基质金属蛋白酶表达和MVD计数与垂体腺瘤侵袭性的关系研究

目的研究基质金属蛋白酶表达和微血管密度(MVD)计数与垂体腺瘤侵袭性相关性。方法选取垂体腺瘤手术标本41例,分为侵袭组(18例)和非侵袭组(23例)。采用免疫组化法检测MMP-2在两组中的表达水平,并计数垂体腺瘤组织中MVD。结果MMP-2在侵袭组和非侵袭组表达阳性率分别为72.2%(13/18)、26.1%(6/23),两组比较有显著性差异(P<0.05);MVD计数在侵袭组和非侵袭组分别为50.51、13.41,两组比较有显著性差异(P<0.05);侵袭性垂体腺瘤中MMP-2的表达水平与MVD计数呈正相关(P=0.000)。结论MMP-2和MVD表达与垂体腺瘤侵袭性密切相关。     

Ki-67、MMP-9蛋白表达与垂体腺瘤侵袭性的相关性研究

目的 检测细胞核内增殖抗原Ki-67与基质金属蛋白酶-9(MMP-9)在侵袭性、非侵袭性及复发垂体腺瘤中的表达,探讨其与垂体腺瘤侵袭性及肿瘤复发的相关性.方法 免疫组化SP法对86例垂体腺瘤患者标本的Ki-67、MMP-9的表达进行检测.结果 侵袭性垂体腺瘤的Ki-67、MMP-9蛋白表达明显高于非侵袭性垂体腺瘤(P＜0.01);侵袭性腺瘤复发组Ki-67、MMP-9蛋白表达明显高于侵袭性腺瘤非复发组(P＜0.01),且Ki-67、MMP-9蛋白在垂体腺瘤中表达呈正相关.结论 Ki-67、MMP-9蛋白表达增高与侵袭性垂体腺瘤的发生及术后复发存在相关性,且两者在垂体腺瘤的侵袭性生长中可能起协同作用.     

MMP-9、HPA及CD34在侵袭性垂体腺瘤中表达的研究

目的检测基质金属蛋白酶-9(MMP-9)、乙酰肝素酶(HPA)及CD34在侵袭性和非侵袭性垂体腺瘤中的表达,探讨其与肿瘤侵袭发生的关系及它们之间的相关性。方法用免疫组化SP法和RT-PCR方法对63例垂体腺瘤患者标本的MMP-9、HPA及CD34的表达进行检测,记数CD34标记的肿瘤内微血管密度(MVD)。结果63例标本中,34例为侵袭性垂体腺瘤,29例为非侵袭性垂体腺瘤,免疫组化显示,侵袭性垂体腺瘤的MMP-9和HPA阳性表达率及强阳性率均高于非侵袭性垂体腺瘤(P均<0.01);侵袭性垂体腺瘤中微血管密度(MVD)也明显高于非侵袭性垂体腺瘤(P(0.01)。RT-PCR法显示,侵袭性垂体腺瘤组MMP-9及HPAmRNA的表达明显高于非侵袭性垂体腺瘤组(P均<0.01);侵袭性腺瘤组中MMP-9与HPAmRNA的表达成正相关(r=0.65,P<0.05),非侵袭性腺瘤组中MMP-9与HPAmRNA的表达无明显相关性(r=-0.32,P>0.05)。结论MMP-9、HPA高表达及高MVD与垂体腺瘤的侵袭性密切相关。MMP-9、MVD和HPA可以作为判别垂体腺瘤侵袭性的有效参考指标。在肿瘤侵袭过程中HPA可能与MMP-9的产生有关。     

