基质金属蛋白酶与颅脑损伤研究进展

<正>颅脑损伤(traumatic brain injury,TBI)病理反应包括直接损伤和继发性损伤,均可破坏神经血管单元(neurovascular unit,NVU)的结构和功能完整性[1],从而导致一系列的中枢神经系统(central nervoussystem,CNS)功能紊乱和结构变化。基质金属蛋白     

大鼠胸主动脉损伤后基质金属蛋白酶组织抑制因子1，2的表达与血管内膜增生

背景：已有研究发现,基质金属蛋白酶及其组织特异性抑制因子通过影响血管平滑肌细胞迁移以及细胞外基质的代谢参与再狭窄过程。 目的：观察基质金属蛋白酶组织抑制因子1,2在大鼠胸主动脉损伤后不同时间的表达情况。 设计、时间及地点：随机对照动物实验,于2008-07在辽宁医学院动物实验中心完成。 材料：选用SD雄性大鼠60只,按随机数字表法分为2组,单纯球囊损伤组及对照组各30只。 方法：单纯球囊损伤组大鼠采用2F Fogarty导管损伤胸主动脉;对照组行左颈总动脉结扎术,不插入2F Fogarty导管。 主要观察指标：2组于术后第1,3,7,10,14,28天分别处死5只大鼠,取完整的血管内膜,应用蛋白印迹法检测动脉损伤后不同时间点基质金属蛋白酶组织抑制因子1,2表达水平,并进行比较。 结果：基质金属蛋白酶组织抑制因子1于大鼠动脉损伤后第1天开始表达增加,第7天达到高峰,第28天几乎无表达。基质金属蛋白酶组织抑制因子2于大鼠动脉损伤后第1,3天仅有较弱的表达,第7,10天表达明显增加,第14天达到高峰,第28天仍有较强表达。对照组中各时间点基质金属蛋白酶组织抑制因子1,2的表达均无明显变化(P > 0.01)。术后各时间点基质金属蛋白酶组织抑制因子1,2的表达水平单纯球囊损伤组均显著高于对照组(P < 0.01)。 结论：大鼠胸主动脉球囊损伤后基质金属蛋白酶组织抑制因子1,2的表达均明显增加。 关键词：基质金属蛋白酶组织抑制因子1,2;动脉损伤;再狭窄     

基质金属蛋白酶与脑血管病

脑缺血和脑出血启动了一系列链锁样反应,导致兴奋性氨基酸的释放、Ca内流和自由基的释放,并激活细胞内蛋白溶解酶,引起细胞膜不可逆损伤,细胞死亡.缺血和再灌流诱发了炎症反应,随着炎性细胞因子、趋化因子的释放,即早基因(immediate early genes,IEGs)的开放,激活星形胶质细胞和小胶质细胞,释放细胞外基质降解酶类,并进一步造成脑组织继发性损伤.     

基质金属蛋白酶及其抑制剂与脑血管疾病

基质金属蛋白酶的含量和活性在脑缺血、颈动脉粥样硬化斑块、脑动静脉畸形、脑动脉瘤等病理状态下明显增高,提示该蛋白酶与脑血管疾病的发生关系密切。动物试验显示,基质金属蛋白酶抑制剂能明显减小脑梗死体积及脑损伤范围,并可稳定易破裂的动脉粥样硬化斑块,抑制脑动脉瘤的膨胀。由此基质金属蛋白酶可能成为防治脑卒中的新靶点。     

