fixed quickly, coronal cut to prepare wax block in the hippocampal area, paraffin block cut into 4um consecutive coronal sections, stained, brain tissue pathological changes observed by light microscope.
2) Comparative study of nerve cell damage
Other 6 rats were taken from each sub-group,2/3 of cortical tissue of ischemic side were taken to make 10% brain tissue homogenate.
①Determination of brain energy metabolism:
Determination of lactic acid in homogenate activity levels and changes in ATPase.
②Determination of antioxidant enzymes and lipid peroxidation products:
Determination of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activity and malondialdehyde (MDA) content by colorimetry
3) Changes of inflammatory cytokines of rats brain tissue
The expression of IL-1β, IL-6, TNF-amRNA detected by RT-PCR in 4) The research of rats nerve cell apoptosis
①Apoptosis analysed by TUNEL assay:
The experimental animals were anesthetized, heart perfusion, fixation, heads were removed, brain slices were taken in the hippocampal area, apoptotic cells were detected by TUNEL in situ label of DNA fragments.
②Immunohistochemical detection of Bcl-2. Bax expression:
Immunohistochemical staining method using SABC. DAB coloration.
(4) Statistical analysis:
All experimental data were analyzed using SPSS 16.0, the data were presented as mean= standard deviation (χ±s) and t-test was used to compare the two groups in the same time point.
(5) Results:
1) The pathological changes in rats
Normal hippocampal structure, no congestion, edema were found in control group, uremia group at each time point. Pyramidal cells were normal, boundary clear, large round nucleus, nucleolus and nuclear membrane were clearly visible. Edema hippocampal tissues were found in ischemia-reperfusion group, the number of pyramidal cells reduced, disorganized, and no hierarchical structure, cell gap widened, eosinophilic cytoplasm, nucleus dissolution. Compared with ischemia-reperfusion group, hippocampus structure of rats were damaged obviously by cell body swelling, angular, nuclear condensation or nuclear dissolution, nucleoli disappeared, cells ill-defined in uremia with cerebral ischemia and reperfusion group. With time prolonged, these changes gradually worsened in both two groups of rats with ischemia-reperfusion.
2) Comparative study of nerve cell damage
①Determination of brain energy metabolism:
Compared with the control group, LA content was higher and ATPase activity declined in uremia group at every time points, but no significant difference (P>0.01). LA content decreased gradually and ATPase activity increased gradually of the other two groups of rats in the 2-24h after reperfusion; Compared with cerebral ischemia group, LA content was higher and ATPase activity declined in uremia with cerebral ischemia reperfusion group at every time points (P＜0.01).
②Determination of antioxidant enzymes and lipid peroxidation products of brain tissues:
Compared with the control group. MDA content was higher and SOD and GSH-PX activity decreased in uremia group at every time points, but no significant difference (P> 0.01); MDA content increased gradually and SOD and GSH-PX activity decreased gradually of the other two groups of rats in the 2-24h after reperfusion; Compared with cerebral ischemia group. MDA content increased significantly and SOD and GSH-PX activity decreased significantly in uremia with cerebral ischemia reperfusion group at every time points (P＜0.01).
3) Changes of inflammatory cytokines of rats nerve cells
①TNF-αmRNA:the expression of TNF-amRNA increased in uremia group at every time points than the control group, but no significant difference (P> 0.01); the expression of TNF-αmRNA reached the peak at 2h time points and decreased gradually, but still higher than control group (P<0.01); the expression of TNF-amRNA increased in uremia with cerebral ischemia reperfusion group at every time points (P<0.01), compared with cerebral ischemia group.
②IL-1βmRNA, IL-6 mRNA:the expression of IL-1βmRNA. IL-6 mRNA increased in uremia group at every time points than the control group, but no significant difference (P> 0.01); the expression of IL-1βmRNA, IL-6 mRNA increased gradually in both other groups with reperfusion time prolonged; Compared with cerebral ischemia group, the expression of IL-1βmRNA, IL-6 mRNA increased significantly in uremia with cerebral ischemia reperfusion group at every time points (P<0.01).
4) The research of rats nerve cell apoptosis
①Apoptosis analysed by TUNEL assay:Apoptotic cells were found occasionally in hippocampal area in uremic group at each time point. Apoptotic cells were found in hippocampal area in ischemia-reperfusion group at 2h time points, increased gradually with time prolonged, reached the peak at 24h time points; Compared with cerebral ischemia group, the Apoptotic cells increased in uremia with cerebral ischemia reperfusion group at every time points., but no significant difference between the two groups (P> 0.01).
②Immunohistochemical detection of Bcl-2, Bax expression:The expression of Bcl-2 and Bax were rare in control group and the uremic group at each time point, no significant difference between the two groups (P> 0.01). The expression of Bcl-2 reached the peak at 12h time points in the other two groups, and then decreased gradually, but still expressed at 24h: the number of Bcl-2 positive cells in uremia with cerebral ischemia reperfusion group less than ischemia reperfusion group at every time points, but no significant difference (P> 0.01); the expression of Bax reached the peak at 24h in other 2 groups, the number of Bcl-2 positive cells in uremia with cerebral ischemia reperfusion group more than ischemia reperfusion group at every time points, but no significant difference (P> 0.01)
Conclusions
(1) Pathological changes of brain tissue in uremia with cerebral ischemia reperfusion group are more evident than it in cerebral ischemia-reperfusion group.
(2) Disturbance of Energy Metabolism is more significant in uremic rats after cerebral ischemia-reperfusion, the oxidative stress injury is greater, the antioxidant capacity is weaker.
(3) High expression of TNF-a in the early stage of cerebral ischemia confirmed that it is the initiating factor of the inflammatory response; IL-1β, IL-6 were expressed during reperfusion process revealed the close relationship of inflammation and cerebral ischemia-reperfusion injurys; inflammatory response has been strengthened in uremic rats with cerebral ischemia-reperfusion injury confirmed that the mini-inflammatory state of uremic rats has continuing effects on the nervous system.
(4) The neuronal apoptosis of uremic rats with cerebral ischemia and reperfusion injury is not obvious than cerebral ischemia rats.
(5) Uremia may be independent risk factors of ischemia-reperfusion injury.
The incidence of chronic kidney disease (CKD) and cerebrovascular disease was increased with obesity, hypertension, diabetes and the growing elderly population in recent years. It has become the serious public health problem for humanity. Uremia is the final stage of deterioration of primary or secondary chronic kidney disease. The kidney function is damaged seriously, a large number of metabolites accumulate in the body, combined with sodium and water retention, resulting in acid-base balance disorders and dysfunction of various systems in uremic patients. Cardiovascular system is the most severely affected and is the important factor influencing uremia prognosis. Higher incidence rate of cerebrovascular disease was found in Uremic patients, its mortality rate even in dialysis patients also occupy a large proportion. At present, there are a lot of researches about the impact of uremia on the cardiovascular system, and the impact of uremia on the nervous system has been in favor of scholars gradually. However, the pathological changes and mechanisms after cerebral ischemia-reperfusion injury of uremic patients have not been reported. Experimental studies of the feature and mechanism of the cerebral ischemia reperfusion in uremic rats in the level of whole animal, cellular, molecular, genetic were made in this paper in order to find the appropriate treatment to reduce the incidence of uremic patients with cerebral ischemia and reduce morbidity and mortality and improve the prognosis.
Methods:
(1) Experimental animals and groups:
90 clean grade healthy male Wistar rats were divided into uremic group (18), uremia with cerebral ischemia-reperfusion group (72) randomly, uremia models were made. The other 90 rats were divided into normal control group (18) and ischemia-reperfusion group (72) randomly. Rats of the uremia with cerebral ischemia-reperfusion group and cerebral ischemia and reperfusion group were made into middle cerebral artery occlusion models. Reperfusion after 2 hours cerebral ischemia. according to different time points after reperfusion (Oh，2h，12h,24h), each group was divided into four sub-groups(18 each sub-group). Rats of normal control group and uremic group were also divided into four sub-groups according to different time points after reperfusion.
(2) Animal Model:
1) Methods of uremic rat model:The classic 5/6 nephrectomy
2) Methods of focal cerebral ischemia-reperfusion injury model:
the classic filament induced by reversible middle cerebral artery occlusion method (MCAO).
(3) Observe indicators and detecting methods:
1) The research of pathological changes in brain tissue
Histopathological examination:6 rats were taken from each sub-group, whole body perfusion fixed quickly, coronal cut to prepare wax block in the hippocampal area, paraffin block cut into 4um consecutive coronal sections, stained, brain tissue pathological changes observed by light microscope.
2) Comparative study of nerve cell damage
Other 6 rats were taken from each sub-group,2/3 of cortical tissue of ischemic side were taken to make 10% brain tissue homogenate.
①Determination of brain energy metabolism:
Determination of lactic acid in homogenate activity levels and changes in ATPase.
②Determination of antioxidant enzymes and lipid peroxidation products:
Determination of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activity and malondialdehyde (MDA) content by colorimetry
3) Changes of inflammatory cytokines of rats brain tissue
The expression of IL-1β, IL-6, TNF-amRNA detected by RT-PCR in 4) The research of rats nerve cell apoptosis
①Apoptosis analysed by TUNEL assay:
The experimental animals were anesthetized, heart perfusion, fixation, heads were removed, brain slices were taken in the hippocampal area, apoptotic cells were detected by TUNEL in situ label of DNA fragments.
②Immunohistochemical detection of Bcl-2. Bax expression:
Immunohistochemical staining method using SABC. DAB coloration.
