基质金属蛋白酶9在大鼠糖尿病肾病发病中的作用

目的 探讨糖尿病肾病大鼠肾局部金属蛋白酶9(MMP-9)在糖尿病肾病发生发展的作用.方法 健康雌性清洁级大鼠,随机分成糖尿病组和正常对照组,采用腹腔注射链脲佐菌素制备糖尿病大鼠模型.分别于4、8周处死,应用免疫组化及酶谱分析方法(zymography)观察各组肾组织MMP9的蛋白表达及其活性水平,分析MMP-9与细胞外基质Ⅳ型胶原、层粘连蛋白(LN)的相关性.结果 MMP-9在正常对照组肾小球、肾小管细胞均有阳性表达(4周,26.63%+2.94%;8周,29.86%±0.89%);而糖尿病组随病程延长表达明显减弱(4W,16.11%±2.86%;8周,13.14%±2.68%),MMP-9活性也明显降低(正常组4周110.47±7.12;8周,111.50±6.95;糖尿病组4周82.74±10.92;8周,80.05±12.83),两组间各项指标的差异有统计学意义(均P＜0.01).MMP-9活性与Ⅳ型胶原(r=-0.852,-0.795,P＜0.01)、LN(r=-0.897,-0.832,P＜0.01)呈显著负相关.结论 糖尿病肾病时肾组织中MMP-9表达水平降低,糖尿病肾病的发病机制可能与MMP-9水平降低有关.     

糖尿病肾病肾组织中基质金属蛋白酶-9表达的定量分析

目的对糖尿病肾病(DN)大鼠模型的肾组织中的基质金属蛋白酶-9(MMP-9)的表达进行定量研究。方法取成年健康SD大鼠20只,随机分成糖尿病组(DM组)和正常对照组(NC组),DM组大鼠采用一次性腹腔内注射STZ诱导制造糖尿病大鼠模型。分别于造模后第4、8周行HE染色,在光镜下观察肾小球大小和肾小球内细胞数目的变化。通过免疫组织化学方法观察肾脏局部MMP-9的表达,以MMP-9平均光密度做为观察指标。结果HE染色:DM组8周时见肾小球体积增大,肾小球内系膜区增宽.细胞核数目增加。免疫组织化学:DM组大鼠肾脏MMP-9的表达明显低于正常大鼠(P<0.05)。结论糖尿病肾病时MMP-9表达水平降低,可能是引起肾小球细胞外基质积聚和降解减少的重要原因之一。     

基质金属蛋白酶-2和基质金属蛋白酶-9在胶质瘤侵袭和转移中的作用

胶质瘤是一种中枢神经系统恶性肿瘤,病死率高。胶质瘤细胞的侵袭和转移是其致死的重要原因之一,而基质金属蛋白酶通过溶解细胞外基质实现侵袭和转移。基质金属蛋白酶(mat r i x metalloproteinase,MMP)是锌离子依赖性蛋白水解酶,广泛分布于人体各组织和器官,参与细胞外基质的降解和重塑,调节细胞粘着,在肿瘤细胞的侵袭中起着重要作用。本文就基质金属蛋白酶-2和基质金属蛋白酶-9在胶质瘤中的侵袭作用及其机制进行综述。     

金属蛋白酶及其抑制物与糖尿病肾病

基质金属蛋白酶（MMPs)和金属蛋白酶组织抑制剂（TIMPs)是细胞外基质（ECM）合成与降解代谢平衡调节中两个重要的酶系，它们的调节在导致糖尿病肾病的发生发展中起重要作用。检测血清MMPs和TIMPs水平变化能早期诊断糖尿病肾病，应用干预措施有利于糖尿病肾病的早期防治。     

基质金属蛋白酶-9与多发性硬化发病机制及治疗相关性研究

多发性硬化(MS)是一种进展的自身免疫性疾病,特征是中枢神经系统(CNS)的炎症、脱髓鞘和轴索变性.基质金属蛋白酶(MMPs)是蛋白水解酶,由23个肽链内切酶组成的家族,是MS中神经炎症及血脑屏障破坏的主要参与者,其在MS的发生和发展中具有重要意义.     