MMP-2及MMP-9表达在侵袭性垂体腺瘤中的生物学意义

目的本研究的目的是探讨基质金属蛋白酶-2(matrix metalloproteinase 2, MMP-2)及基质金属蛋白酶-9(matrix metalloproteinase 9, MMP-9)的表达与侵袭性垂体腺瘤相关性研究.以寻找垂体腺瘤侵袭性可能的发病机理.方法用免疫组化方法对54例垂体瘤患者的组织标本进行研究.并对其中16例患者采用逆转录-聚合酶链反应(RT-PCR)的方法对MMP-2及MMP-9 mRNA的表达进行分析.结果 54例垂体瘤患者中,有32例女性,22例男性.平均年龄为49.9岁(从18～76岁).其中,12例为侵袭性垂体腺瘤,42例为非侵袭性垂体腺瘤.免疫组化显示,侵袭性垂体腺瘤的MMP-2及MMP-9的表达明显高于非侵袭性垂体腺瘤(3.9±0.5; 2.3±0.2;P<0.01)和(4.1±0.4; 2.6±0.2; P<0.01).MMP-2及MMP-9的表达与MIB-1的表达无明显相关性(r=–0.05; P>0.05).侵袭性垂体腺瘤MMP-2及MMP-9 mRNA的表达,明显高于非侵袭性垂体腺瘤[(59.7±12.5)%; (33.3±5.4)%, P<0.05] 及[(68.2±15.3)%; (21.8±8.2)%; P<0.05] .结论 MMP-2及MMP-9的高表达与肿瘤的侵袭性密切相关.但与肿瘤的大小及分泌功能无明显关系.MMP-2及MMP-9可以作为肿瘤侵袭性一项有效的指标.肿瘤的侵袭性和增殖之间可能存在不同的生物学机制.     

MMP-2及CD147在侵袭性垂体腺瘤中的表达及其相互关系的研究

目的检测基质金属蛋白酶(MMP-2)及CD147在侵袭性和非侵袭性垂体腺瘤中的表达,以探讨其与肿瘤侵袭发生的关系及两者之间的相关性。方法用免疫组化SP法和RTPCR方法对55例垂体腺瘤患者标本MMP2及CD147的表达进行检测。结果免疫组化显示,侵袭性垂体腺瘤的MMP-2强阳性及阳性表达率明显高于非侵袭性垂体腺瘤(65.6%和93.8%,13.0%和43.5%,P<0.05),CD147强阳性及阳性表达率明显高于非侵袭性垂体腺瘤(53.1%和96.9%,21.7%和52.2%,P<0.01)。侵袭性垂体腺瘤组MMP-2及CD147mRNA的表达(1.126±0.081,0.887±0.043,P<0.01),明显高于非侵袭性垂体腺瘤组(0.425±0.083,0.179±0.051,P<0.01)。侵袭性腺瘤组中MMP2与CD147的表达成正相关(r=0.73,P<0.05),非侵袭性腺瘤组中MMP-2与CD147的表达无明显相关性(r=0.34,P>0.05)。结论MMP2及CD147的高表达与垂体腺瘤的侵袭性密切相关。MMP-2和CD147可以作为垂体腺瘤侵袭性的2项有效指标。在肿瘤侵袭过程中CD147与MMP-2的产生关系密切。     

MMP-9、VEGF和p16在垂体腺瘤中的表达及其与该腺瘤侵袭性的相关性研究

目的研究基质金属蛋白酶-9(MMP-9)、血管内皮细胞生长因子(VEGF)和p16在侵袭性和非侵袭性垂体腺瘤中的表达及其与垂体腺瘤侵袭性的相关性。方法用免疫组化方法检测MMP-9、VEGF和p16在30例侵袭性和24例非侵袭性垂体腺瘤中的表达水平,并分析其垂体腺瘤侵袭性的关系。结果 MMP-9、VEGF标记指数在侵袭性垂体腺瘤中分别为(39.44±5.61)%和(24.28±3.94)%,均较非侵袭性垂体腺瘤中的(22.17±4.32)%和(17.62±1.89)%显著增高(P0.01)。p16在非侵袭性垂体腺瘤中的标记指数为(27.49±4.07)%,较侵袭性垂体腺瘤的标记指数(20.18±3.26)%显著增高(P0.01)。垂体腺瘤的侵袭性与MMP-9和VEGF的表达呈正相关(P0.05),而与p16表达呈负相关(P0.05)。结论 MMP-9、VEGF的表达增高和p16的表达降低与垂体腺瘤的侵袭性密切相关。     

