急性一氧化碳中毒后大鼠脑内小血管变化的初步研究
摘要
背景:急性一氧化碳中毒(Acute carbon monoxide poisoning,ACOP)占全世界中毒性急救的第一位,也是我国发病和死亡人数最多的急性职业中毒。ACOP后能引起机体多器官的损害,其中以大脑受累最严重。部分患者经过数天或数周表现正常或接近正常的“假愈期”后,会再次出现以急性痴呆为主的一组神经,精神症状,称为迟发性脑病(delayed encephalopathy after acute carbon monoxide poisoning, DEACMP),为CO中毒最严重的类型,部分患者遗留永久性神经功能损害。由于该病的发病机制尚未呈阐明,临床治疗只能对症,无法从根本上在有效的时间窗内对DEACMP的发生进行预防并阻遏其进展。近年来CO中毒后引起的血管改变日益引起学者的关注。α-肌动蛋白(α-actin)是血管平滑肌细胞(vessel smooth muscle cell, VSMC)中重要的功能蛋白,在VSMC中特异性表达。α-肌动蛋白表达的变化对于提示VSMC结构和功能的改变有重要意义,是VSMC表型转化的标志。当α-肌动蛋白数量减少时,合成型的平滑肌细胞占优势,细胞合成分泌及增值能力十分旺盛,可以导致血管腔狭窄甚至闭塞。Ⅳ型胶原(collagenⅣ)和弹性蛋白(Elastin)是血管壁细胞外基质的重要成分,对维持血管功能有重要作用。许多研究发现多种脑血管疾病中都伴有Ⅳ型胶原和弹性蛋白的变化,如有研究发现在玻璃样变小动脉的中层和外层发现了Ⅳ型胶原的异常堆积。β-淀粉样蛋白在正常神经细胞及非神经细胞中不断分泌,并向细胞外释放,进入血液和脑脊液,在异常情况下沉积在小血管的管壁上,可引起血管淀粉样变性;沉积在大脑实质成为老年斑,可导致阿尔茨海默病的发生。上述几种物质的异常表达不仅引起血管壁结构的异常变化,而且还导致小动脉对神经调节和生化调节的反应能力减弱,从而引起一系列血管疾病。
目的:本实验建立在动物实验的基础上,动态观察CO中毒后α-肌动蛋白、Ⅳ型胶原、弹性蛋白、β淀粉样蛋白的表达变化和脑组织病理学的变化。探讨CO中毒后脑组织血管壁结构的变化规律,可能为阐明DEACMP的发病机制提供线索,同时也为DEACMP治疗中的血管干预提供实验依据。
方法:健康昆明系雄性大鼠108只,体重180-220g,然后随机均衡分成2组即空气对照组和染毒组,各54只。每组各设9个亚组(时间点):6小时(h)、1天(d)、2d、3d、4d、7d、14d、21d、28d,每个亚组6只大鼠。用单次腹腔注射式染毒法建立CO中毒大鼠模型,对照组腹腔注射等量空气。建立模型后,依各个时间点灌注固定后取苍白球区脑组织。常规HE染色观察脑组织病理及形态学变化,并对小动脉内径和外径进行测量,计算出小动脉硬化指数(SI),比较不同外径小动脉SI的变化;电镜下观察血管壁超微结构的变化;免疫组化法检测不同时间点α-肌动蛋白、Ⅳ型胶原、弹性蛋白、β-淀粉样蛋白的表达变化;数据以均数±标准差表示。统计学处理采用SSPS13.0软件统计,P<0.05有统计学意义,P<0.01有显著统计学意义。
结果:
1.光镜下,脑组织水肿,血管周围间隙增大,有红细胞溢出。晚期可见小动脉血管内膜变粗糙,管壁不规则增厚,血管腔变狭窄。电镜下,晚期可见血管壁平滑肌细胞数量增多,细胞增大呈椭圆形,细胞内粗面内质网增多。
2.染毒组硬化指数早期无明显变化,从第14d开始染毒组外径为30-50μm和50-100μm的小动脉硬化指数明显升高,与对照组比较出现统计学意义(P﹤0.05),至28d达到最高。而外径>100μm的小动脉硬化指数全程变化与对照组比较都无统计学意义。不同外径动脉的硬化指数比较也有统计学差异,外径为30-50μm的血管SI高于其他两种外径的血管(P﹤0.05)。
3.与对照组相比,染毒后早期α-肌动蛋白的表达强度下降,至2d时表达强度最低,3d时表达有所升高,至21d时PU值达到最高。染毒组2d、21d、28d的PU值与对照组的差异有统计学意义(P﹤0.05)。
4.与对照组相比,染毒组早期Ⅳ型胶原的PU值降低,4d时最低,之后呈上升趋势,至28d达到最高。染毒组4d、21d、28d三个时间点的PU值与对照组的差异有统计学意义(P﹤0.05)。
5.与对照组相比,染毒组3d脑实质开始出现β-淀粉样蛋白的阳性表达,7d时表达强度达到最高,之后表达开始下降,至28d时消失。染毒组3d、4d、7d、14d、21d时间点的表达强度与对照组的差异有统计学意义(P﹤0.05)。6.染毒组和对照组的弹性蛋白阳性表达均极低。两者比较后差异无统计学意义(P﹥0.05)。
结论:
1.CO中毒后大鼠脑小血管壁α-肌动蛋白和Ⅳ型胶原的变化,提示了平滑肌细胞和Ⅳ型胶原的增生,说明了CO中毒后大鼠脑小动脉病理改变为类玻璃样变性,并且小动脉外径越小,血管壁增厚越明显。
2.本实验首次发现了CO中毒后大鼠脑组织内β-淀粉样蛋白的动态变化,并且其高峰为染毒后14d,推测CO中毒后的迟发性脑病可能与β-淀粉样蛋白的异常升高有关。
Background: Carbon monoxide is a colorless, odorless, toxic gas, which is the production environment and living environment up to see the asphyxiating gas. Acute carbon monoxide poisoning is the largest number of morbidity and mortality of acute occupational poisoning. ACOP can cause the body after multiple organ damage, of which the most severe brain involvement.Some patients a few days or weeks after the performance of normal or near normal "false Overdue", will appear again to acute dementia, a group of mainly neurological, psychiatric symptoms, known as delayed encephalopathy(delayed encephalopathy after acute carbon monoxide poisoning, DEACMP), which is the most serious type of CO poisoning, some patients left permanent neurological damage. The clinical manifestation is a series of spirit and nerve function disorder, especially acute stupid primarily energetic. Even part of the permanent neurological damage in patients with left. Because the clear pathogenesis has not been discovered, there`s no effective way in clinical treatment of DEACMP and repressor the happening trend. In recent years, caused by CO poisoning caused by vascular changes in the increasing attention of scholars.α-actin in vascular smooth muscle cell is an important functional proteins,which is specifically expressed in the VSMC.α-actin expression in VSMC for the prompt changes in the structure and function is very important, it is a sign of VSMC phenotypic. When the number ofα-actin decreased, the synthesis of the dominant type of smooth muscle cells, cell synthesis and secretion and the added value is very strong, can lead to vascular stenosis or occlusion.Ⅳcollagen and elastin in the vessel wall is an important component of the extracellular matrix.Ⅳcollagen constitutes the main component of basement membrane, Recently some scholars have smaller arteries in the glass-like outer layer of the middle and found abnormal accumulation ofⅣcollagen. Main components of elastic fiber elastin or elastic membrane, the blood vessels flexible. Many studies have found a variety of cerebral vascular diseases are associated with typeⅣcollagen and elastin changes.