颈动脉内膜切除后基质金属蛋白酶9动态表达对早期血管再狭窄形成的意义

背景：颈动脉内膜切除后发生血管再狭窄是影响治疗效果的重要因素。 目的：观察颈动脉内膜切除后基因基质金属蛋白酶9 mRNA动态表达在早期血管再狭窄发生中的意义。 设计、时间及地点：随机分组设计,对比观察,实验于2006-02/2007-12在解放军北京军区总医院完成。 材料：健康雄性新西兰兔41只,体质量3.0 kg左右,其中36只用于制备颈动脉粥样硬化性狭窄模型。 方法：将41只新西兰兔分为2组,对照组(n=5)：不做任何干预。实验组(n=36)：于造模后4 h,1,3,7,30,90 d 6个时间点各取6只,以40 g/L多聚甲醛灌注固定取材,行常规病理切片苏木精-伊红染色观察形态变化。 主要观察指标：采用实时定量-聚合酶链反应技术观察术前即刻、术后1,3,7 d颈动脉内膜切除后基因基质金属蛋白酶9 mRNA在早期血管再狭窄过程中的表达变化。 结果：颈动脉内膜切除后内膜修复过程大体上可以分为血栓形成阶段,炎症反应阶段,内皮修复阶段,血管平滑肌增殖阶段,基质形成、堆积阶段。基质金属蛋白酶9 mRNA水平在术后1 d开始表达,术后3 d达峰值,术后7 d显著回落。 结论：基质金属蛋白酶9对早期血管平滑肌细胞的增殖、迁移,介导的局部血管重建和再塑,对血管再狭窄的形成有重要作用。     

基质金属蛋白酶与神经系统疾病

基质金属蛋白酶是一大类细胞外基质降解酶。目前认为ＭＭＰｓ尤其是明胶酶（ＭＭＰ－２，ＭＭＰ－９）与脑血管病、脑肿瘤、脱髓鞘病变等关系密切。已有研究证实ＭＭＰｓ抑制剂能减轻某些神经系统病变。本文将阐述ＭＭＰｓ的特性、调节及其与神经系统疾病的关系。     

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。     

基质金属蛋白酶与脑创伤

脑创伤中基质金属蛋白酶(MMPs)表达升高,可降解Ⅳ型胶原、层粘连蛋白等基质成分以及紧密连接蛋白ZO-1和髓鞘碱性蛋白。从而,使血脑屏障结构破坏,通透性增加,导致血管源性脑水肿;细胞-基质间相互作用破坏,诱导神经细胞死亡,以及髓鞘脱失,白质损伤。同时,MMPs促进新生血管形成,水解胶质疤痕,有益于脑创伤的恢复。     

基质金属蛋白酶与垂体腺瘤的侵袭性

基质金属蛋白酶（MMPS）是一大类细胞外基质降解酶，影响肿瘤的侵袭和转移。对侵袭性垂体腺瘤来说，MMPS尤其是MMPS-9与其侵袭性关系密切，本就该方面及MMPS的分类、特性等作一概述。     

基质金属蛋白酶与神经系统疾病

<正> 基质金属蛋白酶(matrix metalloproteinases,MMPs)属Zn2+依赖的中性蛋白酶,与分离整和素金属蛋白酶(a disintegrin and metalloproteinase,ADAMs),分离整和素金属蛋白酶血栓收缩蛋白(a disintegr in and metalloproteinase throm-bospondin,ADAMTs)共同组成金属蛋白酶(metalloproteinas-es,MPs)超家族。MMPs既参与正常生理过程如伤口愈合、妊娠分娩等,也参与病理损伤过程如恶性肿瘤细胞扩散、风湿性     

Matrix metalloproteinases and skeletal muscle: a brief review

Matrix metalloproteinases (MMPs) are a family of zinc- dependent proteolytic enzymes that function mainly in the extracellular matrix, where they contribute to the development, functioning, and pathology of a wide range of tissues. This mini-review describes the MMPs and tissue inhibitors of MMPs (TIMPs) in skeletal muscle, and considers their involvement in muscle development, ischemia, myonecrosis, angiogenesis, denervation, exercise-induced injuries, disuse atrophy, muscle repair and regeneration, and inflammatory myopathies and dystrophies. Despite the very limited information currently available on MMPs and their inhibitors in skeletal muscle, it is becoming increasingly clear that they have important physiological functions in maintenance of the integrity and homeostasis of muscle fibers and of the extracellular matrix. Understanding the roles of MMPs and TIMPs may lead to the development of new drug-related treatments for various muscle disorders based on suppression or upregulation of their expression.     