基质金属蛋白酶—2和9在垂体腺瘤中的表达

目的探讨基质金属蛋白酶-2(MMP-2)和9(MMP-9)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MMP-2和MMP-9的表达。结果MMP-2在正常垂体前叶组织、非侵袭性垂体腺瘤和侵袭性垂体腺瘤中均有表达,且依次呈现增高趋势,但差别无统计学意义(P>0.05)。MMP-9在侵袭性垂体腺瘤中的表达强度明显高于非侵袭性垂体腺瘤和正常垂体前叶组织(P<0.05)。MMP-2和MMP-9在功能性垂体腺瘤中的表达高于非功能性垂体腺瘤,但差别无统计学意义(P>0.05)。结论垂体腺瘤的侵袭性与MMP-9的异常高表达有关,MMP-9的高表达可能作为临床评价垂体腺瘤侵袭性的参考指标。     

MMP-2-PEX与MMP-2在侵袭性垂体腺瘤中的表达及意义

目的研究基质金属蛋白酶-2在C端的血红素样结构域(MMP-2-PEX)和基质金属蛋白酶-2(MMP-2)在侵袭性垂体腺瘤中的表达及其意义。方法用逆转录酶-聚合酶链反应(RT-PCR)法检测116例垂体腺瘤标本的MMP-2-PEX及MMP-2的表达,分析其与侵袭性垂体腺瘤的关系及两者之间的相关性。结果侵袭性垂体腺瘤组MMP-2-PEX mRNA表达较非侵袭性垂体腺瘤组显著降低(P<0.01)。侵袭性垂体腺瘤组的MMP-2 mRNA表达明显高于非侵袭性垂体腺瘤组(P<0.01)。侵袭性垂体腺瘤组中MMP-2-PEX mRNA表达与MMP-2 mRNA表达呈负相关(r=-0.66,P<0.05),而非侵袭性腺垂体腺瘤组中无相关性(r=-0.22,P>0.05)。结论 MMP-2-PEX低表达及MMP-2高表达与垂体腺瘤的侵袭性密切相关,MMP-2-PEX及MMP-2可以作为垂体腺瘤侵袭性的重要参考指标。     

儿童及青少年垂体腺瘤临床病理特征及MMP-9的表达意义

目的研究儿童及青少年垂体腺瘤的临床病理特征及MMP-9表达与肿瘤侵袭性的相关性。方法分析53例儿童及青少年垂体腺瘤的临床特征、形态学特征及MMP-9的表达情况。结果31例大腺瘤中,侵袭性16例,占51.6%;12例巨腺瘤中,侵袭性9例,占75.0%;而10例微腺瘤中仅2例有侵袭性,占20.0%。形态学显示:核分裂相Ⅱ级21例,核仁显著24例,瘤巨细胞28例。肿瘤形态学特征、内分泌类型与肿瘤侵袭性无显著相关性(P0.05)。27例侵袭性腺瘤中(侵袭组),MMP-9表达20例,占74.1%;26例非侵袭腺瘤中(非侵袭组),MMP-9表达12例,占46.2%;两组比较,差异有统计学意义(P0.05)。37例获随访,放疗组(11例)术后复发5例,平均53.3个月复发;未放疗组(26例)复发7例,平均19.4个月复发。结论儿童与青少年垂体腺瘤形态学特征与肿瘤侵袭性无显著相关,与肿瘤大小有关,而MMP-9可能参与垂体腺瘤侵袭性的发生。     

垂体腺瘤中MMP-9与VEGF的表达及其与侵袭性的关系

目的探讨基质金属蛋白酶-9(MMP-9)与血管内皮生长因子(VEGF)在垂体腺瘤中的表达及其与垂体腺瘤侵袭性的关系。方法应用免疫组化染色法和逆转录聚合酶链式反应(RT-PCR)方法检测侵袭性(20例)和非侵袭性(10例)垂体腺瘤组织标本中MMP-9与VEGF的表达,分析二者与垂体腺瘤侵袭性的关系及二者的相关性。结果侵袭性垂体腺瘤组MMP-9、VEGF的蛋白及mRNA表达均较非侵袭性腺瘤组显著增高(P<0.01)。在蛋白水平,侵袭性腺瘤组中MMP-9与VEGF表达水平无显著性相关;在mRNA水平,侵袭性腺瘤组中MMP-9与VEGF表达水平成正相关(P<0.05)。结论侵袭性垂体腺瘤的生物学行为与MMP-9基因表达增高及血管生成正调节因子VEGF表达上调有关。MMP-9与VEGF在新生血管形成过程中存在着内在联系。     

Matrix metalloproteinases MMP-2, MMP-7 and MMP-9 in denervated human muscle.