β-amyloid protein in normal neural cells and non-neuronal cells continuously secreted to the extracellular release into the blood and cerebrospinal fluid, in exceptional cases deposited on the wall of small blood vessels, can cause vascular amyloidosis; deposition Substance into the brain senile plaques that can lead to Alzheimer's disease. The abnormal expression of several substances not only cause the abnormal changes of the vascular wall structure, but also lead to a small artery on the nervous control and regulate biochemical reactions diminished capacity, which led to a series of vascular diseases.
Objective: In this study, based on animal experiments, based on the dynamic observation of CO poisoning,α-actin,Ⅳcollagen, elastin,β-amyloid protein changes and histopathological changes in the brain. CO poisoning of the structure of brain tissue changes of the vascular wall, may elucidate the pathogenesis of DEACMP provide clues, but also for the treatment of vascular intervention DEACMP provide the experimental basis.
Methods:Health Kunming male rats 108, weight 180-220g, and then randomly divided into 2 groups that a balanced air control group and the control group, all 54. Each group has 9 sub-groups (time points):6 hours (h)、1 day (d)、2d、3d、4d、7d、14d、21d、28d, each sub-group of 6 rats. Intraperitoneal injection with a single exposure to CO poisoning in rats was established by the control group were injected with equal amount of air. To model it after the perfusion fixed at each time point, and then to the brain tissue. Immunohistochemical detection basal gangliaα-actin,Ⅳcollagen, elastin,β-amyloid protein changes; conventional HE staining and morphological changes in brain pathology, and small vessels were counted; electron microscope vessel diameter and vessel wall observed ultrastructural changes. Data presented as mean±standard deviation, statistical analysis software used SSPS13.0 statistics, P<0.05 was statistically significant, P <0.01 are statistically significant.
Result:
1. By light microscope, brain edema, blood vessels around the gap increases, a red blood cell overflow. Intima of small arteries can be seen later become rough, irregular wall thickening, vessel lumen narrowed. By electron microscope, shows the late vascular smooth muscle cells increased, increasing the oval cells, the cell rough endoplasmic reticulum
2. Early poisoning group no significant changes, starting from the 14d group and the outer diameter of 30-50μm and 50-100μm small vessel's SI began to increase. compared with the control group there was statistically significant (P <0.05). The diameter> 100μm full of small vessel's SI in poisoning compared with the control group were not statistically significant. Hardening of the arteries of different diameter have significantly different index, diameter of blood vessels for the 30-50μm diameter SI higher than the other two vessels(P﹤0.05).
3. Compared with the control group, early after poisoning the expression ofα-actin decreased,2d group' expression reach the minimum, 3d group expression was increased, to the 21d group reached the peak when the PU. Exposed group 2d、21d、28d of the PU with the control group was statistically significant difference (P <0.05).
4. Compared with the control group, early poisoning group of collagenⅣPU values decrease, 4d the lowest, followed by the rise to the highest 28d. Exposed group 4d、21d、28d PU three time points difference with the control group was statistically significant(P <0.05).
5. In poisoning group, 3d group began to appear when the brain parenchymalβ-amyloid protein expression, 7d group when the highest expression intensity, and then began to decrease expression to 28d group when disappeared. No expression in the control group. Exposed 3d、4d、7d、14d、21d group's expression difference with the control group was statistically significant(P﹤0.05).
6. In poisoning group and control group were very low elasticity of protein expression. Comparison between the two was no significant difference(P﹥0.05).
