c-Jun在颅内动脉瘤中的表达及对MMP-9表达调控作用的研究

目的检测c-Jun在颅内动脉瘤中的表达及探讨其对基质金属蛋白酶-9（MMP-91表达调控的意义。方法对15例颅内动脉瘤标本和6例非脑血管病患者的正常脑血管应用免疫组化SP法和实时荧光定量RT-PCR法分别检测脑血管壁组织内c-Jun免疫活性和MMP-9mRNA的表达水平。结果c-Jun免疫活性在颅内动脉瘤壁组织内为1．92±0．51，正常脑血管壁内为0．17±0．41，二者有显著性差异（P〈0．01）。动脉瘤壁组织中MMP-9mRNA的表达是正常血管的10．06倍（P〈0．01）。颅内动脉瘤壁组织内c-Jun的免疫活性和MMP-9mRNA的表达呈正相关（r=．818，P〈0．001）。结论活化后的c-Jun可能通过其结构域内MMP-9结合位点启动MMP-9大量转录而参与颅内动脉瘤的发病机制。     

实验性大鼠脑动脉瘤形成过程中MMP-2、MMP-9表达的动态变化

目的探讨实验性大鼠动脉瘤形成过程中基质金属蛋白酶2(MMP-2)、基质金属蛋白酶9(MMP-9)的表达规律。方法制作肾性高血压大鼠脑动脉瘤模型,通过免疫组化在蛋白水平系统动态观察肾性高血压大鼠脑动脉瘤形成过程中MMP-2、MMP-9表达的变化。结果实验组在术后1 w脑动脉壁即可见MMP-2、MMP-9表达增加,随着术后时间的推移和大鼠血压的增高,其表达也迅速增加,术后1个月基本达最高峰并一直持续至4个月,其中MMP-9较正常状态的增加比MMP-2的表达增加更为显著。对照组脑动脉壁MMP-2、MMP-9也有微弱表达,且MMP-2表达较MMP-9略强。结论脑动脉壁MMP-9、MMP-2特别是MMP-9的过度表达导致的脑动脉壁胶原纤维及内弹力层破坏是脑动脉瘤形成的主要原因之一。     

基质金属蛋白酶与颅内动脉瘤

颅内动脉瘤破裂所致蛛网膜下腔出血致残率和致死率均很高。细胞外基质重塑在颅内动脉瘤的形成和破裂机制中起着重要作用。基质金属蛋白酶是重要的蛋白水解酶,在细胞外基质的降解过程中扮演重要角色。本文综述基质金属蛋白酶最新分类、作用及在颅内动脉瘤发生、发展过中的调节机制及与之相关的治疗最新进展。     

颅内动脉瘤的病理改变与氧自由基

自由基是具有未配对电子的原子或原子团,参与生物体内许多化学反应,是生物体内最重要的电子受体。氧在生物体内通过单电子还原产生化学性质活泼的物质称活性氧(ROS),它们包括超氧负离子自由基(·O2-)、过氧化氢(H2O2)和羟基自由基(·OH)等。氧自由基包括·O2-和·OH。动脉瘤是动脉某一部分的局限性或弥漫性扩张。颅内动脉瘤的主要病理改变有瘤壁内膜、中膜弹力纤维、胶原蛋白的降解和消失,中层平滑肌的凋亡和动脉粥样硬化等改变。近年来,越来越多的文献报道氧自由基与动脉瘤的发生、发展有关。1动脉瘤瘤体氧自由基的表达及其机制Miller…     

颅内动脉瘤的血管生物学研究现状

颅内动脉瘤是目前仍有较高致残率与死亡率的神经外科疾患,目前对它的病因与发病机制机仍不太了解。 一般认为颅内动脉瘤是在长期血流应力作用下发生的血管退行性改变,本文从内皮细胞,基质金属蛋白酶,细胞外 基质三个方面讨论了它们在颅内动脉瘤发病机制中的作用。     