Proteolytic enzyme expression was studied by matrix metalloproteinases (MMP) immunoreactivity (-IR) in muscle biopsies from patients with amyotrophic lateral sclerosis (ALS), spinal muscle atrophy (SMA) and chronic axonal neuropathies (CANP). In normal muscle MMP-2-, MMP-7-, and MMP-9-IR was localized at neuromuscular junctions, in vessels and nerve branches. ALS biopsies of clinically non-affected muscles revealed neither MMP-2, -7-IR nor MMP-9-IR in atrophied myofibers. ALS-affected biopsies revealed MMP-9-IR, and to lesser extent MMP-2- and MMP-7-IR at normal sized and atrophied myofibers. Biopsies of SMA showed MMP-9- and MMP-7-IR at normal sized and atrophic myofibers, while MMP-2-IR was undetectable. In CANP MMP-9-IR was found at normal sized and atrophied myofibers. Distinct expression patterns of MMPs may thus reflect different stages of muscle denervation atrophy.     

MMP-2 and MMP-9 levels in peripheral blood after subarachnoid hemorrhage

MMPs play an important role in ischemic and hemorrhagic stroke. We analyzed replicate serum samples from 20 normal healthy individuals to assess reproducibility of MMP determinations, and found that MMP-2 and MMP-9 determinations were quite consistent. We then studied the serum levels of MMP-2 and MMP-9 in patients suffering from subarachnoid hemorrhage (SAH), another stroke subtype. Serum MMP-2 and MMP-9 levels from SAH patients were measured sequentially using gelatine zymography in 11 patients after acute SAH. The occurrence of intracerebral aneurysms and vasospasms and the initial Hunt and Hess score were analysed in relation to MMP-levels. MMP-2 levels are significantly decreased while MMP-9 levels are increased in SAH patients relative to controls. MMP-2 levels remain depressed out to day 12 post SAH, but MMP-9 levels may recover by day 12.     

Matrix metalloproteinases MMP-2 and MMP-9 in denervated muscle and injured nerve

Nerve crush or axotomy results in a transient or long-term denervation accompanied by remodelling in nerve, muscle and neuromuscular junctions. These changes include an increased turnover of several extracellular matrix molecules and proliferation of Schwann cells in injured nerves. Given the role of matrix degrading metalloproteinases MMP-2 and MMP-9 (gelatinases-type IV collagenases) in extracellular matrix remodelling, we investigated their regulation and activation in denervated muscles and injured nerves in mice. For this, immunofluorescence using MMP-2 and MMP-9 antibodies was carried concomitantly with gelatin zymography and quantification of gelatinase activity using [³H]-gelatin substrate. Results show that in normal mouse muscles MMP-2 and MMP-9 are localized at the neuromuscular junctions, in Schwann cells and the perineurium of the intramuscular nerves. In denervated mouse muscles, MMP-2 immunolabelling persists at the neuromuscular junctions but decreases in the nerves whereas MMP-9 immunolabelling persists at the neuromuscular junctions but is enhanced in degenerated intramuscular nerves. Denervated muscles did not show any significant change of gelatinolytic activity or expression pattern, while injured nerves exhibited a transient increase of MMP-9 and activation of MMP-2. In conclusion, this study demonstrates that MMP-2 and MMP-9 are expressed at mouse neuromuscular junctions and that their localization and expression pattern appear not to be modified by denervation. Their modulation in injured nerves suggests they are involved in axonal degeneration and regeneration.     