Increased matrix metalloproteinase activity is associated with migraine and migraine‐related metabolic dysfunctions

Objective: Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are discussed to be involved in the pathophysiology of migraine. Moreover, MMPs may also be involved in migraine‐related metabolic alterations like an atherogenic lipid profile and hyperinsulinemia. The aim of this study was to investigate the impact of MMPs and TIMPs on migraine with and without aura and related metabolic dysfunctions. Methods: MMP activity, six MMPs and three TIMPs, parameters of the insulin and lipid metabolism as well as anthropometric parameters were determined in 124 non‐obese subjects. Results: We found highly significant increased MMP activity in migraine patients independent of aura symptoms, which was associated with migraine with an odds ratio of 7.57. Interestingly, none of the determined MMPs and TIMPs showed significant different serum levels between migraine patients and healthy controls. We found significant correlations between MMP activity and parameters of the insulin and lipid metabolism, like Homeostasis Model Assessment index (HOMA index), cholesterol, triglycerides, and oxidized LDL. Conclusion: We show here that increased MMP activity is tightly associated with migraine and migraine‐related hyperinsulinemia and atherogenic lipid alterations. Our findings represent a new pathophysiological mechanism, which may be of clinical relevance, especially in regard to therapeutic approaches using MMP inhibitors.     

Matrix metalloproteinase-9 expression and blood brain barrier permeability in the rat brain after cerebral ischemia/reperfusion injury**☆

BACKGROUND： The integrity of the blood brain barrier （BBB） plays an important role in the patho-physiological process of cerebral ischemia/reperfusion injury. It has been recently observed that metalloproteinase-9 （MMP-9） is closely related to cerebral ischemia/reperfusion injury OBJECTIVE： This study was designed to observe MMP-9 expression in the rat brain after cerebral ischemia/reperfusion injury and to investigate its correlation to BBB permeability. DESIGN, TIME AND SETTING： This study, a randomized controlled animal experiment, was performed at the Institute of Neurobiology, Central South University between September 2005 and March 2006. MATERIALS： Ninety healthy male SD rats, aged 3-4 months, weighing 200-280 g, were used in the present study. Rabbit anti-rat MMP-9 polyclonal antibody （Boster, Wuhan, China） and Evans blue （Sigma, USA） were also used. METHODS： All rats were randomly divided into 9 groups with 10 rats in each group： normal control group, sham-operated group, and ischemia for 2 hours followed by reperfusion for 3, 6, 12 hours, 1, 2, 4 and 7 days groups. In the ischemia/reperfusion groups, rats were subjected to ischemia/reperfusion injury by suture occlusion of the right middle cerebral artery. In the sham-operated group, rats were merely subjected to vessel dissociation. In the normal control group, rats were not modeled. MAIN OUTCOME MEASURES： BBB permeability was assessed by determining the level of effusion of Evans blue. MMP-9 expression was detected by an immunohistochemical method. RESULTS： All 90 rats were included in the final analysis. BBB permeability alteration was closely correlated to ischemia/reperfusion time. BBB permeability began to increase at ischemia/reperfusion for 3 hours, then it gradually reached a peak level at ischemia/reperfusion for 1 day, and thereafter it gradually decreased. MMP-9 expression began to increase at ischemia/reperfusion for 3 hours, then gradually reached its peak level 2 days after perfusion, and thereafter it grad     

Matrix metalloproteinase-9 expression and blood brain barrier permeability in the rat brain after cerebral ischemia/reperfusion injury

BACKGROUND: The integrity of the blood brain barrier (BBB) plays an important role in the patho-physiological process of cerebral ischemia/reperfusion injury. It has been recently observed that metalloproteinase-9 (MMP-9) is closely related to cerebral ischemia/reperfusion injuryOBJECTIVE: This study was designed to observe MMP-9 expression in the rat brain after cerebral ischemia/reperfusion injury and to investigate its correlation to BBB permeability.DESIGN, TIME AND SETTING: This study, a randomized controlled animal experiment, was performed at the Institute of Neurobiology, Central South University between September 2005 and March 2006.MATERIALS: Ninety healthy male SD rats, aged 3-4 months, weighing 200-280g, were used in the present study. Rabbit anti-rat MMP-9 polyclonal antibody (Boster, Wuhan, China) and Evans blue (Sigma, USA) were also used.METHODS: All rats were randomly divided into 9 groups with 10 rats in each group: normal control group, sham-operated group, and ischemia for 2 hours followed by reperfusion for 3,6,12 hours, 1,2,4 and 7 days groups. In the ischemia/reperfusion groups, rats were subjected to ischemia/reperfusion injury by suture occlusion of the right middle cerebral artery. In the sham-operated group, rats were merely subjected to vessel dissociation. In the normal control group, rats were not modeled.MAIN OUTCOME MEASURES: BBB permeability was assessed by determining the level of effusion of Evans blue. MMP-9 expression was detected by an immunohistochemical method.RESULTS: All 90 rats were included in the final analysis. BBB permeability alteration was closely correlated to ischemia/reperfusion time. BBB permeability began to increase at ischemia/reperfusion for 3 hours, then it gradually reached a peak level at ischemia/reperfusion for 1 day, and thereafter it gradually decreased. MMP-9 expression began to increase at ischemia/reperfusion for 3 hours, then gradually reached its peak level 2 days after perfusion, and thereafter it gradually decreased.CONCLUSION: MMP-9 expression increases in rat brain tissue after focal cerebral ischemia/reperfusion injury, which correlates with increased permeability of the BBB.     