血管结构蛋白、生成因子和基质蛋白酶在颅内动脉瘤破裂进程中的表达规律研究

目的 拟通过同一患者的不同阶段的颅内动脉瘤(IA)血管结构蛋白、生长因子和基质蛋白酶的表达进行分析,探索动脉瘤破裂的分子机制,为IA的早期筛查和预防提供理论依据。方法 采集6名IA患者未破裂动脉瘤、破裂动脉瘤的动脉瘤壁和颞浅动脉血管壁样本。通过qRT-PCR和Western blotting检测3种结构蛋白(III型胶原、纤维连接蛋白和层粘连蛋白)、2种血管生成因子(血管内皮生长因子、碱性成纤维细胞生长因子）和2种基质蛋白酶的表达水平变化趋势。结果 正常血管壁样本（颞浅动脉）中III型胶原、层粘连蛋白、成纤维细胞生长因子和基质金属蛋白酶2呈现高水平表达;未破裂动脉瘤样本中,大多数蛋白趋于中度表达水平;动脉瘤破裂后III型胶原和层粘连蛋白表达水平降低,纤维连接蛋白和血管内皮生长因子表达水平升高。mRNA水平表达与蛋白表达水平基本一致。结论 正常血管壁、未破裂动脉瘤壁和破裂动脉瘤壁中结构蛋白和血管生成因子表现出不同的表达水平和模式。 [国际神经病学神经外科学杂志, 2022, 49(3): 14-20.]     

血管介入与动脉瘤夹闭治疗颅内动脉瘤的临床效果及对患者NF-κB、MMP-9水平的影响

目的 探讨血管介入手术和动脉瘤夹闭术治疗颅内动脉瘤的临床效果以及对患者体内核因子κB(Nuclear Factor κB,NF-κB)、基质金属蛋白酶-9(Matrix metalloproteinases-9,MMP-9)水平的影响。方法 选取2010年1月-2018年3月在本院收治的颅内动脉瘤患者120例,采用数字随机法分为介入组和夹闭组,每组各60例; 对夹闭组患者采用动脉瘤夹闭术进行治疗,对介入组患者采用血管介入术进行治疗,记录2组患者治疗期间的手术时间、术中出血量和住院时间,对2组患者手术后的神经功能情况作出评价,同时对2组患者的手术治疗效果进行评定,检测2组患者手术前后的NF-κB、MMP-9水平,最后观察2组患者治疗期间的并发症发生情况。结果 介入组患者手术时间、术中出血量和住院时间三项手术相关指标均优于夹闭组患者(P<0.05); 介入组患者手术后的神经功能显著优于夹闭组患者术后的神经功能(P<0.05); 介入组患者手术后的疗效分级显著优于夹闭组患者手术后的疗效分级(P<0.05),且介入组患者手术后的NF-κB、MMP-9水平明显低于夹闭组患者手术后(P<0.05); 介入组患者手术后的并发症发生率低于夹闭组患者(P<0.05)。结论 血管介入手术治疗颅内动脉瘤的用时短、创少小,能够提高患者的神经功能,改善NF-κB、MMP-9的水平,总体效果显著且安全性较高。     

基质金属蛋白酶-9和血管内皮生长因子在颅内动脉瘤中的表达

目的通过观察基质金属蛋白酶-9(MMP-9)和血管内皮生长因子(VEGF)在颅内动脉瘤中的表达情况,并且与正常脑动脉血管组织中两者的表达相比较,为研究动脉瘤的发病原因及机制提供线索。方法用免疫组织化学方法对16例经手术和病理证实的脑动脉瘤标本中的MMP-9、VEGF的表达进行检测,同时将7例颞叶癫痫间患者手术切除颞极的颞叶皮层动脉血管组织标本作为相对正常脑动脉血管组织的对照,进行MMP-9、VEGF的表达检测,将所得染色标本在光镜下观察,并用医学图像分析系统进行定量分析。结果7例正常脑动脉血管组织中无MMP-9、VEGF阳性表达,而动脉瘤的MMP-9、VEGF阳性表达率分别为81.2%(13/16)和87.5%(14/16),2组标本相对照具有显著差异(P<0.05);MMP9-在动脉瘤壁内、中、外膜中均有表达,其中外、中膜阳性表达较高;VEGF主要在动脉瘤壁中、外膜表达,而内膜表达较少。结论动脉瘤的发生、生长和破裂是个很复杂的过程,MMP-9及VEGF可能是主要的影响因素之一,两者可能与动脉瘤的发生,增长以及结构维持有关。     