(4) Statistical analysis:
All experimental data were analyzed using SPSS 16.0, the data were presented as mean= standard deviation (χ±s) and t-test was used to compare the two groups in the same time point.
(5) Results:
1) The pathological changes in rats
Normal hippocampal structure, no congestion, edema were found in control group, uremia group at each time point. Pyramidal cells were normal, boundary clear, large round nucleus, nucleolus and nuclear membrane were clearly visible. Edema hippocampal tissues were found in ischemia-reperfusion group, the number of pyramidal cells reduced, disorganized, and no hierarchical structure, cell gap widened, eosinophilic cytoplasm, nucleus dissolution. Compared with ischemia-reperfusion group, hippocampus structure of rats were damaged obviously by cell body swelling, angular, nuclear condensation or nuclear dissolution, nucleoli disappeared, cells ill-defined in uremia with cerebral ischemia and reperfusion group. With time prolonged, these changes gradually worsened in both two groups of rats with ischemia-reperfusion.
2) Comparative study of nerve cell damage
①Determination of brain energy metabolism:
Compared with the control group, LA content was higher and ATPase activity declined in uremia group at every time points, but no significant difference (P>0.01). LA content decreased gradually and ATPase activity increased gradually of the other two groups of rats in the 2-24h after reperfusion; Compared with cerebral ischemia group, LA content was higher and ATPase activity declined in uremia with cerebral ischemia reperfusion group at every time points (P＜0.01).
②Determination of antioxidant enzymes and lipid peroxidation products of brain tissues:
Compared with the control group. MDA content was higher and SOD and GSH-PX activity decreased in uremia group at every time points, but no significant difference (P> 0.01); MDA content increased gradually and SOD and GSH-PX activity decreased gradually of the other two groups of rats in the 2-24h after reperfusion; Compared with cerebral ischemia group. MDA content increased significantly and SOD and GSH-PX activity decreased significantly in uremia with cerebral ischemia reperfusion group at every time points (P＜0.01).
3) Changes of inflammatory cytokines of rats nerve cells
①TNF-αmRNA:the expression of TNF-amRNA increased in uremia group at every time points than the control group, but no significant difference (P> 0.01); the expression of TNF-αmRNA reached the peak at 2h time points and decreased gradually, but still higher than control group (P<0.01); the expression of TNF-amRNA increased in uremia with cerebral ischemia reperfusion group at every time points (P<0.01), compared with cerebral ischemia group.
②IL-1βmRNA, IL-6 mRNA:the expression of IL-1βmRNA. IL-6 mRNA increased in uremia group at every time points than the control group, but no significant difference (P> 0.01); the expression of IL-1βmRNA, IL-6 mRNA increased gradually in both other groups with reperfusion time prolonged; Compared with cerebral ischemia group, the expression of IL-1βmRNA, IL-6 mRNA increased significantly in uremia with cerebral ischemia reperfusion group at every time points (P<0.01).
4) The research of rats nerve cell apoptosis
①Apoptosis analysed by TUNEL assay:Apoptotic cells were found occasionally in hippocampal area in uremic group at each time point. Apoptotic cells were found in hippocampal area in ischemia-reperfusion group at 2h time points, increased gradually with time prolonged, reached the peak at 24h time points; Compared with cerebral ischemia group, the Apoptotic cells increased in uremia with cerebral ischemia reperfusion group at every time points., but no significant difference between the two groups (P> 0.01).
②Immunohistochemical detection of Bcl-2, Bax expression:The expression of Bcl-2 and Bax were rare in control group and the uremic group at each time point, no significant difference between the two groups (P> 0.01). The expression of Bcl-2 reached the peak at 12h time points in the other two groups, and then decreased gradually, but still expressed at 24h: the number of Bcl-2 positive cells in uremia with cerebral ischemia reperfusion group less than ischemia reperfusion group at every time points, but no significant difference (P> 0.01); the expression of Bax reached the peak at 24h in other 2 groups, the number of Bcl-2 positive cells in uremia with cerebral ischemia reperfusion group more than ischemia reperfusion group at every time points, but no significant difference (P> 0.01)
Conclusions
(1) Pathological changes of brain tissue in uremia with cerebral ischemia reperfusion group are more evident than it in cerebral ischemia-reperfusion group.
(2) Disturbance of Energy Metabolism is more significant in uremic rats after cerebral ischemia-reperfusion, the oxidative stress injury is greater, the antioxidant capacity is weaker.
(3) High expression of TNF-a in the early stage of cerebral ischemia confirmed that it is the initiating factor of the inflammatory response; IL-1β, IL-6 were expressed during reperfusion process revealed the close relationship of inflammation and cerebral ischemia-reperfusion injurys; inflammatory response has been strengthened in uremic rats with cerebral ischemia-reperfusion injury confirmed that the mini-inflammatory state of uremic rats has continuing effects on the nervous system.
(4) The neuronal apoptosis of uremic rats with cerebral ischemia and reperfusion injury is not obvious than cerebral ischemia rats.
(5) Uremia may be independent risk factors of ischemia-reperfusion injury.
引文
[1]肖炜,马云.傅江南.慢性肾衰动物模型方法学研究现状[J].中国实验动物学杂志,2002.12(3)：176-179.
[2]包玉生,毕增祺.慢性肾功能衰竭动物模型.国外医学泌尿系分册，1994，14：66-69.
[3]王钢,邹燕勤.陈正芳.等.用冷冻手术制作慢性肾衰竭动物模型.中华肾脏病杂志，1988，4：344-346.
[4]Gagnon RF, Duguid WP. A reproducible model for chronic renal failure in the mouse. UP Urol Res.1983,11:11-14.
[5]Alevy YG, Slavin RG, Hutcheson P, et al. Immune response in experimentally induced uremia. ClinImmnuolImmunopathol,1981,19:8-18.
[6]Gibb IA, Hamilton DH. An experimental model of chronic renal failure in mice.Clin Immnuol Immunopathol,1985,35:276-284.
[7]周小舟,张盛光,阳晓,等.腺嘌呤所致大鼠慢性肾功能衰竭的机理研究.基础医学与临床,1997,17：54-57.
[8]郑平东,朱燕俐,丁名城,等.用腺嘌呤制作慢性肾功能衰竭动物模型.中华肾脏病杂志,1989,5：342-344.
[9]Fries JW, Sandstrom DJ, Meyer TW, et al. Glomerular hypertrophy and eqithelial cell 205-218.
[10]熊祖应,梅俏,丁长海,等.松果体摘除联合阿霉素肾病动物模型的建立.中国药理学通报,1999,15：283-285.
[11]Scholey JW, Miller PL, Rennke HG, et al. Effect of converting enzyme inhibition on the course of adriamycin-induced nephropathy.Kidney Int,1989,36:816-818.
[12]林娜,陈荣华,黄松明,等.加速型肾小球硬化动物模型的建立.南京医科大学学报,2000,20：166-170.
[13]王泰华,钱家麒,张介玉,等.阿霉素肾病肾硬化动物模型的实验改进.肾脏病与透析肾移植杂志,1997,6：191-193.
[14]Provoost AP, Baudoin P, DeKeijzer MH, et al. The role of nephron loss in the progression of renal failure:experimental evidence.Am J Kidney Dis,1991,17:27-32.
[15]李瀚昊,章如虹.杨德才.等.中药消痔灵致大白鼠慢性肾衰模型的复制.中国中药科学.1996，3：6-8.
[16]Barata K, Yoshida M. Hokao R. et al. Functionin 5/6 nephrectomizedrats basic study for renal toxicit yusing 5/6 nephrectomized rats[J]. J Toxicol Sci,1998.23(5):433-442.
[17]何立群，王怡，郑平东.阳离子化牛血清白蛋白制作慢性肾衰动物模型.安徽中医临床杂志,1998,10：356.
[18]窦万臣,王任直,张波.等.大鼠局灶性脑缺血模型制作方法的改进.中国脑血管病杂志，2004，1(2)：81-84.
[19]Tamura A, Nakayama H. Narita K, et al. Rat middle cerebral artery occlusion models. CVD Grand Round Series,2001.4:75-90.
[20]Bederson JB, Pitts LH, Tsuji M, et al. Rat middle cerebral artery occlusion:evaluation of the model and development of a neurologic examination. Stroke,1986,17(3):472-476.
[21]历建元,张亚卓,姚维成,等.两种方法制作大鼠大脑中动脉栓塞再灌注模型比较.青岛大学医学院学报,2008,4(5)：382-384.
[22]Koizumi J, Yoshid Y, Nakazawa T. et al. Experimental studies of ischemic brain edema: A new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemic area. Stroke,1986,8:1.
[23]Longa EZ, Weinstain PR, Carlson S, et al. Reversible middle cerebral artery occlusion without cranietomy in rats. Stroke,1989,20:84-91.
[24]田士强,王任直,李桂林,等.大鼠局灶性脑缺血模型的改进[J].基础医学与临床,2004，24(4)：449-451.
[25]Laiug RJ, Jakubowski J, Laing RW. Middle cerebral artery occlusion without cranietomy in rats. Which method works best? Stroke.1993,24:294-298.
[26]刘亢丁,苏志强,李毅平.实验性脑栓塞再灌注动物模型的改进及评价.中风与神经疾病杂志,1997,14(2)：87-89.
[27]Menzies SA, Hoff JT, Betz AL. Middle cerebral artery occlusion in rats:a neurological and pathological evaluation of a reproducible model. Neurosurgery,1992,31:100-107.