Matrix metalloproteinases in neuroinflammation

Matrix metalloproteinases (MMPs) are a gene family of neutral proteases that are important in normal development, wound healing, and a wide variety of pathological processes, including the spread of metastatic cancer cells, arthritic destruction of joints, atherosclerosis, and neuroinflammation. In the central nervous system (CNS), MMPs have been shown to degrade components of the basal lamina, leading to disruption of the blood-brain barrier (BBB), and to contribute to the neuroinflammatory response in many neurological diseases. Brain cells express both constitutive and inducible MMPs in response to cellular stress. MMPs are tightly regulated to avoid unwanted proteolysis. Secreted as inactive enzymes, the MMPs require activation by other proteases and free radicals. The MMPs are part of a larger class of metalloproteinases (MPs), which includes the recently discovered ADAMs (a disintegrin and metalloproteinase domain) and ADAMTS (a disintegrin and metalloproteinase thrombospondin) families. MPs have complex roles at the cell surface and within the extracellular matrix. At the cell surface, they act as sheddases, releasing growth factors, death receptors, and death-inducing ligands, making them important in cell survival and death. Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors that regulate the activity of the MMPs. Synthetic inhibitors have been developed for the treatment of arthritis and cancer. These hydroxymate-based compounds have been shown to reduce injury in experimental allergic encephalomyelitis (EAE), experimental allergic neuritis (EAN), cerebral ischemia, intracerebral hemorrhage, and viral and bacterial infections. MPs have both beneficial and detrimental roles; understanding their expression in various CNS insults will allow for the use of MMP inhibitors in the treatment of neurological disorders.     

Matrix metalloproteinases in neuromuscular disease

Matrix metalloproteinases (MMPs), a family of zinc-dependent endoproteinases, are effector molecules in the breakdown of the blood-brain and blood-nerve barrier, and promote neural tissue invasion by leukocytes in inflammatory diseases of the central and peripheral nervous systems. Moreover, MMPs play an important role in synaptic remodeling, neuronal regeneration, and remyelination. Recent work concerning MMPs in patients with neuropathy, myopathy, spinal cord injury, and amyotrophic lateral sclerosis (ALS), and in corresponding animal models, is discussed in this review.     

Imaging biomarkers of vascular and axonal injury are spatially distinct in chronic traumatic brain injury

Traumatic Brain Injury (TBI) is associated with both diffuse axonal injury (DAI) and diffuse vascular injury (DVI), which result from inertial shearing forces. These terms are often used interchangeably, but the spatial relationships between DAI and DVI have not been carefully studied. Multimodal magnetic resonance imaging (MRI) can help distinguish these injury mechanisms: diffusion tensor imaging (DTI) provides information about axonal integrity, while arterial spin labeling (ASL) can be used to measure cerebral blood flow (CBF), and the reactivity of the Blood Oxygen Level Dependent (BOLD) signal to a hypercapnia challenge reflects cerebrovascular reactivity (CVR). Subjects with chronic TBI (n = 27) and healthy controls (n = 14) were studied with multimodal MRI. Mean values of mean diffusivity (MD), fractional anisotropy (FA), CBF, and CVR were extracted for pre-determined regions of interest (ROIs). Normalized z-score maps were generated from the pool of healthy controls. Abnormal ROIs in one modality were not predictive of abnormalities in another. Approximately 9-10% of abnormal voxels for CVR and CBF also showed an abnormal voxel value for MD, while only 1% of abnormal CVR and CBF voxels show a concomitant abnormal FA value. These data indicate that DAI and DVI represent two distinct TBI endophenotypes that are spatially independent.     