高压氧联合颅内动脉瘤夹闭术对脑动脉瘤患者的疗效评估

目的探讨高压氧联合颅内动脉瘤夹闭术对脑动脉瘤(IA)患者术后NIHSS评分及血清基质金属蛋白酶-9(MMP-9)、胱抑素C(Cys C)水平变化的影响。方法选取2014-01—2016-03我院收治的91例IA患者,按照随机数字表法分为观察组(n=46)与对照组(n=45)。患者入院后均行颅内动脉瘤夹闭术,术后对照组给予常规治疗,观察组在对照组基础上联合高压氧治疗。对比2组术前及术后10dNIHSS评分、血清MMP-9、Cys C水平,术后随访3个月,统计2组预后情况。结果术前2组NIHSS评分及血清MMP-9、Cys C水平比较无显著差异(P0.05),术后10d2组NIHSS评分及血清MMP-9、Cys C水平均较术前显著改善(P0.05),且观察组均低于对照组(P0.05);术后随访3个月,观察组预后情况优于对照组(P0.05)。结论高压氧联合颅内动脉瘤夹闭术治疗IA疗效显著,可有效改善患者神经功能缺损程度及血清MMP-9、Cys C水平。     

PDGF-B与IL-1α对大鼠动脉平滑肌细胞MMP表达影响的实验研究

目的:探讨血小板源性生长因子-B(PDGF)与白介素-1α(IL-1α)对动脉平滑肌细胞基质金属蛋白酶(MMP)-2、9及基质金属蛋白酶的组织抑制因子(TIMP)-1表达的影响。方法:通过免疫组化与RT-PCR方法,研究体外原代培养的大鼠主动脉平滑肌细胞在使用PDGF-B及IL-1α的情况下,MMP-2、9及TIMP-1表达的情况。结果:正常大鼠动脉平滑肌细胞有MMP-2与TIMP-1的表达,但没有MMP-9的表达,单独使用PDGF-B与IL-1α不能诱导MMP-9的表达,但是同时使用即可诱导其表达。结论:在病理情况下,PDCF-B与IL-1α协同作用诱导MMP-9表达,降解胶原蛋白,这可能是颅内动脉瘤形成机制中的重要途径之一。     

Phase-dependent expression of matrix metalloproteinases and their inhibitors in demyelinating canine distemper encephalitis

Matrix metalloproteinases (MMPs) are zinc- and calcium-dependent enzymes that cleave molecules of the extracellular matrix, and thus are able to open the blood-brain-barrier and affect myelin. Their inhibitors (TIMPs) are important candidates for the therapy of demyelinating diseases. To establish an immunohistochemical profile of MMP and TIMP expression in plaque variants in dogs with spontaneous demyelinating distemper encephalitis, paraffin-embedded cerebella were studied employing the avidin-biotin-peroxidase complex method with a panel of nine polyclonal (anti-MMP-1, -3, -7, -9, -12, -13, -14, -TIMP-1, and -2) and two monoclonal antibodies (anti-latent MMP-2, and -MMP-11). All MMPs and TIMPs were prominently up-regulated in acute and subacute non-inflammatory lesions, and double-labeling techniques showed that they were mainly expressed by astrocytes and brain macrophages/microglia. In subacute inflammatory and chronic plaques, a moderate to strong decrease of MMP and TIMP expression compared to acute lesions was observed. In these phases MMP-11, -12, and -13 were still moderately present. In addition to astro- and microglia, invading perivascular mononuclear cells were positive for MMPs and TIMPs. In summary, there seems to be a phase-dependent expression of MMPs and TIMPs in demyelinating canine distemper encephalitis, and an MMP-TIMP imbalance might account for the lesion progression in this disease.     