[28]龚彪.李长清,黄剑.SD大鼠线栓法局灶性脑缺血／再灌注模型的改进[J].重庆医学,2006,35(4)：313-315.
[29]张成英，赵旭东.线栓法制作大鼠局灶性脑缺血模型插线部位的选择[J].解剖学杂志,2004,12(2)：110-111.
[30]Miyata T, van Ypersele de Strihou C, Kurokawa K. et al. Alterrations in nonenzymatic biochemistry in uremia:Origin and significance of "carbonyl stress"in longterm uremic complications. Kidney Int,1999,55:389-399.
[31]Kiyoshi Tamaki, Seiya Okuda. Role of TGF-β1 in the progression of renal Fibrosis. Razzaque MS, Taguchi T (eds):Renal Fibrosis. Contrib Nephrol[J]. Basel Karger， 2003.139:44.
[32]Anita L, Cochrane, Sharon D. Ricardo oxidant stress and regulation of chemokines in the development of renal interstitial fibrosis razzaque.MS， Taguchi T(eds):Renal Fibrosis. Contrib Nephrol [M]. Basel, Karger,2003:102-11.
[33]李荟，马宏.肾小管上皮细胞-间充质细胞转分化在肾间质纤维化中的作用[J].国外医学.泌尿系统分册,2005，25(3)：20.
[34]Vaziri ND. Role of oxidative stress and antioxidant therapy in chronic kidney disease and hypertension [J]. Currop in Nephrol Hypertens,2004,13:93.
[35]Dominguez-Rosales JA, Mavi G. Levenson SM, et al. H2O2 is an important mediator of physiological and pathological healing p rocesses[J]. Arch Med Res,2000,31:15.
[36]Wratten ML, Sereni L, Tetta C. Hemolipo dialysis attenuates oxidative stress and removes hydrophobic toxins. Artif Organs,2000,24(9):685-690.
[37]Miyata T, Ueda Y, Yamada Y, et al. Carbonyl stress in uremia:Accumulation of carbnyls accelerate the formation of pentosidine, an advanced glycation end product. J Am Soc Nephrol,1998,9:2349-2356.
[38]Miyata T. Ueda Y, Shizato T. et al. Accumulation of albumin-linked and free-form pentosidine in the circulation of uremic patients with end-stage renal failure:Renal implications in the pathophysiology of pentosidine. J Am Soc Nephrol,1996,7:1198-1206.
[39]Miyata T, Ueda Y. Yoshida A, et al. Clearance of pentosidine, an advanced glycation end product, by different modalities of renal replacement therapy. Kidney Int,1997. 51:880-887.
[40]Witko-Sarsat V, Friedlander M, Capeillere-Blandin C. et al. Advanced oxidation protein produ cts as a novel marker of oxidative stress in uremia. Kidney Int,1996,49: 1304-1313.
[41]Fu MX, Requena J R. Jenkins AJ. et al. The advanced glycation end-product， Nε-(carboxymethyl) lysine (CML), is a product of both lipid peroxidation and glycation reactions. J Biol Chem,1996,271:9982-9986.
[42]Miyata T. Wada Y, Cai Z. et al. Implication of an increased oxidative stress in the formation of advanced glycation end products in patients with end-stage renal failure. Kidney Int,1997,51:1170-1181.
[43]侯凡凡.张训.王斌会，等.Nε-羧甲基赖氨酸时慢性血液透析病人晚期糖基化终产物的天然结构.中华内科杂志.1998，37(10)：663-666.
[44]Miyata T. Fu MX, Kurokawa K, et al. Autoxidation products of both carbohydrates and lipids are increased in uremic plasma:Is there oxidative stress in uremia? Kidney Int,1998,54:1290-1295.
[45]Peuchant E, Carbonneau MA, Dubourg L, et al. Lipoperoxidation in plasma and red blood cells of patients undergoing hemodialysis:Vitamin A. E and iron status. Free Radic Biol Med,1994,16(3):339-346.
[46]Miyata T, Taneda S, Kawai R. et al. Identification of pentosidine as a native structure for advanced glycation end products inβ2-microglobulin forming amyloid fibrils in patients with dialysis-related amyloidosis. Proc Nalt Acad Sci USA,1996,93:2353-2358.
[47]Mcgrath L T, Douglas AF, McClean E, et al. Oxidative stress and erythrocyte membrane fluidity in patients undergoing regular HD. Clin Chim Acta,1995.235:179-188.
[48]Hassan MQ. Hussain SA, Zaki MA, et al. Prospective effects of antioxidants against uraemia-induced lipid peroxidation and glutathione depletion in humans. Pharmocol Toxicol.1995.77:407-411.
[49]Tsuzuki D, Sumino K, Yokoyama M, et al. Analysis of 7-ketocholesterol in low density lipoprotein and fatty acid composition in erythrocyte membranes of patients on maintenance hemodialysis and healthy controls. Clinica Chimica Acta,2000.295: 155-168.
[50]叶云洁，倪兆慧，钱家麒,等.终末期肾病微炎症状态和动脉粥样硬化的关系.中 华肾脏病杂志,2004，20(3)：173-176.
[51]Bistrian B, Mccowen KC, Chan S. Protein-energy malnutrition in dialysis patients. J Am Kidney Dis,1999,33(1):172-175.
[52]Kaysen GA. The microinflammatory state in uremia:causes and potential consequences. J Am Soc Nephrol, 2001,12(7):1549-1557.
[53]钱家麒.姚强.慢性肾衰竭透析患者中炎症发生的原因和后果.中国中西医结合肾病杂志,2005，6(8)：435-437.
[54]Schomig M. Eisenhandt A, Ritz E. The microinflammatory state of uremia.Blood Puf. 2000,18(4):327-330.
[55]Tsirpanlis G, Chatzipanagiotou S, Nicolaou C, et al. Microinflammation versus inflammation in chronic renal failurepatiems. Kidney Int,2004,66(12):2093-2098.
[56]Pupim LB, Himmelfarb J, McMonagle E, et al. Influence of initiation of maintenance hemodialysis on biomarkers of inflammation and oxidative stress. Kidney Int,2004, 65(6):2371-2379.
[57]张琳,曾庆波,曾章超.白细胞介素6(IL-6)与肾脏疾病.实用中西医结合临床,2005,5(2)：80-81.
[58]Bologa RM, Levine DM, Parker TS, et al. Interleukin-6 predicts hypoalbuminemia, hypocholesterolemia, and mortality in hemodialysis patients. Am J Kidney Dis,1998, 32(1):107-114.
[59]郑智华,马祖等,郝元涛,等.持续性非卧床腹膜透析患者生存质量影响因素的研究.中华肾脏病杂志,2005,21(5)：290-294.
[60]姚英.ESRD患者C反应蛋白水平与炎症[J].国外医学泌尿系统分册,2003.23(6)：737-742.
[61]George AK. TheMicroinflammatory state in uremia:causes and potential consequences [J]. J Am Soc Nephrol, 2001,12(7):1549-1557.
[62]侯凡凡,任昊,郭志坚,等.单核细胞RAGE表达上调：慢性肾功能衰竭微炎症的机制.中华医学杂志,2004,84(19)：1614-1619.
[63]陈丹.髓过氧化物酶与终末期肾病患者炎症和氧化应激反应[J].肾脏病与透析肾移植杂志,2005,14(5)：469-472.
[64]张道友,孙亚南.慢性肾功能衰竭患者血脂变化.中国动脉硬化杂志.1998.6(3)：249-250.
[65]叶任高.内科学.第6版.北京：人民卫生出版社.2004：264-265.
[66]高学军.刘子栋.慢性肾衰竭血液透析与腹膜透析患者微炎症反应的比较及相关因素分析.中国血液净化.2005.4(4)：208-210.
[67]George AK. TheMicroinflammatory state in uremia:causes and potential consequences[J]. J Am Soc Nephrol.2001.12(7):1549-1557.
[68]Suzuki Y, Ruiz OrtegaM, Lorenzo O, et al. Inflammation and angiotensin Ⅱ [J]. The Internatiomal Jounal ofBiochemistry & CellBilogy.2003.35(6):881-900.
[69]Pankow JS, Folsom AR, Cushman M. et al. Familial and genetic determinants of systemic marker of inflammation:The NHLBI family heart study. Atherosclerosis, 2001,154(7):681-689.
[70]Bergstrom J. Lindholm B, Lacson E. et al. What are the causes and consequences of the chronic inflammatory state in chronic dialysis patients? Semin Dial.2000,13(3): 163-175.
[71]Bergstrom J, Lindholm B. Malnutrition, cardiac disease, and mortality:an integrated point of view. Am J Kidney Dis,1998,32(5):834-841.
[72]Davie SJ, Phillips L. Griffiths AM. et al. An analysis of the effects of increasing delivered dialysis treatment to malnourish peritoneal dialysis patients. Kidney Int. 2000,57(4):1743-1754.
[73]吴惠玲.何国祥,刘建平.等.血浆超敏C反应蛋白水平与冠心病及动脉粥样硬化的关系[J].临床心血管病杂志.2006.22(7)：405-407.
[74]曹礼应.余月明,郭虹,等.维持性血液透析患者C反应蛋白异常与营养、冠心病发病率的关系[J].临床肾脏病杂志,2005,5(2)：82-83.
[75]谢恺庆,杨海波,周红卫.等.尿毒症维持性血液透析患者微炎症状态与脂蛋白(a)的关系.中国动脉硬化杂志,2004,12(4)：469-470.