Functional MMP-9 polymorphisms modulate plasma MMP-9 levels in multiple sclerosis patients

We have described that MMP-9 C(-1562)T and (CA)(n) polymorphisms contribute to multiple sclerosis (MS). Here, we evaluate whether plasma MMP-9 levels are related to disease severity, drug therapy resistance and polymorphisms. For sub-study 1, 36 patients with MS and 35 controls were recruited. For sub-study 2, 88 individuals (53 patients and 35 controls) were included in a cross-sectional analysis. MS patients presented higher MMP-9 activity (1.4±0.18 versus 0.93±0.18A.U. for control, P<0.05). Drug-therapy resistant individuals exhibited increased MMP-9 activity (1.96±0.25 versus 1.21±0.09A.U. for non-resistant patients). EDSS score was also related to MMP-9 levels. The CT+TT and HH genotypes had higher MMP-9 levels as compared to patients carrying the CC and LL. Drug therapy resistance, disease severity, MMP-9 plasma activity and polymorphisms are associated with MS.     

Serum MMP-2 and MMP-9 are elevated in different multiple sclerosis subtypes

In multiple sclerosis (MS), matrix metalloproteinase (MMP) activity in tissues is the result of a balance between MMPs and their tissue inhibitors (TIMPs). MMP-9 predominates in acute MS lesions and is inhibited by TIMP-1, while MMP-2 may participate in the remodeling of the extracellular matrix (ECM) such as in chronic disease and is inhibited by TIMP-2. These differences may be reflected in serum and cerebrospinal fluid (CSF). We have tried to characterize MMP-2 and MMP-9 activities, in relation to their respective TIMPs, 2 and 1, as a factor of different types of the disease, as this information was not previously clearly stated. We found the MMP-2/TIMP-2 ratio in serum to show higher values in secondary progressive (SP, p=0.02) and primary progressive (PP, p=0.01) MS than short disease duration (SDD) relapsing-remitting (RR) MS, but not different from the healthy control (HC) group. Whereas the MMP-9/TIMP-1 ratio in serum showed higher (p=0.04) values in SDD RR MS than PP but also in active patients, evaluated either clinically (p=0.006) or from the magnetic resonance imaging (MRI, p<0.05), compared to inactive disease. CSF MMP to TIMP ratios did not differ between MS subtypes, suggesting systemic rather CNS-restricted changes. These results show that an increase in MMP-2/TIMP-2 ratio marks chronic progression in MS, but it is as high as in HC, and also confirm that high MMP-9 activity characterizes short duration relapsing and active forms of the disease.     

凝血酶对大鼠脑内MMP-9、MMP-2表达的影响

目的探讨凝血酶对大鼠脑内MMP-9、MMP-2表达的影响。方法Wistar大鼠随机分为假手术组及实验组。实验组脑内注入凝血酶,在不同时间点采用干湿重法测脑水含量,免疫组化方法检测脑内MMP-9、MMP-2的表达。假手术组注入等量生理盐水。结果脑组织水含量在凝血酶注入后6h开始增加,3d达高峰。MMP-9阳性细胞在注射凝血酶后6h即开始表达增加,与对照组相比差异显著(P<0.01),3d达高峰,随后持续下降。阳性微血管数也有相似的变化趋势。MMP-2阳性细胞在注射凝血酶后1d才开始有少量表达,后持续增多,5d达高峰,随后有所下降,但14d仍有明显表达,与对照组相比差异显著(P<0.01)。阳性微血管数也有相似的变化趋势。结论凝血酶在脑出血后脑水肿及脑组织损伤中起了关键的作用,MMP-9、MMP-2参与了急性期脑水肿、炎症反应等过程,MMP-2在损伤修复中可能有重要作用。     

Enhanced expression of MMP-7 and MMP-9 in demyelinating multiple sclerosis lesions

The pathology of multiple sclerosis (MS) is characterised by breakdown of the blood-brain barrier accompanied by infiltration of macrophages and T cells into the central nervous system (CNS). Myelin is degraded and engulfed by the macrophages, producing lesions of demyelination. Some or all of these mechanisms might involve proteinases, and here we have studied the cellular localisation and distribution of two matrix metalloproteinases (MMPs), MMP-7 (matrilysin) and MMP-9 (92-kDa gelatinase), in the normal human CNS and active demyelinating MS lesions. Cryostat sections of CNS samples were immunostained with antisera to MMP-7 and MMP-9. In addition, non-radioactive in situ hybridisation (ISH) was performed using a digoxygenin-labelled riboprobe to detect the expression of MMP-7. MMP-7 immunoreactivity was weakly detected in microglial-like cells in normal brain tissue sections, and was very strong in parenchymal macrophages in active demyelinating MS lesions. This pattern of expression was confirmed using ISH. MMP-7 immunoreactivity was not detected in macrophages in spleen or tonsil, indicating that it is specifically induced in infiltrating macrophages in active demyelinating MS lesions. MMP-9 immunoreactivity was detected in a few small blood vessels in normal brain tissue sections, whereas many blood vessels stained positive in CNS tissue sections of active demyelinating MS lesions. The up-regulation of MMPs in MS may contribute to the pathology of the disease. Received: 19 December 1996 / Revised: 22 May 1997 / Accepted: 4 June 1997     