Effects of age, gender, ethnicity, diurnal variation and exercise on circulating levels of matrix metalloproteinases (MMP)-2 and -9, and their inhibitors, tissue inhibitors of matrix metalloproteinases (TIMP)-1 and -2

BACKGROUND: Circulating metalloproteinases (MMP) and their inhibitors (TIMP) are indices of vascular and cardiac tissue matrix turnover. However, the temporal changes and relationship of these parameters to age, gender, ethnicity and exercise have been poorly defined. We therefore studied these aspects on plasma levels of MMP-2 and -9 and TIMP-1 and -2, as the major metalloproteinases (and their inhibitors) implicated in pathophysiology of vascular disease. METHODS: Venous citrated blood was collected from 93 normal healthy volunteers from four ethnic groups (Afro-Caribbean, South Asian, Caucasian and Far Eastern) for a cross-sectional study. In addition, 20 separate healthy volunteers were studied during supine rest, before and immediately following peak treadmill stress using a Bruce protocol. MMP-2 and -9 and TIMP-1 and -2 were all measured by ELISA. RESULTS: There was a categorical distribution of MMP-2 concentration with individual subjects showing high levels, yet others being undetectable, although these changes were unrelated to age, gender or ethnicity. TIMP-1 and -2 showed a modest negative correlation with age (r=-0.251, p=0.015; r=-0.254, p=0.014). There was a positive correlation between MMP-2 and TIMP-2 (r=0.399, p<0.001), MMP-9 and TIMP-1 (r=0.45, p<0.001) and between TIMP-1 and TIMP-2 (r=0.275, p=0.008). When adjusted for age and gender, there were no significant differences in MMP-2 and TIMP-1 and -2 between the four ethnic groups. MMP-9 was significantly lower in the Far Eastern group compared to the other three ethnic groups (p=0.012). Only TIMP-1 (p=0.042) and TIMP-2 (p=0.024) were significantly altered after exercise. CONCLUSION: Age and exercise both have modest effects on circulating concentrations of TIMP-1 and-2. MMP-9 appears lower in individuals of Far Eastern/Chinese origin regardless of age or gender. The positive association between MMPs and TIMPs suggests that in healthy individuals, enzyme activity may be regulated by this interaction. The reasons for the categorical distribution of MMP-2 remain unclear but this would be important in any studies designed to use circulating MMPs as a surrogate for tissue MMPs around clinical events, such as myocardial infarction or in response to therapies affecting extracellular matrix composition.     

Minocycline suppresses experimental autoimmune encephalomyelitis by increasing tissue inhibitors of metalloproteinases

Matrix metalloproteinases (MMPs) that are secreted by activated T cells play a significant role in degradation of the extracellular matrix around the blood vessels and facilitate autoimmune neuroinflammation; however, it remains unclear how MMPs act in lesion formation and whether MMP‐targeted therapies are effective in disease suppression. In the present study, we attempted to treat experimental autoimmune encephalomyelitis (EAE) by administration of small interfering RNAs (siRNAs) for MMP‐2, MMP‐9, and minocycline, all of which have MMP‐inhibiting functions. Minocycline, but not siRNAs, significantly suppressed disease development. In situ zymography revealed that gelatinase activities were almost completely suppressed in the spinal cords of minocycline‐treated animals, while significant gelatinase activities were measured in the EAE lesions of control animals. However, MMP‐2 and MMP‐9 mRNAs and proteins in the spinal cords of treated rats were unexpectedly upregulated. At the same time, mRNA for tissue inhibitors of MMPs (TIMP)‐1 and ‐2 were also upregulated. The EnzChek Gelatinase/Collagenase assay using tissue containing native MMPs and TIMPs demonstrated that gelatinase activity levels in the spinal cords of treated rats were suppressed to the same level as those in normal spinal cord tissues. Finally, double immunofluorescent staining demonstrated that MMP‐9 immunoreactivities of treated rats were almost the same as those of control rats and that MMP‐9 and TIMP‐1 immunoreactivities were colocalized in the spinal cord. These findings suggest that minocycline administration does not suppress MMPs at mRNA and protein levels but that it suppresses gelatinase activities by upregulating TIMPs. Thus, MMP‐targeted therapies should be designed after the mechanisms of candidate drugs have been considered.     