[76]Locatelli F, Manzoni C, Difilippo S. The importance of convective transport. Kidney Int,2002,80(Suppl):115-120.
[77]Stenvinkel P, Alrestrand A. Inflammation in end2stage renal disease:sources. consequences, and therapy[J]. Seminars in Dialysis,2002.15(5):329-337.
[78]陈江华，何强,徐莹.维持性血液透析患者微炎症状态的认识和防治.中华肾脏病杂志，2005，21(2)：117-118.
[79]刘彬,王殿华.肾脏细胞的凋亡.国外医学生理病理科学与临床分册,1998，18(3).
[80]Bin Y. Timothy I. Graham L, et al. Expression of apoptosis-related genes and proteins in experimental chronic renal scarring[J]. J Am Soc Nephrol,2001,12(2):275-288.
[81]彭黎明,等.细胞凋亡的基础与临床[M].北京：人民卫生出版社,2000，127.
[82]Jerry M, et al. [J]. Sci,1998,281(5381):1322-1326.
[83]Standey J, et al. [J]. Cancer Res,1999,59:1670-1673.
[84]Saito M, et al. [J]. Nat Cell Biol,2000,75:253-261.
[85]Eskes R, et al. [J]. Cell Biol,1998,143:217-224.
[86]Desagher S, et al. [J]. Trends Cell Biol,2000(10):369-377.
[87]刘秉文,等.医学分子生物学[M].北京：中国协和医科大学出版社，2000：247.
[88]Felici M. et al. [J]. Eur J Neurosci,2000,12(3):819-827.
[89]Gobe G, et al. [J]. Cancer Invest,2002,20(3):324-332.
[90]Yang B, et al. [J]. Kidney Int,2002,62(4):1301-1318.
[91]Yang B, et al. [J]. J Am Soc Nephrol,2001,12(2):275-288.
[92]李树全,阳冠明.细胞凋亡及其相关基因蛋白在阿霉素肾病中的作用.中国病理生理杂志,2002,18(6)：704-705.
[93]Wang W, Alex T, Divjak M, et al. Alter signaling and regulatory mechanisms of apoptosis in focal and segmental glomerulosclerosis[J]. J Am Soc Nephrol.2001. 12(7):1422-1433.
[94]杨晓,沈延春,朱忠华，等.大鼠残肾细胞凋亡及凋亡相关基因的动态表达及意义[J].中国病理生理杂志,2007，(23)5：916-920.
[95]陈修,陈维洲,曾贵云.心血管药理学第二版.北京人民卫生出版社,1997：143.
[96]邵福源,王宇卉.分子神经药理学.上海：上海科学技术出版社,2005：453.
[97]Wei J, Quast MJ. Effect of nitricoxide synthesis inhibitor on a hypergly cemiarat model of reversible focal ischemia:detection of excitatory aminoacids release and hydroxylradical formation[J]. Brain Res,1998,791(122):146-156.
[98]梅和珊，王永利.脑缺血时谷氨酸释放机制[J].中国药理学通报，2005，21(4)：393-396.
[99]Kato S, Ndgeshi K, Nawatari K, Kuo CH. A mechanism for glutamate toxicity in the C6 glioma cells involving inhibition of cystine uptake leading to glutathione depletion. Neuroscience 1992,48:903-914.
[100]Simonian NA. Coyle JT. Oxidative stress in neurodegenerative disease. Annu Rev Pharmacol Toxicol 1996.36:83-106.
[101]Nishizawa Y. Glutamate release and neuronal damage in ischemia[J]. Life Sci.2001. 69(4):369-381.
[102]Obrenovitch TP, Urenjak J. Zilkha E. et al. Excitotoxicity in neurological disorders-the glutamate paradox[J]. Int J Dev Neurosci,2000,18(223):281-287.
[103]Lewen A, Matz P, Chan PH. Free radical pathways in CNS injury[J]. J Neurotrauma. 2000,17(10):871-890.
[104]Cao G, Minnamim M, Pei W, Yan C, Chen D, O'Horo C. et al. Intracellular bax translocation after transient cerebral ischemia:implications for a role of the mitochondrial apoptotic signaling pathway in ischemic neuronal death. J Cerebral Blood Flow Metab 2001,21:321-333.
[105]Chan PH. Reactive oxygen radical in signaling and damage in the ischemic brain[J]. J Cereb Blood Flow Metab.2001.21(1):2214.
[106]Fujimura M, Morita Fujimura Y, Kawase M, et al. Manganese super oxidedis mutase mediates the early release of mitochondrial cytochromec and subsequent DNA fragmentation after permanent focal cerebral ischemia in mice [J]. J Neurosci,1999. 19(9):3414-3422.
[107]Green DR. Apoptotic pathway:the roads to ruin [J]. Cell.1998,94(6):695-698.
[108]Yamasaki Y, Matsuo Y, Zagorski J, et al. New therapeutic possibility of Block lngcytokine-induced neutro philchemoattractant on transient ischemic brain damage in rats [J]. Brain Res,1997,759 (1):103-111.
[109]Fujimura M, Morita Fujimura Y, Murakami K, et al. Cytosolicredistri butionofcy to chromec after transient focal cerebralischemia in rats [J]. J Cereb Blood Flow Metab, 1998,18(11):1239-1247.
[110]Martin Villalba A, Herr I. Jeremias I. et al. CD95 ligand (Fas-L/APO-1L) and tumor necrosis factor-related apoptosis-inducing ligand mediate ischemia-induced apoptosis in neurons [J]. J Neurosci,1999(10):3809-3817.
[111]Rosenbaum DM, Gupta G, D Amore J, et al. Fas (CD95/APO-1) plays a role in the pathophysiology of focal cerebral ischemia [J]. J Neurosci Res.2000,61(6):686-692.
[112]Schiepptai A, Remuzzi G. Chronic renal disease as a public health problem: Epidemiology, social and economic implications [J]. Kidney Int Suppl,2005,98:S7-S10.
[113]United States Renal Data System:USRDS 1994 annual data report. Am J Kidney Dis, 1994 (suppl 2),24:88-95.
[114]Toyoda K, Fujii K, Ando T, et al. Incidence, etiology, and outcome of stroke in patients on continuous ambulatory peritoneal dialysis. Cerebrovaseases,2004,17(2-3): 98-105.
[115]overas J. Roquer J. Puig JM. et al. Stroke in renal transplant rccipients epidemiology predietive risk factors and outeome. Clin Transplant.2003,17(1):1-8.
[116]中华医学会肾脏病分会透析移植登记工作组.1999年度全国透析移植登记报告.中华肾脏病杂志,2001,17：77-78.
[117]Port FK, Hullben-Shearon, Wolfe RA, et al.P redialysis blood pressure and mortaily risk in a national sample of maintenance hemo-dialysis patients. Am J Kidney Dis, 1999,33:507-517.
[118]张葆樽.脑血管疾病流行病学.北京：北京人民卫生出版社,2007：721.
[119]Node M. Effect of candesartan cilexetil in rats with chronic renal failure. Kidney Int. 1999,56(3):898-909.
[120]Longa EZ. Weinstain PR, Carlson S, et al. Reversible middle cerebral artery occlusion without cranietony in rats. Stroke,1989,20(1):84-91.
[121]Rogers DC, Campbell CA, Stretton JL, et al. Correllation between motor impairment and infarct volume after permanent and transient middle cerebral artery occlusion in the rat. Stroke 1997,28:2060-2065.
[122]George AK. TheMicroinflammatory state in uremia:causes and potential consequences[J]. J Am Soc Nephrol,2001.12(7):1549-1557.
[123]周凤鑫.组织血液灌注与微循环的病理生理[J].外科理论与实践，2007.12(6)：附5-12.
[124]杜国伟,鲍晓荣.早期慢性肾脏疾病心脏病变的实验研究[J].老年医学与保健,2008,14(1)：26-28.
[125]Zauner A, Daugherty W P. Bullock M R. et al. Brain oxygenation and energy metabolism:part Ⅰ-biological function and pathophysiology. Neurosurgery.2002. 51(2):289-301.
[126]Nisson OG， Brand L, Ungersted U. Detection of brain ischemia using intracerebrchal microdialysis:subaranoid hemorrhage and delayed ischemic deterioration. Neruosurgery, 1999,45(5):1176-84.
[127]毛捷,陈劲草，饶慧蓉.GM1对大鼠脑缺血再灌注损伤的乳酸及葡萄糖含量的影响.安徽医科大学学报，2004,12(39)：449-451.
[128]邵福源.王宇卉.分子神经药理学.上海：上海科学技术出版社，2005：453.
[129]Nisson OG, Brand L. Ungersted U. Detection of brain ischemia using intracerebrchal microdialysis:subaranoid hemorrhage and delayed ischemic deterioration. Neruosurgery, 1999,45(5):1176-84.
[130]Biros MH, Dimlich RVW. Brain lactate during partial global ischemia and reperfusion: Effect of pretreatment with dichloroacetate in a rat model. Am J Emerg Med,1987,5(2):271.
[131]Biros MH, Dimlich RVW. Brain lactate during partial global ischemia and reperfusion: Effect of pretreatment with dichloroacetate in a rat model. Am J Emerg Med,1987.5 (2):271.
[132]Fresu L, Dehpour A. GenazzaniA A. et al. Plasma membrane calcium ATPase isoforms in astrocytes [J]. Glia,1999.28:150-155.
[133]Phillis JW, O'Regan MH. Characterization of models of release of amino acids in the ischemic/reperfusion ratcerebral cortex.Neurochem Int 2003,43:461-467.