Conclusion:
1. CO poisoning of small blood vessels in rat brainα-actin and typeⅣcollagen changes, suggesting a smooth muscle cell proliferation and typeⅣcollagen, indicating that the rat brain after CO poisoning, pathological changes in small artery hyalinosis for the class, And the smaller the diameter of small arteries, vascular wall thickening is more obvious.
2. In this study, CO poisoning, first discovered in rat brainβ-amyloid protein expression, and its peak after the exposure to 14d group, speculated that CO poisoning may be delayed encephalopathy andβ-amyloid Abnormalities related to the rise.
目的:本实验建立在动物实验的基础上,动态观察CO中毒后α-肌动蛋白、Ⅳ型胶原、弹性蛋白、β淀粉样蛋白的表达变化和脑组织病理学的变化。探讨CO中毒后脑组织血管壁结构的变化规律,可能为阐明DEACMP的发病机制提供线索,同时也为DEACMP治疗中的血管干预提供实验依据。
方法:健康昆明系雄性大鼠108只,体重180-220g,然后随机均衡分成2组即空气对照组和染毒组,各54只。每组各设9个亚组(时间点):6小时(h)、1天(d)、2d、3d、4d、7d、14d、21d、28d,每个亚组6只大鼠。用单次腹腔注射式染毒法建立CO中毒大鼠模型,对照组腹腔注射等量空气。建立模型后,依各个时间点灌注固定后取苍白球区脑组织。常规HE染色观察脑组织病理及形态学变化,并对小动脉内径和外径进行测量,计算出小动脉硬化指数(SI),比较不同外径小动脉SI的变化;电镜下观察血管壁超微结构的变化;免疫组化法检测不同时间点α-肌动蛋白、Ⅳ型胶原、弹性蛋白、β-淀粉样蛋白的表达变化;数据以均数±标准差表示。统计学处理采用SSPS13.0软件统计,P<0.05有统计学意义,P<0.01有显著统计学意义。
结果:
1.光镜下,脑组织水肿,血管周围间隙增大,有红细胞溢出。晚期可见小动脉血管内膜变粗糙,管壁不规则增厚,血管腔变狭窄。电镜下,晚期可见血管壁平滑肌细胞数量增多,细胞增大呈椭圆形,细胞内粗面内质网增多。
2.染毒组硬化指数早期无明显变化,从第14d开始染毒组外径为30-50μm和50-100μm的小动脉硬化指数明显升高,与对照组比较出现统计学意义(P﹤0.05),至28d达到最高。而外径>100μm的小动脉硬化指数全程变化与对照组比较都无统计学意义。不同外径动脉的硬化指数比较也有统计学差异,外径为30-50μm的血管SI高于其他两种外径的血管(P﹤0.05)。
3.与对照组相比,染毒后早期α-肌动蛋白的表达强度下降,至2d时表达强度最低,3d时表达有所升高,至21d时PU值达到最高。染毒组2d、21d、28d的PU值与对照组的差异有统计学意义(P﹤0.05)。
4.与对照组相比,染毒组早期Ⅳ型胶原的PU值降低,4d时最低,之后呈上升趋势,至28d达到最高。染毒组4d、21d、28d三个时间点的PU值与对照组的差异有统计学意义(P﹤0.05)。
5.与对照组相比,染毒组3d脑实质开始出现β-淀粉样蛋白的阳性表达,7d时表达强度达到最高,之后表达开始下降,至28d时消失。染毒组3d、4d、7d、14d、21d时间点的表达强度与对照组的差异有统计学意义(P﹤0.05)。6.染毒组和对照组的弹性蛋白阳性表达均极低。两者比较后差异无统计学意义(P﹥0.05)。
结论:
1.CO中毒后大鼠脑小血管壁α-肌动蛋白和Ⅳ型胶原的变化,提示了平滑肌细胞和Ⅳ型胶原的增生,说明了CO中毒后大鼠脑小动脉病理改变为类玻璃样变性,并且小动脉外径越小,血管壁增厚越明显。
2.本实验首次发现了CO中毒后大鼠脑组织内β-淀粉样蛋白的动态变化,并且其高峰为染毒后14d,推测CO中毒后的迟发性脑病可能与β-淀粉样蛋白的异常升高有关。
Background: Carbon monoxide is a colorless, odorless, toxic gas, which is the production environment and living environment up to see the asphyxiating gas. Acute carbon monoxide poisoning is the largest number of morbidity and mortality of acute occupational poisoning. ACOP can cause the body after multiple organ damage, of which the most severe brain involvement.Some patients a few days or weeks after the performance of normal or near normal "false Overdue", will appear again to acute dementia, a group of mainly neurological, psychiatric symptoms, known as delayed encephalopathy(delayed encephalopathy after acute carbon monoxide poisoning, DEACMP), which is the most serious type of CO poisoning, some patients left permanent neurological damage. The clinical manifestation is a series of spirit and nerve function disorder, especially acute stupid primarily energetic. Even part of the permanent neurological damage in patients with left. Because the clear pathogenesis has not been discovered, there`s no effective way in clinical treatment of DEACMP and repressor the happening trend. In recent years, caused by CO poisoning caused by vascular changes in the increasing attention of scholars.α-actin in vascular smooth muscle cell is an important functional proteins,which is specifically expressed in the VSMC.α-actin expression in VSMC for the prompt changes in the structure and function is very important, it is a sign of VSMC phenotypic. When the number ofα-actin decreased, the synthesis of the dominant type of smooth muscle cells, cell synthesis and secretion and the added value is very strong, can lead to vascular stenosis or occlusion.Ⅳcollagen and elastin in the vessel wall is an important component of the extracellular matrix.Ⅳcollagen constitutes the main component of basement membrane, Recently some scholars have smaller arteries in the glass-like outer layer of the middle and found abnormal accumulation ofⅣcollagen. Main components of elastic fiber elastin or elastic membrane, the blood vessels flexible. Many studies have found a variety of cerebral vascular diseases are associated with typeⅣcollagen and elastin changes.β-amyloid protein in normal neural cells and non-neuronal cells continuously secreted to the extracellular release into the blood and cerebrospinal fluid, in exceptional cases deposited on the wall of small blood vessels, can cause vascular amyloidosis; deposition Substance into the brain senile plaques that can lead to Alzheimer's disease. The abnormal expression of several substances not only cause the abnormal changes of the vascular wall structure, but also lead to a small artery on the nervous control and regulate biochemical reactions diminished capacity, which led to a series of vascular diseases.