基质金属蛋白酶-9及其组织抑制物-1在妊娠输卵管黏膜中的表达

目的:检测基质金属蛋白酶-9(MMP-9)及其组织抑制物-1(TIMP-1)在输卵管黏膜中的表达,探讨与输卵管妊娠的关系。方法:采用免疫组织化学显色技术和图像半定量分析法,检测MMP-9和TIMP-1在人妊娠输卵管黏膜、人正常输卵管黏膜及正常宫内早孕子宫蜕膜组织中的表达。结果:MMP-9和TIMP-1在正常宫内早孕组中表达最强,在输卵管妊娠组中的表达较强,在正常输卵管组中表达较弱。两两比较差异均有显著性。结论:MMP-9/TIMP-1参与了输卵管妊娠中胚胎着床过程,且与输卵管妊娠缺乏蜕膜化反应有关。     

可溶性趋化因子对人单核细胞表达及基质金属蛋白酶-9的影响

目的观察趋化因子Fractalkine（CX3CL1,Fkn）对人单核细胞株U937细胞表达与分泌基质金属蛋白酶-9（matrix metalloproteinase-9,MMP-9）的影响。方法使用不同浓度的人重组Fkn干预U937细胞,RT-PCR法检测细胞MMP-9基因表达,明胶酶谱法检测细胞上清中MMP-9水平。结果不同浓度人重组Fkn干预U937细胞MMP-9基因表达及上清中MMP-9水平低于空白对照组。结论Fkn可抑制U937细胞表达与分泌MMP-9。     

两种透析方法治疗终末期糖尿病肾病前后患者血管内皮生长因子和基质金属蛋白酶-9水平变化

目的:分析两种透析方法对终末期糖尿病肾病(ESDN)患者血清血管内皮生长因子(VEGF)和基质金属蛋白酶-9(MMP-9)水平的影响及临床意义。方法:80例ESDN患者,按照随机数字表法分为观察组(n=40)和对照组(n=40)。观察组采用维持性血液透析,对照组采用不卧床持续腹膜透析,均治疗6个月。观察两组患者治疗前后血压(BP)、血清白蛋白(SA)、血红蛋白(Hb)、VEGF、MMP-9水平变化和不良反应。结果:治疗前,两组患者上述各项指标差异均无统计学意义(P均0.05);治疗后,观察组上述各项指标较治疗前明显改善(P0.05或P0.01);对照组除SA、Hb外,其它指标均较治疗前好转(P0.05或P0.01)。观察组治疗后各项指标改善明显好于对照组(P0.05或P0.01)。两组不良反应发生率差异无统计学意义(P0.05)。结论:ESDN患者透析治疗可优先选择持续性血液透析。     

大肠癌组织中基质金属蛋白酶-2和基质金属蛋白酶-9的表达

目的：探讨大肠癌组织中基质金属蛋白酶－2（MMP－2）和基质金属蛋白酶－9（MMP－9）的表达与临床病理参数之间的关系。方法：应用免疫组织化学S－P法检测87例大肠癌组织中MMP－2和MMP－9的表达情况。结果：87例大肠癌组织中MMP－2和MMP－9的表达阳性率分别为56．3％和55．2％。MMP－2和MMP－9在侵及肌层的阳性表达率明显低于侵及浆膜层，淋巴结转移阳性组高于淋巴结转移阴性组，差异均有显著性（P＜0．05）。Dukes分期中，C、D期中MMP－2和MMP－9的阳性表达率明显高于A、B期（P＜0．05），而与性别、年龄、肿瘤部位、组织学类型和分化程度均无关（P＞0．05）。结论：MMP－2和MMP－9可能在大肠癌浸润转移过程中发挥重要作用。     

急性心肌梗死患者PCI术前后血清基质金属蛋白酶-2与基质金属蛋白酶-9的相关性

目的: 探讨急性心肌梗死(AMI)患者在急诊经皮冠状动脉介入(PCI)术治疗前后血清基质金属蛋白酶-2 (MMP-2)和基质金属蛋白酶-9 (MMP-9)变化的相关性.方法: 应用酶图(SDS-PAGE zymograph)和Western blot的方法检测56例行PCI术治疗的AMI患者及20例冠状动脉造影正常者术前及术后第1~7 天血清中MMP-2和MMP-9的酶活性及蛋白表达水平,并分析MMP-2和MMP-9变化的相关性.结果: AMI患者PCI术前及术后血清MMP-2和MMP-9的酶活性及蛋白表达水平较对照组明显升高(P<0.01),PCI术患者在术后第1天血清MMP-2和MMP-9的酶活性及蛋白表达水平显著升高,并在术后第3天达高峰(P<0.01),第5天开始明显下降(P<0.05).经Spearman相关性分析表明,各组血清MMP-2的酶活性与MMP-9的酶活性呈正相关(P<0.01);各组血清MMP-2的表达水平与MMP-9的表达水平亦呈正相关(P<0.01).结论: 血清MMP-2和MMP-9酶活性及蛋白表达水平的增加可能是AMI患者心肌缺血再灌注损伤的机制之一.MMP-2和MMP-9是AMI病程进展中同样重要的炎性标志物.     