[134]Stojavic T, Mrsulja BB. Alterations in synaptomosal membrane Na, K-ATPase of the gerbil cortex and hippocampus following reversible brain ischemia. Metab Brain Dis 1988,3:265-272.
[135]Cao G. Minnami M, Pei W. Intracellular bax translocation after transientcerebral ischemia:implications for a role of the mitochondrial apoptotic signaling pathway in ischemic neuronal death[J]. J Cereb Blood Flow Metab,2001,21(4):321-333.
[136]Lou M. Chen Y. Ding M, et al. Involvement of the mitochondrial ATP sensitive potassium channel in the neuro protective effect of hyperbaric oxygenation after cerebral ischemia [J]. Brain Res Bull.2006.69:109-116.
[137]Sakanak M. Wen TC, Matsuda S, et al. In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci USA,1998,95:4635-4640.
[138]Rogers SA, Talcott M, Hammerman MR. Transplantation of pig met anephroi. ASAIO J.2003,49(1):48-52.
[139]Lian SL, Chen W, Raung SL, et al. Association of immune responses and ischemic brain in farction in rat [J]. Neuroreport,2001,12(9):1943-1947.
[140]Zheng Z, Zhao H, Steinberg GK, et al. Cellular and molecular events underlying ischemia induced neuronal apoptosis [J]. Drug News Perspect,2003,16(12):497-503.
[141]Iadecola C, Alexander M. Cerebral ischemia and inflammation [J]. Curr Opin Neurol, 2001,14(1):89-94.
[142]Green DR. Apoptotic pathway:the roads to ruin [J]. Cell,1998,94(6):695-698.
[143]Vilan N, Castillo J, Davalos A, et al. Proinflammatory cytokines and early neurological worsening in ischemic stroke[J]. Stroke,2000,31(10):2325-2329.
[144]Vaziri ND. Role of oxidative stress and antioxidant therapy in chronic kidney disease and hypertension [J]. Currop in Nephrol Hypertens,2004,13:93.
[145]Margaill I, Plotkine M. Lerouet D. Antioxdent strategies in the treatment of stroke. Free Radic Bio Med 2005,39:429-443.
[146]潘家枯,江明华.生化药理学.上海：复旦大学出版社，2004：91.
[147]方舒东,朱也森.脑缺血再灌注损伤的病理生理研究进展.医学综述,2006,12(18)：4111-6111.
[148]Grynkiewicz G, Poenie M, Tsien RY. A new generation of Ca2+indicators with greatly improved fluorscence properties. J Biol Chem 1985,260:3440-50.
[149]Wei J. Quast MJ. Effect of nitricoxide synthesis inhibitor on a hyper glycemia rat model of reversible focal ischemia:detection of excitatory aminoacids release and hydroxyl radical formation[J]. Brain Res,1998,791 (122):146-156.
[150]梅和珊,王永利.脑缺血时谷氨酸释放机制[J].中国药理学通报，2005,21(4)：393-396.
[151]Butcher SP, Bullock R, Graham DI. Correlation between amino acid release and neuropathologic outcome in rat brain following middle cerebral artery occlusion. Stroke,1990.21(12):17-27
[152]Alessandri B. Bullock R. Glutamate and its receptors in the pathophysiology of brain and spinal cord injuries. Progr Brain Res,1998,116:303.
[153]Iadecola C, Alexander M. Cerebral ischemia and inflammation[J]. Curr Opin Neurol, 2001,14(1):89-94.
[154]Matsumoto K, Lo EH, Pierce AR, et al. Secondary elevation of extra cellular neuro transmitter aminoacids in the reperfusion phase following focal cerebral ischemia [J]. J Cereb Blood Flow Metab,1996,16(1):114.
[155]Nishizawa Y. Glutamate release and neuronal damage in ischemia[J]. Life Sci,2001.69(4):369-381.
[156]Lewen A, Matz P, Chan PH. Freeradical pathways in CNS injury [J]. J Neurotrauma. 2000,17(10):871-890.
[157]Nishizawa Y. Glutamate release and neuronal damage in ischemia[J]. Life Sci,2001. 69(4):369-381.
[158]Zh, Zhao H, Steinberg GK, et al. Cellular and molecular event eng Zs underlying ischemia-induced neuronal apoptosis [J]. Drug News Perspect,2003.16(12):497-503.
[159]Lewen A. Matz P. Chan PH. Free radical pathways in CNS injury[J]. J Neurotrauma. 2000.17(10):871-890.
[160]Zaleska MM. Mercado ML, Chavez J. et al. The development of stroke therapeutics: promising mechanisms and translational challenges [J]. Neuro pharmacology,2009,56(2): 329-341.
[161]Williams AJ, Dave JR, Tortella FC. Neuro protection with the proteasome inhibitor MLN519 in focal ischemic brain injury:Relation to nuclear factoncB (NF-κB), inflammatory gene expression, and leukocyte infilt ration[J]. Neurochem Int, 2006,49 (2):106-112.
[162]Jean WC, Spellman SR, N ussbaum ES, et al. Reperfusion injury after focal cerebral ischemia:the role of inflammation and the therapeutic horizon[J]. Neuro surgery, 1998,43(6):1382-1396.
[163]Yamasak i Y, Itoyama Y, Kogure K. Involvement of cytokine production in pathogenesis of transient cerebral ischemic damage[J]. Keio J M ed,1996,45(3):225-229.
[164]Lao CJ, Lin JG, Kuo JS. Microglia, apoptosis and interleukin-1 beta expression in the effect of sophora japonica on cerebral infarct induced by ischemia-reperfusion in rats. Am J Chin Med.2005,33(3):425-438.
[165]Yamagami H, Kitagawa K, Nagai Y, et al. Higher levels of interleukin-6 are associated with lower echogenicity of carotid artery plaques. Stroke.2004,35(3): 677-681.
[166]Laskowitz DT, Grocott H, Hsia A, et al. Serum markers of cerebral ischemia. Stroke Cerebrovasc. Dis.1998,7(4):234-241.
[167]Relton JK, Martin RC, Russell DA. Peripheral administration of interleukin-1 receptor antagonist inhibits brain damage after focal cerebral ischemia in the rat. Exp Neurol. 1996,138:206-213.
[168]Mohri I, Taniike M, Taniguchi H, et al. ProstaglandinD2-mediated microglia/ astrocyteinte raction enhance sastrogliosis and demyelination in twitcher[J]. J Neurosci,2006,26(16):4383-4393.
[169]梁静,曹灵.慢性肾衰竭微炎症状态的研究进展.中国中西医结合肾病杂志,2008,8(7)：428-430.
[170]刘斌,张强,张宇,等.脑缺血再灌注后不同时间点病理变化与细胞凋亡的研究.陕西医学杂志,2007,4(36)：395-397.
[171]Allsopp TE, Paterson HF, et al. The proto-oncongene Bcl-2 can selectively rescue neurotrophic factor-dependent neurons from apoptosis[J]. Cell,1993,73(2):295-307.
[172]金华,孙抒,于柏艳,等.蛴螬提取物对MCF-7人乳腺癌细胞株凋亡的影响[J].中国病理生理杂志,2008,24(1)：93-96.
[173]Oltvai ZN, Milliaman CL, Kosmeyer SJ. Bcl-2 hererodimerizes in vivo with a conserved homolog Bax, that acclerates programmed cell death[J]. Cell,1993,74(4):609-619.
[2]包玉生,毕增祺.慢性肾功能衰竭动物模型.国外医学泌尿系分册，1994，14：66-69.
[3]王钢,邹燕勤.陈正芳.等.用冷冻手术制作慢性肾衰竭动物模型.中华肾脏病杂志，1988，4：344-346.
[4]Gagnon RF, Duguid WP. A reproducible model for chronic renal failure in the mouse. UP Urol Res.1983,11:11-14.
[5]Alevy YG, Slavin RG, Hutcheson P, et al. Immune response in experimentally induced uremia. ClinImmnuolImmunopathol,1981,19:8-18.
[6]Gibb IA, Hamilton DH. An experimental model of chronic renal failure in mice.Clin Immnuol Immunopathol,1985,35:276-284.
[7]周小舟,张盛光,阳晓,等.腺嘌呤所致大鼠慢性肾功能衰竭的机理研究.基础医学与临床,1997,17：54-57.
[8]郑平东,朱燕俐,丁名城,等.用腺嘌呤制作慢性肾功能衰竭动物模型.中华肾脏病杂志,1989,5：342-344.
[9]Fries JW, Sandstrom DJ, Meyer TW, et al. Glomerular hypertrophy and eqithelial cell 205-218.
[10]熊祖应,梅俏,丁长海,等.松果体摘除联合阿霉素肾病动物模型的建立.中国药理学通报,1999,15：283-285.
[11]Scholey JW, Miller PL, Rennke HG, et al. Effect of converting enzyme inhibition on the course of adriamycin-induced nephropathy.Kidney Int,1989,36:816-818.
[12]林娜,陈荣华,黄松明,等.加速型肾小球硬化动物模型的建立.南京医科大学学报,2000,20：166-170.
[13]王泰华,钱家麒,张介玉,等.阿霉素肾病肾硬化动物模型的实验改进.肾脏病与透析肾移植杂志,1997,6：191-193.
[14]Provoost AP, Baudoin P, DeKeijzer MH, et al. The role of nephron loss in the progression of renal failure:experimental evidence.Am J Kidney Dis,1991,17:27-32.
[15]李瀚昊,章如虹.杨德才.等.中药消痔灵致大白鼠慢性肾衰模型的复制.中国中药科学.1996，3：6-8.