Objective: In this study, based on animal experiments, based on the dynamic observation of CO poisoning,α-actin,Ⅳcollagen, elastin,β-amyloid protein changes and histopathological changes in the brain. CO poisoning of the structure of brain tissue changes of the vascular wall, may elucidate the pathogenesis of DEACMP provide clues, but also for the treatment of vascular intervention DEACMP provide the experimental basis.
Methods:Health Kunming male rats 108, weight 180-220g, and then randomly divided into 2 groups that a balanced air control group and the control group, all 54. Each group has 9 sub-groups (time points):6 hours (h)、1 day (d)、2d、3d、4d、7d、14d、21d、28d, each sub-group of 6 rats. Intraperitoneal injection with a single exposure to CO poisoning in rats was established by the control group were injected with equal amount of air. To model it after the perfusion fixed at each time point, and then to the brain tissue. Immunohistochemical detection basal gangliaα-actin,Ⅳcollagen, elastin,β-amyloid protein changes; conventional HE staining and morphological changes in brain pathology, and small vessels were counted; electron microscope vessel diameter and vessel wall observed ultrastructural changes. Data presented as mean±standard deviation, statistical analysis software used SSPS13.0 statistics, P<0.05 was statistically significant, P <0.01 are statistically significant.
Result:
1. By light microscope, brain edema, blood vessels around the gap increases, a red blood cell overflow. Intima of small arteries can be seen later become rough, irregular wall thickening, vessel lumen narrowed. By electron microscope, shows the late vascular smooth muscle cells increased, increasing the oval cells, the cell rough endoplasmic reticulum
2. Early poisoning group no significant changes, starting from the 14d group and the outer diameter of 30-50μm and 50-100μm small vessel's SI began to increase. compared with the control group there was statistically significant (P <0.05). The diameter> 100μm full of small vessel's SI in poisoning compared with the control group were not statistically significant. Hardening of the arteries of different diameter have significantly different index, diameter of blood vessels for the 30-50μm diameter SI higher than the other two vessels(P﹤0.05).
3. Compared with the control group, early after poisoning the expression ofα-actin decreased,2d group' expression reach the minimum, 3d group expression was increased, to the 21d group reached the peak when the PU. Exposed group 2d、21d、28d of the PU with the control group was statistically significant difference (P <0.05).
4. Compared with the control group, early poisoning group of collagenⅣPU values decrease, 4d the lowest, followed by the rise to the highest 28d. Exposed group 4d、21d、28d PU three time points difference with the control group was statistically significant(P <0.05).
5. In poisoning group, 3d group began to appear when the brain parenchymalβ-amyloid protein expression, 7d group when the highest expression intensity, and then began to decrease expression to 28d group when disappeared. No expression in the control group. Exposed 3d、4d、7d、14d、21d group's expression difference with the control group was statistically significant(P﹤0.05).
6. In poisoning group and control group were very low elasticity of protein expression. Comparison between the two was no significant difference(P﹥0.05).
Conclusion:
1. CO poisoning of small blood vessels in rat brainα-actin and typeⅣcollagen changes, suggesting a smooth muscle cell proliferation and typeⅣcollagen, indicating that the rat brain after CO poisoning, pathological changes in small artery hyalinosis for the class, And the smaller the diameter of small arteries, vascular wall thickening is more obvious.
2. In this study, CO poisoning, first discovered in rat brainβ-amyloid protein expression, and its peak after the exposure to 14d group, speculated that CO poisoning may be delayed encephalopathy andβ-amyloid Abnormalities related to the rise.
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15.Grey E, Bratteli C, Glasser SP. Reduced small artery but not large artery elasticity is an independent risk marker for cardiovascular events[J].Am JHypertens ,2003 ,16 :2652269.
16.Lammie GA,Rakshi J,Rossor MN,et al.Cerebral autosomal dominantarteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL ) - confirmation by cerebral biopsy in 2 cases. ClinNeuropathol.1995, 14(4):201-6.
17.朱光明,张微微,李娟.脑梗死患者脑内不同节段小动脉硬化程度差异的相关性.中华老年心脑血管病杂志,2006,8(1): 31-33.
18.Pan CZ, Li LJ, Yang ZG, et al, A statistical analysis of revelant indicators for cardiovascular state of narcotics. Zhongguo Linchuang Kangfu, 2003;7(7):1031-2.
19.血管平滑肌细胞的表型标志α-SM-Actin的表达与调控的研究进展。数理医药学杂志2001,14(5): 443-445.
20.朱光明,张微微,赵文芳。大鼠局灶性脑缺血再灌注小动脉VSMC表型转化的实验研究[J].中华老年心脑血管病杂志,2004,6: 50-52.
21.Gidday JM, Gasche YG, Copin JC. Leukocyte derived matrix metallo proteinase9 mediates blood brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia [J].Am J Physiol Heart Circ Physiol, 2005, 289 (1Pt2):H558.