Investigation of matrix metalloproteinases, MMP-2 and MMP-9, in plasma reveals a decrease of MMP-2 in Alzheimer's disease

Pathological changes in the Alzheimer's disease (AD) brain include amyoid-β (Aβ) plaques, and neurofibrillary tangles, as well as neuronal death and synaptic loss. Matrix metalloproteinases MMP-2 and MMP-9 are known to degrade Aβ, and their expressions are increased in the AD brain, in particular in the astrocytes surrounding amyloid plaque. To investigate a possible association between plasma metalloproteinases and AD, we quantified MMP-2 and MMP-9 activities in the plasma of healthy controls (HC, n = 56), cases with mild cognitive impairment (MCI, n = 45), and AD (n = 50). All cases had previously been imaged with Pittsburgh compound B (PiB) and had a Mini-Mental Status Examination (MMSE) assessment. MMP-2 and MMP-9 activity was determined using gelatine-zymography. There was a significant 1.5-fold decrease in MMP-2 activity in the AD group compared to HC (p < 0.001) and a 1.4-fold decrease compared to MCI (p < 0.01). There was no difference in MMP-9 levels between the three groups. A positive correlation was identified between MMP-2 plasma activity and MMSE score (r = 0.16, p < 0.05), but there was no association with PiB. This is the first report of a change in MMP-2 activity in AD plasma and these findings may provide some insight into AD pathogenesis.     

基质金属蛋白酶(MMP-2、MMP-9)在人脑星形胶质细胞瘤的表达

目的 探讨基质金属蛋白酶(matrix metalloproteinases，MMP)与人脑星形胶质细胞瘤浸润性生长之间的关系，以及基质金属蛋白酶的阳性表达与星形胶质细胞瘤病理分级的关系。方法 应用免疫组织化学染色法(SP法)检测44例人脑星形胶质细胞瘤组织中MMP-2、MMP-9的表达。结果 Ⅲ、Ⅳ级中MMP-2、MMP-9蛋白的表达显著高于Ⅰ、Ⅱ级，而正常脑组织中无表达；在人脑星形胶质细胞瘤中MMP-2和MMP-9的表达之间无明显相关性。结论 MMP-2、MMP-9的表达与星形胶质细胞瘤的恶性程度有关，其高表达可能与星形胶质细胞瘤的侵袭转移有关。     

MMP-9和MMP-2在多病程大鼠EAE发病过程中的变化

目的:研究MMP-2和MMP-9在多病程EAE不同类型间的变化,探讨MMPs在MS发病过程中的作用机制。方法:建立多病程大鼠EAE模型,以免疫组化的方法检测MMP-2、MMP-9在不同类型EAE中的表达及分布。结果:MMP-2、-9在EAE中的表达是一致的,不同类型EAE表达MMP-2、-9是不同的。1急性型EAE:炎细胞、血管内皮细胞及细胞外基质、脑膜细胞均呈阳性表达。2缓解-复发型EAE:活动性病灶呈阳性表达,非活动性病灶呈阴性表达。3持续进展型EAE:与缓解复发型EAE表达类似,但呈阳性表达的血管内皮细胞数目多于缓解-复发型。4良性型EAE:只有部分胶质细胞呈阳性表达。5隐匿型EAE-多数病灶呈轻度表达。结论:1 MMP-2、MMP-9在EAE中均有表达。2不同类型EAE中MMP-2、MMP-9的表达是不同的,与病理改变和疾病进展是一致和同步的。