[16]Barata K, Yoshida M. Hokao R. et al. Functionin 5/6 nephrectomizedrats basic study for renal toxicit yusing 5/6 nephrectomized rats[J]. J Toxicol Sci,1998.23(5):433-442.
[17]何立群，王怡，郑平东.阳离子化牛血清白蛋白制作慢性肾衰动物模型.安徽中医临床杂志,1998,10：356.
[18]窦万臣,王任直,张波.等.大鼠局灶性脑缺血模型制作方法的改进.中国脑血管病杂志，2004，1(2)：81-84.
[19]Tamura A, Nakayama H. Narita K, et al. Rat middle cerebral artery occlusion models. CVD Grand Round Series,2001.4:75-90.
[20]Bederson JB, Pitts LH, Tsuji M, et al. Rat middle cerebral artery occlusion:evaluation of the model and development of a neurologic examination. Stroke,1986,17(3):472-476.
[21]历建元,张亚卓,姚维成,等.两种方法制作大鼠大脑中动脉栓塞再灌注模型比较.青岛大学医学院学报,2008,4(5)：382-384.
[22]Koizumi J, Yoshid Y, Nakazawa T. et al. Experimental studies of ischemic brain edema: A new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemic area. Stroke,1986,8:1.
[23]Longa EZ, Weinstain PR, Carlson S, et al. Reversible middle cerebral artery occlusion without cranietomy in rats. Stroke,1989,20:84-91.
[24]田士强,王任直,李桂林,等.大鼠局灶性脑缺血模型的改进[J].基础医学与临床,2004，24(4)：449-451.
[25]Laiug RJ, Jakubowski J, Laing RW. Middle cerebral artery occlusion without cranietomy in rats. Which method works best? Stroke.1993,24:294-298.
[26]刘亢丁,苏志强,李毅平.实验性脑栓塞再灌注动物模型的改进及评价.中风与神经疾病杂志,1997,14(2)：87-89.
[27]Menzies SA, Hoff JT, Betz AL. Middle cerebral artery occlusion in rats:a neurological and pathological evaluation of a reproducible model. Neurosurgery,1992,31:100-107.
[28]龚彪.李长清,黄剑.SD大鼠线栓法局灶性脑缺血／再灌注模型的改进[J].重庆医学,2006,35(4)：313-315.
[29]张成英，赵旭东.线栓法制作大鼠局灶性脑缺血模型插线部位的选择[J].解剖学杂志,2004,12(2)：110-111.
[30]Miyata T, van Ypersele de Strihou C, Kurokawa K. et al. Alterrations in nonenzymatic biochemistry in uremia:Origin and significance of "carbonyl stress"in longterm uremic complications. Kidney Int,1999,55:389-399.
[31]Kiyoshi Tamaki, Seiya Okuda. Role of TGF-β1 in the progression of renal Fibrosis. Razzaque MS, Taguchi T (eds):Renal Fibrosis. Contrib Nephrol[J]. Basel Karger， 2003.139:44.
[32]Anita L, Cochrane, Sharon D. Ricardo oxidant stress and regulation of chemokines in the development of renal interstitial fibrosis razzaque.MS， Taguchi T(eds):Renal Fibrosis. Contrib Nephrol [M]. Basel, Karger,2003:102-11.
[33]李荟，马宏.肾小管上皮细胞-间充质细胞转分化在肾间质纤维化中的作用[J].国外医学.泌尿系统分册,2005，25(3)：20.
[34]Vaziri ND. Role of oxidative stress and antioxidant therapy in chronic kidney disease and hypertension [J]. Currop in Nephrol Hypertens,2004,13:93.
[35]Dominguez-Rosales JA, Mavi G. Levenson SM, et al. H2O2 is an important mediator of physiological and pathological healing p rocesses[J]. Arch Med Res,2000,31:15.
[36]Wratten ML, Sereni L, Tetta C. Hemolipo dialysis attenuates oxidative stress and removes hydrophobic toxins. Artif Organs,2000,24(9):685-690.
[37]Miyata T, Ueda Y, Yamada Y, et al. Carbonyl stress in uremia:Accumulation of carbnyls accelerate the formation of pentosidine, an advanced glycation end product. J Am Soc Nephrol,1998,9:2349-2356.
[38]Miyata T. Ueda Y, Shizato T. et al. Accumulation of albumin-linked and free-form pentosidine in the circulation of uremic patients with end-stage renal failure:Renal implications in the pathophysiology of pentosidine. J Am Soc Nephrol,1996,7:1198-1206.
[39]Miyata T, Ueda Y. Yoshida A, et al. Clearance of pentosidine, an advanced glycation end product, by different modalities of renal replacement therapy. Kidney Int,1997. 51:880-887.
[40]Witko-Sarsat V, Friedlander M, Capeillere-Blandin C. et al. Advanced oxidation protein produ cts as a novel marker of oxidative stress in uremia. Kidney Int,1996,49: 1304-1313.
[41]Fu MX, Requena J R. Jenkins AJ. et al. The advanced glycation end-product， Nε-(carboxymethyl) lysine (CML), is a product of both lipid peroxidation and glycation reactions. J Biol Chem,1996,271:9982-9986.
[42]Miyata T. Wada Y, Cai Z. et al. Implication of an increased oxidative stress in the formation of advanced glycation end products in patients with end-stage renal failure. Kidney Int,1997,51:1170-1181.
[43]侯凡凡.张训.王斌会，等.Nε-羧甲基赖氨酸时慢性血液透析病人晚期糖基化终产物的天然结构.中华内科杂志.1998，37(10)：663-666.
[44]Miyata T. Fu MX, Kurokawa K, et al. Autoxidation products of both carbohydrates and lipids are increased in uremic plasma:Is there oxidative stress in uremia? Kidney Int,1998,54:1290-1295.
[45]Peuchant E, Carbonneau MA, Dubourg L, et al. Lipoperoxidation in plasma and red blood cells of patients undergoing hemodialysis:Vitamin A. E and iron status. Free Radic Biol Med,1994,16(3):339-346.
[46]Miyata T, Taneda S, Kawai R. et al. Identification of pentosidine as a native structure for advanced glycation end products inβ2-microglobulin forming amyloid fibrils in patients with dialysis-related amyloidosis. Proc Nalt Acad Sci USA,1996,93:2353-2358.
[47]Mcgrath L T, Douglas AF, McClean E, et al. Oxidative stress and erythrocyte membrane fluidity in patients undergoing regular HD. Clin Chim Acta,1995.235:179-188.
[48]Hassan MQ. Hussain SA, Zaki MA, et al. Prospective effects of antioxidants against uraemia-induced lipid peroxidation and glutathione depletion in humans. Pharmocol Toxicol.1995.77:407-411.
[49]Tsuzuki D, Sumino K, Yokoyama M, et al. Analysis of 7-ketocholesterol in low density lipoprotein and fatty acid composition in erythrocyte membranes of patients on maintenance hemodialysis and healthy controls. Clinica Chimica Acta,2000.295: 155-168.
[50]叶云洁，倪兆慧，钱家麒,等.终末期肾病微炎症状态和动脉粥样硬化的关系.中 华肾脏病杂志,2004，20(3)：173-176.
[51]Bistrian B, Mccowen KC, Chan S. Protein-energy malnutrition in dialysis patients. J Am Kidney Dis,1999,33(1):172-175.
[52]Kaysen GA. The microinflammatory state in uremia:causes and potential consequences. J Am Soc Nephrol, 2001,12(7):1549-1557.
[53]钱家麒.姚强.慢性肾衰竭透析患者中炎症发生的原因和后果.中国中西医结合肾病杂志,2005，6(8)：435-437.
[54]Schomig M. Eisenhandt A, Ritz E. The microinflammatory state of uremia.Blood Puf. 2000,18(4):327-330.
[55]Tsirpanlis G, Chatzipanagiotou S, Nicolaou C, et al. Microinflammation versus inflammation in chronic renal failurepatiems. Kidney Int,2004,66(12):2093-2098.
[56]Pupim LB, Himmelfarb J, McMonagle E, et al. Influence of initiation of maintenance hemodialysis on biomarkers of inflammation and oxidative stress. Kidney Int,2004, 65(6):2371-2379.
[57]张琳,曾庆波,曾章超.白细胞介素6(IL-6)与肾脏疾病.实用中西医结合临床,2005,5(2)：80-81.
[58]Bologa RM, Levine DM, Parker TS, et al. Interleukin-6 predicts hypoalbuminemia, hypocholesterolemia, and mortality in hemodialysis patients. Am J Kidney Dis,1998, 32(1):107-114.
[59]郑智华,马祖等,郝元涛,等.持续性非卧床腹膜透析患者生存质量影响因素的研究.中华肾脏病杂志,2005,21(5)：290-294.
[60]姚英.ESRD患者C反应蛋白水平与炎症[J].国外医学泌尿系统分册,2003.23(6)：737-742.
[61]George AK. TheMicroinflammatory state in uremia:causes and potential consequences [J]. J Am Soc Nephrol, 2001,12(7):1549-1557.
[62]侯凡凡,任昊,郭志坚,等.单核细胞RAGE表达上调：慢性肾功能衰竭微炎症的机制.中华医学杂志,2004,84(19)：1614-1619.
[63]陈丹.髓过氧化物酶与终末期肾病患者炎症和氧化应激反应[J].肾脏病与透析肾移植杂志,2005,14(5)：469-472.