22.Lai CH, Kuo KH, Leo JM. Critical role of actin in modulating BBB permeability [J]. Brain Res Brain Res Rev, 2005, 50:7-13.
23.魏汝云,徐婧婧.基质金属蛋白酶29与脑缺血损伤的关系研究进展[J].中国现代医学杂志,2007,17(5):565.
24.Vardy ER, Catto AJ, Hooper NM. Proteolytic emeehanisms inamyloid- beta metabolism: therapeutic implications for Alzheimer’s disease.Trends Mol Med,2005, 11( 10 ): 464- 472.
25.Yamaguchi H, Yamazaki T, Lemere CA, et al.β- amyloid is focally deposited within the outer basement membrane in the amyloid angiopathy of Alzheimer's disease.An immunoelectron microsco pic study. AM. J. Pathol.1992, 141: 249-259.
26.Cole GM, Frautschy SA. Alzheimer's amyloid story finds its star [ J].Trends Mol Med, 2006, 12( 9 ): 395-6.
27.Wirths O, Multhaup G, Bayer TA. A modified beta- amyloid hypothesis: Intraneuronal accumulation of the beta- amyloid peptide-the first step of a fatal cascade [J ]. J Neurochem, 2004, 91: 513-520.
28.Effect of hypoxia/ischemia and hypoxic preconditioning/reperfusion on expression of some amyloid - degrading enzymes. Ann N Y Acad Sci,2004,1035: 21 - 33.
29.薛素芳,贾建平.缺氧及复氧对淀粉样前体蛋白-去整合蛋白和金属蛋白水解酶10和淀粉样β分泌酶蛋白表达的影响.中风与精神杂志,2006,6(23):267-269. 30.郑莹,闫福岭.脑缺血对脑内β-淀粉样蛋白清除的影响[J].中国脑血管病杂志,2007,4(4): 186-190.
31.Oh-hashi K,Nagai T,Tanaka T,et al.Determination of hypoxic effect on neprilysin activity in human neuroblastoma SH-SY5Y cells using a novel HPLC method. Biochem Biophys Res Commun,2005,334(2):380-386.
32.Coulson E J, Paliga K, Beyreuther K, et al. What the evolution of the amyloid protein precursor supergene family tells us about its function [ J ]. Neurochem Int, 2000,36(3): 175-184.
33.Delacourte A, Sergeant N, WattezA, et al. Tau aggregation in the hippocampal formation: an aging or a pathological process? [ J ].Exp J Gerontol, 2002, 37( 10- 11): 1291-1296.
1.Pantoni L, Simoni M. Pathophy of cerebra small vessels in vascular cognitive impairment. Int Psychogeriatr, 2003, 15:59-65.
2.Bamford J,Sandercock P,Jones L, et al.The nature history of lacunar infarction:the Oxfordshire Community Stroke Project. Stroke, 1987, 18(3): 545-551.
3.Lamnie GA, Brannan F, Slattery J, et al. Nonhypertensive cerebral small-vessel disease. An Autopsy study [J]. Stroke, 1997, 28:2222-2229.
4.张在强.累及中枢神经系统的小血管病.中国卒中杂志,2006,2:151-158.
5.Kinkel WR,Jacobs L, Polachini I, et al.Subcortical arteriosclerotic encephalopathy ( Binswanger’s disease ). Computed tomographic,nuclear magnetic resonance, and clinical corrclations[J]. Arch Neurol, 1985,42: 951-959.
6.刘冬戈,尤发广,韦嘉湖等. Binswanger病的临床病理观察[J].中华老年医学杂志,1995,14: 28-31.
7.De Leeuw FE, De Groot JC, Oudkerk M, et al. Aortic atherosclerosis at middle age predicts cerebral white matter lesions in the elderly. Stroke, 2000, 31: 425-429.
8.Gamble CN. The pathogenesis of arteriolosclerosis[J]. Am J Pathol, 1986,122: 410 -420.
9.Lin Jin Xi, Tomimoto H, Akiguchi I, et al. Vascular Cell Componcents of the Medullary Arteries in Binswanger’s Disease Brains: A Morphometric and Immunoelectron Microscopic study [ J ]. Stroke, 2000, 31:1831-1842.
10.张微微.人脑小动脉玻璃样变细胞外间质免疫组化研究[J].中国临床康复,2003,7(13):1886- 1887.
11.王志勇,邹祖玉,刘维新.血管平滑肌细胞的表型标志α-SM-actin的表达与调控的研究进展.数理医药学杂志,2001,14(5):443- 445.
12.Yoshimura M, Yamanouchi H,Kuauhara S,et al. Dementia in cerebral amyloid angiopathy:a clinicopathological study. J Neurol, 1992, 239:441-450.
13.Johansson BB. Vascular mechanisms in hypertensive cerebrovascular disease [J]. J Cardiovasc Pharmacol, 1992, 19(Suppl 3 ): S11-S15.
14.Lammie A. The role of oedema in lacune formation [J]. Cerebrovasc Dis, 1998, 8:246.
15.Wardlaw JM, Sandercock PA, Dennis MS, et al. Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, anddementia? [J]. Stroke, 2003, 34: 806-812.
16.Pantoni L, Garcia JH. Pathogenesis of leukoaraiosis:a review[J]. Stroke, 1997,28: 652-659.
17.Knottnerus IL, Ten Cate H, Lodder J, et al. Endothelial dysfunction in lacunar stroke:a systematic review[J]. Cerebrovasc Dis,2009, 27:519-526.