Genome-Wide Association Study of the Relationship Between Matrix Metalloproteinases and Intracranial Aneurysms

Background and PurposeMatrix metalloproteinases (MMPs) are expected to play an important role in extracellular matrix (ECM) remodeling in response to hemodynamic stress. We investigated the association between MMPs and intracranial aneurysms (IAs) via a genome-wide association study (GWAS) of IAs.MethodsA GWAS data set of 250 IAs and 294 controls was used to analyze the genetic link between MMPs and IAs via single-nucleotide polymorphisms (SNPs), MMP gene families, and in silico functional analyses of gene ontology (GO) enrichment and protein–protein interaction (PPI).ResultsForty-eight SNPs and 1 indel out of 342 markers of MMP genes were related to IAs. The rs2425024 SNP located on MMP24 was the most strongly associated with IAs (OR=0.43, CI=0.30–0.61, p=2.4×10^-6), suggesting a protective effect. The 16938619 SNP of MMP26 significantly increased the risk of an IA (OR=3.12, 95% CI=1.76–5.50, p=8.85×10^-5). Five MMP genes (MMP24, MMP13, MMP2, MMP17, and MMP1) increased the susceptibility to an IA. MMP24 was the gene most closely related to IAs (p=7.96×10^-7). GO analysis showed that collagen catabolism was the most-enhanced biological process. Further, metalloendopeptidase activity and ECM were predominantly detected in the cellular component and molecular function, respectively. PPI provided evidence that MMP2, TIMP2 (tissue inhibitor of metalloproteinase 2), and TIMP3 genes constitute a network for predicting IA formation.ConclusionsThe present results provide comprehensive insight into the occurrence of IAs associated with MMPs.     

Matrix metalloproteinases in inflammatory myopathies: enhanced immunoreactivity near atrophic myofibers

OBJECTIVES: To further examine the role of proteolytic enzyme expression of matrix metalloproteinases (MMP) and T-cell markers in inflammatory myopathies and controls. MATERIAL AND METHODS: We studied the expression of MMP-2, MMP-7, and MMP-9 in 19 cases of inflammatory myopathies and controls using immunocytochemistry. RESULTS: Inflammatory myopathies showed distinct patterns of up-regulation of MMP. MMP-9 was strongly expressed in atrophic myofibers in all inflammatory myopathies. MMP-2 immunoreactivity was similar in its distribution, however, to a weaker intensity. In dermatomyositis the perifascicular atrophy showed pronounced MMP-9 immunoreactivity, probably reflecting denervated patterns of myofibers. Moreover, MMP-7 strongly immunolabeled invaded myofibers in polymyositis cases only. CONCLUSION: These patterns confirm, that MMP-7 up-regulation is prominent in PM, while MMP-2 immunoreactivity is only slightly elevated in inflamed muscle. In general, MMP-9 up-regulation appears to be an important additional molecular event in the multistep process of all inflammatory myopathies.     

Matrix metalloproteinases and proteoglycans in axonal regeneration

After an injury to the adult mammalian central nervous system (CNS), a variety of growth-inhibitory molecules are upregulated. A glial scar forms at the site of injury and is composed of numerous molecular substances, including chondroitin sulfate proteoglycans (CSPGs). These proteoglycans inhibit axonal growth in vitro and in vivo. Matrix metalloproteinases (MMPs) can degrade the core protein of some CSPGs as well as other growth-inhibitory molecules such as Nogo and tenascin-C. MMPs have been shown to facilitate axonal regeneration in the adult mammalian peripheral nervous system (PNS). This review will focus on the various roles of proteoglycans and MMPs within the injured nervous system. First, we will present a general background on the injured central nervous system and explore the roles that proteoglycans play in the injured PNS and CNS. Second, we will discuss the various functions of MMPs within the injured PNS and CNS. Special attention will be paid to the possibility of how MMPs might modify the growth-inhibitory extracellular environment of the injured adult mammalian spinal cord and facilitate axonal regeneration in the CNS.