[64]张道友,孙亚南.慢性肾功能衰竭患者血脂变化.中国动脉硬化杂志.1998.6(3)：249-250.
[65]叶任高.内科学.第6版.北京：人民卫生出版社.2004：264-265.
[66]高学军.刘子栋.慢性肾衰竭血液透析与腹膜透析患者微炎症反应的比较及相关因素分析.中国血液净化.2005.4(4)：208-210.
[67]George AK. TheMicroinflammatory state in uremia:causes and potential consequences[J]. J Am Soc Nephrol.2001.12(7):1549-1557.
[68]Suzuki Y, Ruiz OrtegaM, Lorenzo O, et al. Inflammation and angiotensin Ⅱ [J]. The Internatiomal Jounal ofBiochemistry & CellBilogy.2003.35(6):881-900.
[69]Pankow JS, Folsom AR, Cushman M. et al. Familial and genetic determinants of systemic marker of inflammation:The NHLBI family heart study. Atherosclerosis, 2001,154(7):681-689.
[70]Bergstrom J. Lindholm B, Lacson E. et al. What are the causes and consequences of the chronic inflammatory state in chronic dialysis patients? Semin Dial.2000,13(3): 163-175.
[71]Bergstrom J, Lindholm B. Malnutrition, cardiac disease, and mortality:an integrated point of view. Am J Kidney Dis,1998,32(5):834-841.
[72]Davie SJ, Phillips L. Griffiths AM. et al. An analysis of the effects of increasing delivered dialysis treatment to malnourish peritoneal dialysis patients. Kidney Int. 2000,57(4):1743-1754.
[73]吴惠玲.何国祥,刘建平.等.血浆超敏C反应蛋白水平与冠心病及动脉粥样硬化的关系[J].临床心血管病杂志.2006.22(7)：405-407.
[74]曹礼应.余月明,郭虹,等.维持性血液透析患者C反应蛋白异常与营养、冠心病发病率的关系[J].临床肾脏病杂志,2005,5(2)：82-83.
[75]谢恺庆,杨海波,周红卫.等.尿毒症维持性血液透析患者微炎症状态与脂蛋白(a)的关系.中国动脉硬化杂志,2004,12(4)：469-470.
[76]Locatelli F, Manzoni C, Difilippo S. The importance of convective transport. Kidney Int,2002,80(Suppl):115-120.
[77]Stenvinkel P, Alrestrand A. Inflammation in end2stage renal disease:sources. consequences, and therapy[J]. Seminars in Dialysis,2002.15(5):329-337.
[78]陈江华，何强,徐莹.维持性血液透析患者微炎症状态的认识和防治.中华肾脏病杂志，2005，21(2)：117-118.
[79]刘彬,王殿华.肾脏细胞的凋亡.国外医学生理病理科学与临床分册,1998，18(3).
[80]Bin Y. Timothy I. Graham L, et al. Expression of apoptosis-related genes and proteins in experimental chronic renal scarring[J]. J Am Soc Nephrol,2001,12(2):275-288.
[81]彭黎明,等.细胞凋亡的基础与临床[M].北京：人民卫生出版社,2000，127.
[82]Jerry M, et al. [J]. Sci,1998,281(5381):1322-1326.
[83]Standey J, et al. [J]. Cancer Res,1999,59:1670-1673.
[84]Saito M, et al. [J]. Nat Cell Biol,2000,75:253-261.
[85]Eskes R, et al. [J]. Cell Biol,1998,143:217-224.
[86]Desagher S, et al. [J]. Trends Cell Biol,2000(10):369-377.
[87]刘秉文,等.医学分子生物学[M].北京：中国协和医科大学出版社，2000：247.
[88]Felici M. et al. [J]. Eur J Neurosci,2000,12(3):819-827.
[89]Gobe G, et al. [J]. Cancer Invest,2002,20(3):324-332.
[90]Yang B, et al. [J]. Kidney Int,2002,62(4):1301-1318.
[91]Yang B, et al. [J]. J Am Soc Nephrol,2001,12(2):275-288.
[92]李树全,阳冠明.细胞凋亡及其相关基因蛋白在阿霉素肾病中的作用.中国病理生理杂志,2002,18(6)：704-705.
[93]Wang W, Alex T, Divjak M, et al. Alter signaling and regulatory mechanisms of apoptosis in focal and segmental glomerulosclerosis[J]. J Am Soc Nephrol.2001. 12(7):1422-1433.
[94]杨晓,沈延春,朱忠华，等.大鼠残肾细胞凋亡及凋亡相关基因的动态表达及意义[J].中国病理生理杂志,2007，(23)5：916-920.
[95]陈修,陈维洲,曾贵云.心血管药理学第二版.北京人民卫生出版社,1997：143.
[96]邵福源,王宇卉.分子神经药理学.上海：上海科学技术出版社,2005：453.
[97]Wei J, Quast MJ. Effect of nitricoxide synthesis inhibitor on a hypergly cemiarat model of reversible focal ischemia:detection of excitatory aminoacids release and hydroxylradical formation[J]. Brain Res,1998,791(122):146-156.
[98]梅和珊，王永利.脑缺血时谷氨酸释放机制[J].中国药理学通报，2005，21(4)：393-396.
[99]Kato S, Ndgeshi K, Nawatari K, Kuo CH. A mechanism for glutamate toxicity in the C6 glioma cells involving inhibition of cystine uptake leading to glutathione depletion. Neuroscience 1992,48:903-914.
[100]Simonian NA. Coyle JT. Oxidative stress in neurodegenerative disease. Annu Rev Pharmacol Toxicol 1996.36:83-106.
[101]Nishizawa Y. Glutamate release and neuronal damage in ischemia[J]. Life Sci.2001. 69(4):369-381.
[102]Obrenovitch TP, Urenjak J. Zilkha E. et al. Excitotoxicity in neurological disorders-the glutamate paradox[J]. Int J Dev Neurosci,2000,18(223):281-287.
[103]Lewen A, Matz P, Chan PH. Free radical pathways in CNS injury[J]. J Neurotrauma. 2000,17(10):871-890.
[104]Cao G, Minnamim M, Pei W, Yan C, Chen D, O'Horo C. et al. Intracellular bax translocation after transient cerebral ischemia:implications for a role of the mitochondrial apoptotic signaling pathway in ischemic neuronal death. J Cerebral Blood Flow Metab 2001,21:321-333.
[105]Chan PH. Reactive oxygen radical in signaling and damage in the ischemic brain[J]. J Cereb Blood Flow Metab.2001.21(1):2214.
[106]Fujimura M, Morita Fujimura Y, Kawase M, et al. Manganese super oxidedis mutase mediates the early release of mitochondrial cytochromec and subsequent DNA fragmentation after permanent focal cerebral ischemia in mice [J]. J Neurosci,1999. 19(9):3414-3422.
[107]Green DR. Apoptotic pathway:the roads to ruin [J]. Cell.1998,94(6):695-698.
[108]Yamasaki Y, Matsuo Y, Zagorski J, et al. New therapeutic possibility of Block lngcytokine-induced neutro philchemoattractant on transient ischemic brain damage in rats [J]. Brain Res,1997,759 (1):103-111.
[109]Fujimura M, Morita Fujimura Y, Murakami K, et al. Cytosolicredistri butionofcy to chromec after transient focal cerebralischemia in rats [J]. J Cereb Blood Flow Metab, 1998,18(11):1239-1247.
[110]Martin Villalba A, Herr I. Jeremias I. et al. CD95 ligand (Fas-L/APO-1L) and tumor necrosis factor-related apoptosis-inducing ligand mediate ischemia-induced apoptosis in neurons [J]. J Neurosci,1999(10):3809-3817.
[111]Rosenbaum DM, Gupta G, D Amore J, et al. Fas (CD95/APO-1) plays a role in the pathophysiology of focal cerebral ischemia [J]. J Neurosci Res.2000,61(6):686-692.
[112]Schiepptai A, Remuzzi G. Chronic renal disease as a public health problem: Epidemiology, social and economic implications [J]. Kidney Int Suppl,2005,98:S7-S10.
[113]United States Renal Data System:USRDS 1994 annual data report. Am J Kidney Dis, 1994 (suppl 2),24:88-95.
[114]Toyoda K, Fujii K, Ando T, et al. Incidence, etiology, and outcome of stroke in patients on continuous ambulatory peritoneal dialysis. Cerebrovaseases,2004,17(2-3): 98-105.
[115]overas J. Roquer J. Puig JM. et al. Stroke in renal transplant rccipients epidemiology predietive risk factors and outeome. Clin Transplant.2003,17(1):1-8.
[116]中华医学会肾脏病分会透析移植登记工作组.1999年度全国透析移植登记报告.中华肾脏病杂志,2001,17：77-78.
[117]Port FK, Hullben-Shearon, Wolfe RA, et al.P redialysis blood pressure and mortaily risk in a national sample of maintenance hemo-dialysis patients. Am J Kidney Dis, 1999,33:507-517.
[118]张葆樽.脑血管疾病流行病学.北京：北京人民卫生出版社,2007：721.
[119]Node M. Effect of candesartan cilexetil in rats with chronic renal failure. Kidney Int. 1999,56(3):898-909.
[120]Longa EZ. Weinstain PR, Carlson S, et al. Reversible middle cerebral artery occlusion without cranietony in rats. Stroke,1989,20(1):84-91.
[121]Rogers DC, Campbell CA, Stretton JL, et al. Correllation between motor impairment and infarct volume after permanent and transient middle cerebral artery occlusion in the rat. Stroke 1997,28:2060-2065.