18.Greenberg,S.M.Cerebral amyloid angiopathy: prospects for Clinical diagnosis and treatment. Neurology,1998,51:690-694.
19.Yamada M. Cerebral amyloid angiopathy: An overview. Neuropathology, 2000, 20(1):8-22.
20.Tolar M,Keller JN,ChanS,et al.Truncated apolipoproteinE(apoE) causes increased intracellular calcium and may mediate apoE neurotoxicity. J Neurosci,1999, 19( 16 ): 7100-7110.
21.Basckai BJ, Xia MQ, Strickland DK, et al. The endocytic receptor, LRP, also mediates neuronal calcium signaling via NMDA receptors. Proc Natl Acad Sci USA, 2000,97: 11551-11556.
22.Van Nostrand WEl. Pathogenic effects of cerebral amyloid angiopathy mutations in the amyloid beta2 protein precursor [ J ]. Ann N Y Acad Sci, 2002, 977: 258-265.
23.Yamaguchi H, Yamazaki T, Lemere CA, et al.β-amyloid is focally deposited within the outer basement membrane in the amyloid angiopathy of Alzheimer's disease. An immunoelectron microscopic study. AM. J. Pathol. 1992,141:249-259.
24.Rhodin J, Thomas T, Clark L, et al. In vivo cerebrovascular actions of amyloid beta-peptides and the protective effect of conjugated estrogens. J- Alzheimers- Dis. 2003,5(4):275-86.
25.Greenberg SM. Cerebral amyloid angiopathy and vessel dysfunction. Cerebrovasc - Dis. 2002, 13 Suppl 2: 42 - 47.
26.Holton JL, Lashley T, Ghiso J, et al. Fmilial Danish dementia: A novel form of cerebral amyloidosis associated with deposition of both amyloid- Dan and amyloid- beta. J Neuropathol Exp Neuro, 2002, 61:254-67.
27.Heraig MC, Van Nostrang WE, Jucker M. Mechanism of cerebral beta- amyloid angiopathy:murine and cellular models [J ]. Brain Pathol, 2006, 16: 40-54.
28.张微微,黄勇华,魏东宁等。脑淀粉样血管病和脑小动脉玻璃样变性的病理学对比研究[J].中华老年心脑血管病杂志,2003,5:312-314.
29.Yamada M. Cerebral amyloid angiopathy and gene polymorphisms [ J ]. J Neuros Sci,2004,216: 41-44.
30.Miller JH, Wardlaw JM, Lammie GA. Intracerebral haemorrhage and cerebral amyloid angiopathy: CT features with pathological correlation. Clin Radiol, 1999, 54: 422-429.
31.李晓兰,杨全,张翱.脑淀粉样血管病脑出血的CT诊断(附9例报告).实用放射学杂志,2005,21: 434-436.
32.Dichgans M. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephathy. Phenotypic and mutational spectrum.J Neurol Sci, 2002, 203- 204:77-80.
33.Bousser MG, Tournier- Lasserve E. Summary of the proceedings of the first international workshop on CADASIL.Stroke, 1994, 25: 704～707.
34.Ruchoux M, Chabriat H, Bousser MG, et al. Presence of ultrastructural arterial lesions in muscleand skin vessels of patients with CADASIL. Stroke, 1994, 25:2291～2292
35.Lechner-scott J, Engelter S, Steck AJ, et al. Patient with cerebral autosomal dominat arteriopathy with subcortical infarcts and leucoencephalopathy(CADASIL) confirmed by sural nerve biopsy. J Neurol Neurosurg Psychiatry, 1996, 60: 235～236
36.LinhartA, Lubanda JC, Palecek T, et al. Cardiac manifestations in Fabry disease [J ]. J Inherit Metab Dis,2001,24(suppl 2):75-78.
2.Park S, Choi S II. Chorea following acute carbon monoxide poisoning [ J ]. Yonsei Med, 2004, 45: 363-366.
3.Thom S R, Bhopale V M, Fisher D et al. Delayed neuropathology after carbon monoxide poisoning is immune-mediated. Proc Natl Acad Sci U S A, 2004, 101 ( 37 ): 13660-5.
4.Wang X, Wang X, Wen T et al. Hemorheological changes in cerebral circulation of rabbits with acute carbon monoxide poisoning. Clin Hemorheol Microcirc. 2009; 43( 4 ): 271-82.
5.Yoshimura M, Yamanouchi H, Kuauhara S, et al. Dementia in cerebral amyloid angiopathy: a clinicopathological study. J Neurol, 1992, 239: 441-450.
6.Johansson BB. Vascular mechanisms in hypertensive cerebrovascular disease. J Cardiovase Pharnacol, 1992, 19 ( Suppl3 ): 511-515.
7.Borneborke M, Haan J, MaaSchieman MLC, et al. Hereditary cerebral hemorrhage with amyloidosis2Dutch type ( HCHWAD ) : a review of clinical, radiologic and genetic aspects [J ]. Brain Pathol ,1996, 6:1112-114.
8.张微微,黄勇华,魏东宁等。脑淀粉样血管病和脑小动脉玻璃样变性的病理学对比研究[J].中华老年心脑血管病杂志,2003,5: 312-314.
9.张伟,卢德宏.小血管,大问题.中国卒中杂志,2006,11:809.
10.Miao Q,PalonevaT,Tuisku S,et al.Arterioles of the lenticular nucleus in CADASIL. Stroke, 2006, 37: 2242-2247.
11.申洪、陆药丹.免疫组织化学染色的定量方法研究.生物医学工程杂志.1993;10 (4):281-284.