糖尿病肾病时血浆基质金属蛋白酶3及血栓前体蛋白的变化

目的： 探讨基质金属蛋白酶3（MMP-3）和血栓前体蛋白（TpP）在2型糖尿病肾病（DN）中的变化。方法: 用ELISA双抗体夹心法测定57例DN患者及35例正常对照者的血浆MMP-3和TpP水平,DM组根据24 h尿白蛋白排泄量（UAE）分DN0(UAE＜30 mg/24 h)、DN1（30 mg/24 h≤UAE＜300 mg/24 h）、DN2（UAE≥300 mg/24 h）3组。 结果: DN0组血浆MMP-3和TpP水平与正常对照组间无显著差异。DN1组血浆MMP-3水平高于正常对照组（P＜0.05）,但TpP水平无显著差异。DN2组血浆MMP-3水平显著高于正常对照组（P＜0.01）、DN0组（P＜0.05）及DN1组（P＜0.05）,TpP水平也高于正常对照组（P＜0.01）。DN患者血浆MMP-3和TpP水平呈正相关（P＜0.01）。 结论: MMP-3及TpP可能参与DN发生,MMP-3水平变化与DN病变程度相关。     

Children with stable asthma have reduced airway matrix metalloproteinase-9 and matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio

BACKGROUND: Childhood asthma is characterized by inflammation of the airways. Structural changes of the airway wall may also be seen in some children early in the course of the disease. Matrix metalloproteinases (MMPs) are key mediators in the metabolism of the extracellular matrix (ECM). OBJECTIVE: To investigate the balance of MMP-8, MMP-9 and tissue inhibitor of metalloproteinases (TIMP)-1 in the airways of children with asthma. METHODS: One hundred and twenty-four children undergoing elective surgical procedures also underwent non-bronchoscopic bronchoalveolar lavage (BAL). MMP-8, MMP-9 and TIMP-1 were measured by ELISA. RESULTS: There was a significant reduction in MMP-9 in atopic asthmatic children (n=31) compared with normal children (n=30) [median difference: 0.57 ng/mL (95% confidence interval: 0.18-1.1 ng/mL)]. The ratio of MMP-9 to TIMP-1 was also reduced in asthmatic children. Levels of all three proteins were significantly correlated to each other and to the relative proportions of particular inflammatory cells in BAL fluid (BALF). Both MMP-8 and MMP-9 were moderately strongly correlated to the percentage neutrophil count (r=0.40 and 0.47, respectively, P<0.001). CONCLUSIONS: An imbalance of MMPs and their inhibitors occurs in children with well-controlled asthma, which may indicate early derangement of the metabolism of the ECM.     

Involvement of matrix metalloproteinase-2 in the development of renal interstitial fibrosis in mouse obstructive nephropathy

Renal fibrosis is a common finding in progressive renal diseases. Matrix metalloproteinases (MMPs) are involved in epithelial-to-mesenchymal transition (EMT). We investigated the role of MMP-2 and the effect of inhibition of MMPs on the development of renal fibrosis. Renal fibrosis was induced in MMP-2 wild-type (MMP-2?/?) mice by unilateral ureteral obstruction (UUO). Renal histopathology, EMT-associated molecules, and activity of MMP-2 and MMP-9 were examined during the development of interstitial fibrosis. UUO-renal fibrosis was also induced in MMP-2 deficient (MMP-2?/?) and MMP-2?/? mice treated with minocycline (inhibitor of MMPs). In MMP-2?/? mice, MMP-2 and MMP-9 were expressed in damaged tubules, and their activities increased in a time-dependent manner after UUO. Interstitial fibrosis was noted at day 14, with deposition of types III and I collagens and expression of markers of mesenchymal cells (S100A4, vimentin, α-smooth muscle actin, and heat shock protein-47) in damaged tubular epithelial cells, together with F4/80+ macrophage infiltration. Fibrotic kidneys expressed EMT-associated molecules (ILK, TGF-β1, Smad, Wnt, β-catenin, and Snail). In contrast, the kidneys of MMP-2?/? mice and minocycline-treated MMP-2?/? mice showed amelioration of renal fibrosis with reduced expression of markers of mesenchymal cells in tubular epithelial cells, inhibition of upregulated EMT-associated molecules, and suppression of macrophage infiltration. The results suggested that MMP-2 have a pathogenic role in renal interstitial fibrosis, possibly through the induction of EMT and macrophage infiltration. Inhibition of MMPs may be beneficial therapeutically in renal fibrosis.     