[122]George AK. TheMicroinflammatory state in uremia:causes and potential consequences[J]. J Am Soc Nephrol,2001.12(7):1549-1557.
[123]周凤鑫.组织血液灌注与微循环的病理生理[J].外科理论与实践，2007.12(6)：附5-12.
[124]杜国伟,鲍晓荣.早期慢性肾脏疾病心脏病变的实验研究[J].老年医学与保健,2008,14(1)：26-28.
[125]Zauner A, Daugherty W P. Bullock M R. et al. Brain oxygenation and energy metabolism:part Ⅰ-biological function and pathophysiology. Neurosurgery.2002. 51(2):289-301.
[126]Nisson OG， Brand L, Ungersted U. Detection of brain ischemia using intracerebrchal microdialysis:subaranoid hemorrhage and delayed ischemic deterioration. Neruosurgery, 1999,45(5):1176-84.
[127]毛捷,陈劲草，饶慧蓉.GM1对大鼠脑缺血再灌注损伤的乳酸及葡萄糖含量的影响.安徽医科大学学报，2004,12(39)：449-451.
[128]邵福源.王宇卉.分子神经药理学.上海：上海科学技术出版社，2005：453.
[129]Nisson OG, Brand L. Ungersted U. Detection of brain ischemia using intracerebrchal microdialysis:subaranoid hemorrhage and delayed ischemic deterioration. Neruosurgery, 1999,45(5):1176-84.
[130]Biros MH, Dimlich RVW. Brain lactate during partial global ischemia and reperfusion: Effect of pretreatment with dichloroacetate in a rat model. Am J Emerg Med,1987,5(2):271.
[131]Biros MH, Dimlich RVW. Brain lactate during partial global ischemia and reperfusion: Effect of pretreatment with dichloroacetate in a rat model. Am J Emerg Med,1987.5 (2):271.
[132]Fresu L, Dehpour A. GenazzaniA A. et al. Plasma membrane calcium ATPase isoforms in astrocytes [J]. Glia,1999.28:150-155.
[133]Phillis JW, O'Regan MH. Characterization of models of release of amino acids in the ischemic/reperfusion ratcerebral cortex.Neurochem Int 2003,43:461-467.
[134]Stojavic T, Mrsulja BB. Alterations in synaptomosal membrane Na, K-ATPase of the gerbil cortex and hippocampus following reversible brain ischemia. Metab Brain Dis 1988,3:265-272.
[135]Cao G. Minnami M, Pei W. Intracellular bax translocation after transientcerebral ischemia:implications for a role of the mitochondrial apoptotic signaling pathway in ischemic neuronal death[J]. J Cereb Blood Flow Metab,2001,21(4):321-333.
[136]Lou M. Chen Y. Ding M, et al. Involvement of the mitochondrial ATP sensitive potassium channel in the neuro protective effect of hyperbaric oxygenation after cerebral ischemia [J]. Brain Res Bull.2006.69:109-116.
[137]Sakanak M. Wen TC, Matsuda S, et al. In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci USA,1998,95:4635-4640.
[138]Rogers SA, Talcott M, Hammerman MR. Transplantation of pig met anephroi. ASAIO J.2003,49(1):48-52.
[139]Lian SL, Chen W, Raung SL, et al. Association of immune responses and ischemic brain in farction in rat [J]. Neuroreport,2001,12(9):1943-1947.
[140]Zheng Z, Zhao H, Steinberg GK, et al. Cellular and molecular events underlying ischemia induced neuronal apoptosis [J]. Drug News Perspect,2003,16(12):497-503.
[141]Iadecola C, Alexander M. Cerebral ischemia and inflammation [J]. Curr Opin Neurol, 2001,14(1):89-94.
[142]Green DR. Apoptotic pathway:the roads to ruin [J]. Cell,1998,94(6):695-698.
[143]Vilan N, Castillo J, Davalos A, et al. Proinflammatory cytokines and early neurological worsening in ischemic stroke[J]. Stroke,2000,31(10):2325-2329.
[144]Vaziri ND. Role of oxidative stress and antioxidant therapy in chronic kidney disease and hypertension [J]. Currop in Nephrol Hypertens,2004,13:93.
[145]Margaill I, Plotkine M. Lerouet D. Antioxdent strategies in the treatment of stroke. Free Radic Bio Med 2005,39:429-443.
[146]潘家枯,江明华.生化药理学.上海：复旦大学出版社，2004：91.
[147]方舒东,朱也森.脑缺血再灌注损伤的病理生理研究进展.医学综述,2006,12(18)：4111-6111.
[148]Grynkiewicz G, Poenie M, Tsien RY. A new generation of Ca2+indicators with greatly improved fluorscence properties. J Biol Chem 1985,260:3440-50.
[149]Wei J. Quast MJ. Effect of nitricoxide synthesis inhibitor on a hyper glycemia rat model of reversible focal ischemia:detection of excitatory aminoacids release and hydroxyl radical formation[J]. Brain Res,1998,791 (122):146-156.
[150]梅和珊,王永利.脑缺血时谷氨酸释放机制[J].中国药理学通报，2005,21(4)：393-396.
[151]Butcher SP, Bullock R, Graham DI. Correlation between amino acid release and neuropathologic outcome in rat brain following middle cerebral artery occlusion. Stroke,1990.21(12):17-27
[152]Alessandri B. Bullock R. Glutamate and its receptors in the pathophysiology of brain and spinal cord injuries. Progr Brain Res,1998,116:303.
[153]Iadecola C, Alexander M. Cerebral ischemia and inflammation[J]. Curr Opin Neurol, 2001,14(1):89-94.
[154]Matsumoto K, Lo EH, Pierce AR, et al. Secondary elevation of extra cellular neuro transmitter aminoacids in the reperfusion phase following focal cerebral ischemia [J]. J Cereb Blood Flow Metab,1996,16(1):114.
[155]Nishizawa Y. Glutamate release and neuronal damage in ischemia[J]. Life Sci,2001.69(4):369-381.
[156]Lewen A, Matz P, Chan PH. Freeradical pathways in CNS injury [J]. J Neurotrauma. 2000,17(10):871-890.
[157]Nishizawa Y. Glutamate release and neuronal damage in ischemia[J]. Life Sci,2001. 69(4):369-381.
[158]Zh, Zhao H, Steinberg GK, et al. Cellular and molecular event eng Zs underlying ischemia-induced neuronal apoptosis [J]. Drug News Perspect,2003.16(12):497-503.
[159]Lewen A. Matz P. Chan PH. Free radical pathways in CNS injury[J]. J Neurotrauma. 2000.17(10):871-890.
[160]Zaleska MM. Mercado ML, Chavez J. et al. The development of stroke therapeutics: promising mechanisms and translational challenges [J]. Neuro pharmacology,2009,56(2): 329-341.
[161]Williams AJ, Dave JR, Tortella FC. Neuro protection with the proteasome inhibitor MLN519 in focal ischemic brain injury:Relation to nuclear factoncB (NF-κB), inflammatory gene expression, and leukocyte infilt ration[J]. Neurochem Int, 2006,49 (2):106-112.
[162]Jean WC, Spellman SR, N ussbaum ES, et al. Reperfusion injury after focal cerebral ischemia:the role of inflammation and the therapeutic horizon[J]. Neuro surgery, 1998,43(6):1382-1396.
[163]Yamasak i Y, Itoyama Y, Kogure K. Involvement of cytokine production in pathogenesis of transient cerebral ischemic damage[J]. Keio J M ed,1996,45(3):225-229.
[164]Lao CJ, Lin JG, Kuo JS. Microglia, apoptosis and interleukin-1 beta expression in the effect of sophora japonica on cerebral infarct induced by ischemia-reperfusion in rats. Am J Chin Med.2005,33(3):425-438.
[165]Yamagami H, Kitagawa K, Nagai Y, et al. Higher levels of interleukin-6 are associated with lower echogenicity of carotid artery plaques. Stroke.2004,35(3): 677-681.
[166]Laskowitz DT, Grocott H, Hsia A, et al. Serum markers of cerebral ischemia. Stroke Cerebrovasc. Dis.1998,7(4):234-241.
[167]Relton JK, Martin RC, Russell DA. Peripheral administration of interleukin-1 receptor antagonist inhibits brain damage after focal cerebral ischemia in the rat. Exp Neurol. 1996,138:206-213.
[168]Mohri I, Taniike M, Taniguchi H, et al. ProstaglandinD2-mediated microglia/ astrocyteinte raction enhance sastrogliosis and demyelination in twitcher[J]. J Neurosci,2006,26(16):4383-4393.
[169]梁静,曹灵.慢性肾衰竭微炎症状态的研究进展.中国中西医结合肾病杂志,2008,8(7)：428-430.
[170]刘斌,张强,张宇,等.脑缺血再灌注后不同时间点病理变化与细胞凋亡的研究.陕西医学杂志,2007,4(36)：395-397.
[171]Allsopp TE, Paterson HF, et al. The proto-oncongene Bcl-2 can selectively rescue neurotrophic factor-dependent neurons from apoptosis[J]. Cell,1993,73(2):295-307.
[172]金华,孙抒,于柏艳,等.蛴螬提取物对MCF-7人乳腺癌细胞株凋亡的影响[J].中国病理生理杂志,2008,24(1)：93-96.
[173]Oltvai ZN, Milliaman CL, Kosmeyer SJ. Bcl-2 hererodimerizes in vivo with a conserved homolog Bax, that acclerates programmed cell death[J]. Cell,1993,74(4):609-619.