12.申洪.免疫组织化学染色定量方法研究(Ⅲ).中国组织化学与细胞化学杂志. 1995; (1):89-91.
13.Lin Jin Xi, Tomimoto H, Akiguchi I, et al. Vascular Cell Componcents of the Medullary Arteries in Binswanger’s Disease Brains: A Morphometric and Immunoelectron Microscopic study [ J ]. Stroke, 2000, 31: 1831- 1842.
14.Rizzoni D, Porteri E , Boari GE , et al. Prognostic significance of small2artery structure in hypertension [J]. Circulation, 2003, 108 : 223022235.
15.Grey E, Bratteli C, Glasser SP. Reduced small artery but not large artery elasticity is an independent risk marker for cardiovascular events[J].Am JHypertens ,2003 ,16 :2652269.
16.Lammie GA,Rakshi J,Rossor MN,et al.Cerebral autosomal dominantarteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL ) - confirmation by cerebral biopsy in 2 cases. ClinNeuropathol.1995, 14(4):201-6.
17.朱光明,张微微,李娟.脑梗死患者脑内不同节段小动脉硬化程度差异的相关性.中华老年心脑血管病杂志,2006,8(1): 31-33.
18.Pan CZ, Li LJ, Yang ZG, et al, A statistical analysis of revelant indicators for cardiovascular state of narcotics. Zhongguo Linchuang Kangfu, 2003;7(7):1031-2.
19.血管平滑肌细胞的表型标志α-SM-Actin的表达与调控的研究进展。数理医药学杂志2001,14(5): 443-445.
20.朱光明,张微微,赵文芳。大鼠局灶性脑缺血再灌注小动脉VSMC表型转化的实验研究[J].中华老年心脑血管病杂志,2004,6: 50-52.
21.Gidday JM, Gasche YG, Copin JC. Leukocyte derived matrix metallo proteinase9 mediates blood brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia [J].Am J Physiol Heart Circ Physiol, 2005, 289 (1Pt2):H558.
22.Lai CH, Kuo KH, Leo JM. Critical role of actin in modulating BBB permeability [J]. Brain Res Brain Res Rev, 2005, 50:7-13.
23.魏汝云,徐婧婧.基质金属蛋白酶29与脑缺血损伤的关系研究进展[J].中国现代医学杂志,2007,17(5):565.
24.Vardy ER, Catto AJ, Hooper NM. Proteolytic emeehanisms inamyloid- beta metabolism: therapeutic implications for Alzheimer’s disease.Trends Mol Med,2005, 11( 10 ): 464- 472.
25.Yamaguchi H, Yamazaki T, Lemere CA, et al.β- amyloid is focally deposited within the outer basement membrane in the amyloid angiopathy of Alzheimer's disease.An immunoelectron microsco pic study. AM. J. Pathol.1992, 141: 249-259.
26.Cole GM, Frautschy SA. Alzheimer's amyloid story finds its star [ J].Trends Mol Med, 2006, 12( 9 ): 395-6.
27.Wirths O, Multhaup G, Bayer TA. A modified beta- amyloid hypothesis: Intraneuronal accumulation of the beta- amyloid peptide-the first step of a fatal cascade [J ]. J Neurochem, 2004, 91: 513-520.
28.Effect of hypoxia/ischemia and hypoxic preconditioning/reperfusion on expression of some amyloid - degrading enzymes. Ann N Y Acad Sci,2004,1035: 21 - 33.
29.薛素芳,贾建平.缺氧及复氧对淀粉样前体蛋白-去整合蛋白和金属蛋白水解酶10和淀粉样β分泌酶蛋白表达的影响.中风与精神杂志,2006,6(23):267-269. 30.郑莹,闫福岭.脑缺血对脑内β-淀粉样蛋白清除的影响[J].中国脑血管病杂志,2007,4(4): 186-190.
31.Oh-hashi K,Nagai T,Tanaka T,et al.Determination of hypoxic effect on neprilysin activity in human neuroblastoma SH-SY5Y cells using a novel HPLC method. Biochem Biophys Res Commun,2005,334(2):380-386.
32.Coulson E J, Paliga K, Beyreuther K, et al. What the evolution of the amyloid protein precursor supergene family tells us about its function [ J ]. Neurochem Int, 2000,36(3): 175-184.
33.Delacourte A, Sergeant N, WattezA, et al. Tau aggregation in the hippocampal formation: an aging or a pathological process? [ J ].Exp J Gerontol, 2002, 37( 10- 11): 1291-1296.
1.Pantoni L, Simoni M. Pathophy of cerebra small vessels in vascular cognitive impairment. Int Psychogeriatr, 2003, 15:59-65.
2.Bamford J,Sandercock P,Jones L, et al.The nature history of lacunar infarction:the Oxfordshire Community Stroke Project. Stroke, 1987, 18(3): 545-551.
3.Lamnie GA, Brannan F, Slattery J, et al. Nonhypertensive cerebral small-vessel disease. An Autopsy study [J]. Stroke, 1997, 28:2222-2229.
4.张在强.累及中枢神经系统的小血管病.中国卒中杂志,2006,2:151-158.
5.Kinkel WR,Jacobs L, Polachini I, et al.Subcortical arteriosclerotic encephalopathy ( Binswanger’s disease ). Computed tomographic,nuclear magnetic resonance, and clinical corrclations[J]. Arch Neurol, 1985,42: 951-959.
6.刘冬戈,尤发广,韦嘉湖等. Binswanger病的临床病理观察[J].中华老年医学杂志,1995,14: 28-31.