Matrix metalloproteinases 2 and 9 in human atherosclerotic and non-atherosclerotic cerebral aneurysms

Matrix metalloproteinases 2 and 9 (MMP 2 and -9) have been implicated in the pathogenesis of atherosclerosis and aneurysm formation. The goal of the study was to establish the role of these metalloproteinases in both human atherosclerotic and non-atherosclerotic cerebral aneurysms. Eleven cerebral aneurysms (four atherosclerotic, seven non-atherosclerotic) were immunohistochemically stained for MMP 2 and -9. As controls, atherosclerotic and normal Circle of Willis arteries were similarly immunostained. All specimens were retrieved at autopsy and were paraffin-embedded. In order to evaluate the real MMP 2 and -9 activities, gelatin zymography was also performed in only two available specimens of non-atherosclerotic intracranial aneurysms, because of the relative unavailability of fresh intracranial aneurysm tissue (i.e. reluctance to excise the aneurysm fundus at surgery). Our data establish that MMP 2 and -9 were expressed minimally or not at all in normal Circle of Willis arteries but were strongly expressed in medial smooth muscle cells of atherosclerotic Circle of Willis arteries. In the aneurysm group, both MMP 2 and -9 were strongly expressed in the atherosclerotic aneurysms, but MMP 2 alone was detected in the non-atherosclerotic aneurysms. Zymography revealed a weak enzyme activity correlating to MMP 9 standard recombinant protein. MMP 2 activity was not demonstrated in either specimen. This study shows that the expression of MMP 2 and -9 is associated with atherosclerosis, be it in aneurysmal or non-aneurysmal cerebral vessels but MMP 2 appears to be specifically expressed in aneurysms devoid of atherosclerosis perhaps suggesting a pathogenic role for MMP 2 in the alteration of the extracellular matrix of cerebral arteries during aneurysm formation.     

手术夹闭动脉瘤颈治疗颅内动脉瘤破裂的疗效及安全性

目的观察手术夹闭动脉瘤颈治疗颅内动脉瘤破裂的临床效果和并发症。方法选取82例颅内动脉瘤破裂患者为研究对象,按照住院号单双分成2组,对照组41例予介入治疗,观察组41例予手术夹闭动脉瘤颈治疗,观察治疗后临床效果和并发症情况。结果对照组mRS评分、即刻动脉瘤完全闭塞率、不完全闭塞、复发率均明显高于观察组(P0.05);2组治疗后较治疗前PF、RP、RE均有提高(P均0.05),观察组治疗后较对照组PF、RP、RE改善幅度明显占优(P0.05);2组治疗后GOS评分比较差异无统计学意义(P0.05);对照组脑水肿、脑梗死、颅内出血、脑积水发生率均高于观察组(P0.05),而脑神经损伤比较差异无统计学意义(P0.05)。结论手术夹闭动脉瘤颈治疗颅内动脉瘤破裂临床效果满意。     

基质金属蛋白酶组织抑制因子-1和2在垂体腺瘤中的表达

目的探讨基质金属蛋白酶组织抑制因子(TIMPs)-1和2 的蛋白表达与垂体腺瘤侵袭性的关系。方法采用免疫组化S-P法检测8例正常垂体前叶组织、20例非侵袭性和31例侵袭性垂体腺瘤组织中TIMP-1和TIMP-2的蛋白表达。结果TIMP-1和TIMP-2在正常垂体前叶组织中阳性率均为100.0%,在非侵袭性垂体腺瘤中的阳性率分别为75.0%和80.0%,在侵袭性垂体腺瘤中的阳性率分别为41.9%和38.7%。TIMP-1和TIMP-2在侵袭性垂体腺瘤中的表达强度显著性低于非侵袭性垂体腺瘤和正常垂体前叶组织(P<0.05)。结论垂体腺瘤的侵袭性与TIMP-1和TIMP-2表达水平降低有关,二者可能在调控垂体腺瘤的侵袭性生长过程中起重要作用。     