Increased expression of matrix metalloproteinase-2, matrix metalloproteinase-9 and matrix metalloproteinase-13 in lesional skin of bullous pemphigoid

BACKGROUND: Matrix metalloproteinase (MMP)-2, MMP-9 and MMP-13 can degrade type IV collagen which is the major component of the basement membrane zone (BMZ). In bullous pemphigoid (BP), the separation occurs within the BMZ. OBJECTIVE: To evaluate the involvement of MMPs in the pathogenesis of BP, we examined the expression of MMP-2, MMP-9 and MMP-13 in the lesional skin of BP patients. METHODS: The expression of MMP-2, MMP-9, MMP-13, tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 was analyzed by immunohistochemistry in the lesional skin of BP patients in comparison with that in normal human skin. Next, the cellular sources of MMP-2, MMP-9 and MMP-13 were analyzed by double immunohistochemistry. Finally, the levels of these MMPs in the serum and blister fluid of BP patients were measured by ELISA. RESULTS: The number of cells expressing MMP-2, MMP-9 and MMP-13 were significantly increased in the lesional skin of BP patients as compared to that in normal skin. Although the number of cells expressing TIMP-1 and TIMP-2 were also increased in the lesional skin of BP patients as compared to that in normal skin, the ratio of MMPs to TIMPs in the lesional skin of BP patients was high (2.4:1). T cells comprised the major source of MMP-2, MMP-9 and MMP-13, while a proportion of mast cells and eosinophils also expressed these MMPs. Furthermore, marked expression of MMP-2 was detected in the epidermal keratinocytes. The levels of these MMPs in the blister fluid were significantly greater than those in the serum. CONCLUSION: These results suggest that MMP-2, MMP-9 and MMP-13 may be involved in the mechanism of blister formation in BP and that besides infiltrating inflammatory cells, structural cells like epidermal keratinocytes may also participate in the induction of blister formation in BP.     

Immunohistochemical expression of matrix metalloproteinase-9 and inhibitor of matrix metalloproteinase-1 in prostate adenocarcinoma

An immunohistochemical study on the cells proliferative activity by Ki-67 protein and localization of the matrix metalloproteinase-9 and the inhibitor of matrix metalloproteinase-1 was carried out at the benign prostatic hyperplasia (BPH) and the adenocarcinoma (AC) of different Gleason’s grades. A significant decrease of the MMP-9 and TIMP-1 level in the AC of different gradations was observed. A moderate positive correlation between the Gleason score and cell proliferation Ki-67 index (rs = 0.674) and a moderate negative correlation with the level of such a score and expression of MMP-9 (rs = -0.660) was detected. A weak negative correlation exists also between the level of proliferative activity of secretory cells and the expression of MMP-9 by tumor cells (rs = -0.369). The invasive properties of AC cells that promote a degradation of the basal membrane and connective tissue in prostate may be explained by the imbalance between the MMP-9 and TIMP-1, which expression is significantly reduced in AC, in comparison with BPH.     

Correlation between matrix metalloproteinase-9 and endometriosis

Endometrial implantation is the major cause of endometriosis (EMS). Matrix metalloproteinase (MMPs) can degrade multiple extracellular matrix and has been postulated to be related with EMC occurrence. This study thus investigated serum and ascites levels of MMP-9 in EMS patients, in an attempt to discuss the correlation between MMP-9 and EMS. A total of 100 EMS patients, including eutopic endometrium and ectopic endometrium, were recruited in this study along with hysteromyoma patients as the control group. Peripheral blood and ascites samples were collected and tested for MMP-9 levels using gelatin zymogram and enzyme-linked immunosorbent assay (ELISA). In EMS patients, MMP-9 levels in serum and ascites were 6.24±0.53 mM and 38.57±4.93 mM, respectively. Both of them were significantly higher than those in control group (P<0.05). Eutopic endometrium group had higher MMP-9 levels compared to those in ectopic endometrium ones (P<0.05). With advancement of disease stage, EMS patients had progressively elevated MMP-9 levels (P<0.05). Patients at proliferative stage had higher MMP-9 secretion (P<0.05). In summary, site of endometrium, clinical stage and proliferative cycle were independent risk factors for EMS. The elevation of serum and ascites MMP-9 existed in EMS patients, of which those had ectopic endometrium, advanced stage and at proliferative stage had higher MMP-9 expression.     

The role of matrix metalloproteinase-9 in dementia

Neurofibrillary tangles and senile plaques, constituted of extracellular amyloid deposits (Aβ), are the two defining pathological hallmarks of Alzheimer's disease (AD). Inhibiting the synthesis or aggregation of Aβ or increasing its clearance may reduce the detrimental effects of this peptide and consequently improve cognitive functions in patients. Previous studies indicated that metalloproteinases are involved in Aβ degradation and the presence of matrix metalloproteinases (MMP) in AD plaques has been described. In this study, we examined the distribution of a functional polymorphism in the gene for MMP-9, −1562 C→T, in an independent population of 229 demented and 253 control individuals. We observed a weak protective effect of the high activity allele (T) in apolipoprotein E ε4 allele non-bearers (odds RATIO=0.5 (95% confidence interval, 0.3–0.9), P=0.04).