7.De Leeuw FE, De Groot JC, Oudkerk M, et al. Aortic atherosclerosis at middle age predicts cerebral white matter lesions in the elderly. Stroke, 2000, 31: 425-429.
8.Gamble CN. The pathogenesis of arteriolosclerosis[J]. Am J Pathol, 1986,122: 410 -420.
9.Lin Jin Xi, Tomimoto H, Akiguchi I, et al. Vascular Cell Componcents of the Medullary Arteries in Binswanger’s Disease Brains: A Morphometric and Immunoelectron Microscopic study [ J ]. Stroke, 2000, 31:1831-1842.
10.张微微.人脑小动脉玻璃样变细胞外间质免疫组化研究[J].中国临床康复,2003,7(13):1886- 1887.
11.王志勇,邹祖玉,刘维新.血管平滑肌细胞的表型标志α-SM-actin的表达与调控的研究进展.数理医药学杂志,2001,14(5):443- 445.
12.Yoshimura M, Yamanouchi H,Kuauhara S,et al. Dementia in cerebral amyloid angiopathy:a clinicopathological study. J Neurol, 1992, 239:441-450.
13.Johansson BB. Vascular mechanisms in hypertensive cerebrovascular disease [J]. J Cardiovasc Pharmacol, 1992, 19(Suppl 3 ): S11-S15.
14.Lammie A. The role of oedema in lacune formation [J]. Cerebrovasc Dis, 1998, 8:246.
15.Wardlaw JM, Sandercock PA, Dennis MS, et al. Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, anddementia? [J]. Stroke, 2003, 34: 806-812.
16.Pantoni L, Garcia JH. Pathogenesis of leukoaraiosis:a review[J]. Stroke, 1997,28: 652-659.
17.Knottnerus IL, Ten Cate H, Lodder J, et al. Endothelial dysfunction in lacunar stroke:a systematic review[J]. Cerebrovasc Dis,2009, 27:519-526.
18.Greenberg,S.M.Cerebral amyloid angiopathy: prospects for Clinical diagnosis and treatment. Neurology,1998,51:690-694.
19.Yamada M. Cerebral amyloid angiopathy: An overview. Neuropathology, 2000, 20(1):8-22.
20.Tolar M,Keller JN,ChanS,et al.Truncated apolipoproteinE(apoE) causes increased intracellular calcium and may mediate apoE neurotoxicity. J Neurosci,1999, 19( 16 ): 7100-7110.
21.Basckai BJ, Xia MQ, Strickland DK, et al. The endocytic receptor, LRP, also mediates neuronal calcium signaling via NMDA receptors. Proc Natl Acad Sci USA, 2000,97: 11551-11556.
22.Van Nostrand WEl. Pathogenic effects of cerebral amyloid angiopathy mutations in the amyloid beta2 protein precursor [ J ]. Ann N Y Acad Sci, 2002, 977: 258-265.
23.Yamaguchi H, Yamazaki T, Lemere CA, et al.β-amyloid is focally deposited within the outer basement membrane in the amyloid angiopathy of Alzheimer's disease. An immunoelectron microscopic study. AM. J. Pathol. 1992,141:249-259.
24.Rhodin J, Thomas T, Clark L, et al. In vivo cerebrovascular actions of amyloid beta-peptides and the protective effect of conjugated estrogens. J- Alzheimers- Dis. 2003,5(4):275-86.
25.Greenberg SM. Cerebral amyloid angiopathy and vessel dysfunction. Cerebrovasc - Dis. 2002, 13 Suppl 2: 42 - 47.
26.Holton JL, Lashley T, Ghiso J, et al. Fmilial Danish dementia: A novel form of cerebral amyloidosis associated with deposition of both amyloid- Dan and amyloid- beta. J Neuropathol Exp Neuro, 2002, 61:254-67.
27.Heraig MC, Van Nostrang WE, Jucker M. Mechanism of cerebral beta- amyloid angiopathy:murine and cellular models [J ]. Brain Pathol, 2006, 16: 40-54.
28.张微微,黄勇华,魏东宁等。脑淀粉样血管病和脑小动脉玻璃样变性的病理学对比研究[J].中华老年心脑血管病杂志,2003,5:312-314.
29.Yamada M. Cerebral amyloid angiopathy and gene polymorphisms [ J ]. J Neuros Sci,2004,216: 41-44.
30.Miller JH, Wardlaw JM, Lammie GA. Intracerebral haemorrhage and cerebral amyloid angiopathy: CT features with pathological correlation. Clin Radiol, 1999, 54: 422-429.
31.李晓兰,杨全,张翱.脑淀粉样血管病脑出血的CT诊断(附9例报告).实用放射学杂志,2005,21: 434-436.
32.Dichgans M. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephathy. Phenotypic and mutational spectrum.J Neurol Sci, 2002, 203- 204:77-80.
33.Bousser MG, Tournier- Lasserve E. Summary of the proceedings of the first international workshop on CADASIL.Stroke, 1994, 25: 704～707.
34.Ruchoux M, Chabriat H, Bousser MG, et al. Presence of ultrastructural arterial lesions in muscleand skin vessels of patients with CADASIL. Stroke, 1994, 25:2291～2292
35.Lechner-scott J, Engelter S, Steck AJ, et al. Patient with cerebral autosomal dominat arteriopathy with subcortical infarcts and leucoencephalopathy(CADASIL) confirmed by sural nerve biopsy. J Neurol Neurosurg Psychiatry, 1996, 60: 235～236
36.LinhartA, Lubanda JC, Palecek T, et al. Cardiac manifestations in Fabry disease [J ]. J Inherit Metab Dis,2001,24(suppl 2):75-78.