颅内动脉瘤夹闭术中动脉瘤破裂的危险因素分析

目的 探讨颅内动脉瘤病人夹闭术中动脉瘤破裂的危险因素。方法 回顾性分析2009年7月至2018年7月夹闭术治疗的296例颅内动脉瘤的临床资料。采用多因素logistic回归分析检验术中动脉瘤破裂的影响因素。结果 296例中,夹闭术中发生动脉瘤破裂59例,未破裂237例。多因素logistic 回归分析,年龄≥60岁、Hunt-Hess分级Ⅲ~Ⅴ级、发病至手术时间>3 d、手术器械不佳及手术操作不细致、动脉瘤瘤体血管弹性差及瘤体粘连是术中动脉瘤破裂的独立危险因素（P<0.05）。结论 高龄、Hunt-Hess分级高、发病至手术时间长、分离动脉瘤颈操作不细致、动脉瘤瘤体粘连为颅内动脉瘤病人夹闭术中动脉瘤破裂的主要危险因素     

颅内动脉瘤血管内介入治疗

颅内动脉瘤是严重危害人们健康的一种疾病,其致残率、死亡率高。传统的治疗方法为动脉瘤颈夹闭手术。随着近二十多年动脉瘤介入治疗的飞速发展,该技术现已达到、甚至超过传统动脉瘤颈夹闭手术的疗效。一、动脉瘤栓塞的发展简史最早应用血管内介入治疗颅内动脉瘤的是Serbinenko,1974年他首先用乳胶球囊经血管内治疗动脉瘤；起初闭塞载瘤动脉,后开始栓寒动脉瘤,保留载瘤动脉通畅(?),随后这一技术被很多人使用并取得了一定的效果。尽管可脱卸球囊的应用使血管内治疗颅内动脉瘤成为可能,但由于可脱卸球囊     

基质金属蛋白酶-9及组织基质金属蛋白酶抑制剂-1在脑动静脉畸形组织中的表达及其与出血的关系

目的 研究基质金属蛋白酶-9（matrix metalloproteinase-9,MMP-9）及组织基质金属蛋白酶抑制剂-1（tissue inhibitors of metalloproteinase1,TIMP-1）在脑动静脉畸形（cerebullar arteriovenous malformations,CAVM）患者组织中的表达及其与出血的关系。方法 选取我院2007年5月至2008年9月间收治的48例CAVM患者。按有无出血症状分为出血组和非出血组,并选取24例原发癫患者为正常对照组。分别对其病史、临床症状、影像学表现等进行研究。对患者术中脑组织标本的MMP-9、TIMP-1含量以免疫组化方法进行研究。结果 MMP-9、TIMP-1均表达在胞浆中。MMP-9在正常对照组仅见微量表达;而在CAVM患者组织标本中可见表达明显升高。TIMP-1在CAVM患者组织中表达水平显著高于对照组,与MMP-9表达平行,出血组组与非出血组之间MMP-9、TIMP-1均无统计学差异,但两者之比（MMP-9/TIMP-1）有统计学差异。结论 ①MMP-9可能是导致CAVM血管壁结构不稳定、生长和过度扩张的重要因素,其水平升高可能是TIMP-1表达的促进因素之一;②MMP-9可能对于CAVM患者的出血具有促进作用,TIMP－1有着抑制MMP-9活性的重要作用,是防止CAVM出血的“保护因子”。MMP-9和TIMP-1比例失衡,造成MMP-9相对“过盛”,可能是引起脑动静脉畸形出血的重要机制。     

Dissecting intracranial aneurysm

Summary A case of spontaneous dissecting aneurysm of the right internal carotid and middle cerebral arteries is presented in a 13-year-old boy. The pathogenetic factors incriminated in previously reported cases are reviewed and the pathological findings are discussed. The abnormalities of the internal elastic lamina as seen in this patient have been observed in numerous cases of intracranial dissecting aneurysms. It is concluded that these defects play an important role in the development of dissection.