MMP-2和MMP-9蛋白在结肠癌中的表达

目的:分析基质金属蛋白酶-2(MMP-2)和MMP-9蛋白与结肠癌病理因素的关系,探讨MMP蛋白在结肠癌发生中的临床意义.方法:用SP免疫组化法检测31例结肠癌中MMP-2和MMP-9蛋白表达情况,并用SPSS10.0forWindows软件统计分析MMP蛋白与临床病理因素的关系.以20例溃疡性结肠炎、21例结肠腺瘤和10例正常结肠黏膜作为对照组.结果:MMP-2除结肠癌组和正常结肠黏膜组间相比具有显著性差异(10.0%vs54.8%,P<0.05)外,其余各组间比较差异无统计学意义,MMP-9各组间比较差异无统计学意义,从溃疡性结肠炎、结肠腺瘤到结肠癌中MMP-2和MMP-9蛋白表达阳性率不同且具有递增趋势.MMP-2和MMP-9蛋白表达与结肠癌的Duke’s分期及有无淋巴结转移显著相关(A B期:38.9%和27.8%;C D期:76.9%和84.6%;无淋巴结转移:38.9%和27.8%;有淋巴结转移:76.9%和84.6%,P<0.05).结论:MMP-2和MMP-9蛋白过度表达对结肠癌的诊断、Duke's分期及有无淋巴结转移判断具有重要的临床意义.     

基质金属蛋白酶-2、基质金属蛋白酶-9与特发性肺纤维化的研究进展

基质金属蛋白酶是一组金属依赖的可降解细胞外基质的蛋白酶类.基质金属蛋白酶与基质金属蛋白酶组织抑制因子之间的比例失衡可能导致细胞外基质的降解异常,这可以促进纤维化的过程.近年来随着研究的进展,发现基质金属蛋白酶-2和基质金属蛋白酶-9与特发性肺纤维化有着密切的关系,现就此作一综述.     

基质金属蛋白酶-9和金属蛋白酶组织抑制物-1在IgA肾病肾组织中的表达

目的 探讨基质金属蛋白酶－9（MMP－9）／金属蛋白酶组织抑制物－1（TIMP－1）系统在IgA肾病肾组织中的表达及其对IgA肾病的进展的影响。方法 采用免疫组织化学和原位杂交技术,分别在蛋白质和基因水平检测38例IgA肾病患者肾组织中的MMP－9和TIMP－1的变化。结果 MMP－9在正常肾脏肾小球的脏层上皮细胞和内皮细胞有少量表达,在肾小管上皮细胞和间质血管壁也有少量表达;在IgA肾病中,MMP－9在系膜增殖性肾小球和间质血管壁的表达均明显增多（P＜0．001）,而在硬化肾小球内的表达则明显减少,肾小管细胞的MMP－9表达无明显变化。TIMP－1在正常肾组织中不能检出,在IgA肾病患者具有系膜增殖性病变的肾小球中有微量表达,在增殖在很重但尚未完全硬化的肾小球内表达增多,在肾小管间质表达最为明显（P＜0．001）,其主要见于肾小管细胞、间质细胞和血管内皮细胞。肾组织中的TIMP－1表达与血清肌酐水平呈显著相关（P＜0．05）,与肾小管间质的纤维化和炎细胞浸润程度亦明显相关（P值均＜0．01）。肾小球中的MMP－9表达与尿蛋白无明显相关性,但与血清肌酐水平呈显著负相关（P＜0．05）。结论 MMP－9和TIMP－1的异常表达可能是影响IgA肾病进展的因素之一。     

Expression of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 in ulcerative colitis

INTRODUCTION Ulcerative colitis (UC) is a chronic, non-specific inflammatory disease of the colonic mucosa with unknown etiology and pathogenesis. Pathologically, it is characterized by ulceration in the mucosal and submucosal areas, and degradation of ex…     

Levels of matrix metalloproteinase-1 and tissue inhibitors of metalloproteinase-1 in gastric cancer

AIM:To evaluate the levels of preoperative serum matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in gastric cancer.METHODS:One hundred gastric cancer patients who underwent gastrectomy were enrolled in this study.The serum concentrations of MMP-1 and TIMP-1 in these patients and in fifty healthy controls were determined using an enzyme-linked immunosorbent assay.RESULTS:Higher serum MMP-1 and TIMP-1 levels were observed in patients than in controls (P < 0.001).Serum M...     

基质金属蛋白酶26与癌

基质金属蛋白酶(matrix metalloproteinase,MMP)是一类高度保守的依赖于锌离子和钙离子的内切蛋白水解酶,几乎能降解构成细胞外基质的所有成分.MMP-26是MMP家族新成员,最早从人子宫内膜癌细胞系cDNA文库克隆成功,其结构和功能与其他成员有许多差异,在癌的发生发展中起着重要的作用.     

基质金属蛋白酶在糖尿病患者动脉粥样硬化斑块中的表达

目的检测2型糖尿病患者动脉粥样硬化斑块内基质金属蛋白酶2(MMP2)和基质金属蛋白酶9(MMP9)的表达和分布,探讨MMP2和MMP9在糖尿病动脉粥样硬化斑块中表达的作用.方法从23例糖尿病足截肢和17例尸检下肢动脉标本中选取晚期动脉粥样硬化病变的组织126块,糖尿病组(74块),非糖尿病组(52块),从中随机选取各40块进行MMP2和MMP9抗原抗体的免疫组织化学染色,观察阳性物质在两组动脉粥样硬化斑块中的分布特点,利用计算机图像分析系统对染色程度作相对定量分析. 结果抗MMP2、抗MMP9免疫沉积物主要集中在斑块核心周围,特别是在斑块的肩部和纤维帽.糖尿病组动脉内膜抗MMP2免疫沉积物表达显著高于非糖尿病组[免疫沉淀物积分吸光度值(IA)69 014±14 459和57 004±16 171,阳性面积百分比(12.97±2.67)% 和(11.08±3.32)%,P<0.05];糖尿病组斑块内MMP9表达也显著高于非糖尿病组[IA 102 485±20 431和75 280±13 106,阳性面积百分比(18.35±3.59)%和(13.65±2.29)%,P<0.01]. 结论 MMP2和MMP9在糖尿病组动脉粥样硬化斑块中的表达显著高于非糖尿病组,MMP2和MMP9在糖尿病患者动脉中表达增强可以部分解释糖尿病患者易于发生动脉粥样硬化斑块破裂.     

L-arginine attenuates acute pulmonary embolism-induced increases in lung matrix metalloproteinase-2 and matrix metalloproteinase-9

STUDY OBJECTIVES: To evaluate the effects of L-arginine on acute pulmonary embolism (APE)-induced pulmonary hypertension and increases in lung matrix metalloproteinase (MMP)-2 and MMP-9 activities. DESIGN: Prospective trial. SETTING: University laboratory. INTERVENTIONS: Using an isolated lung perfusion rat model of APE, we examined whether L-arginine (0, 0.5, 3, and 10 mmol/L; five to seven rats per group) attenuates the pulmonary hypertension induced by the injection of 6.6 mg/kg of 300 microm microspheres into the pulmonary artery. In a second series of experiments (6 to 11 rats per group), we investigated whether nonselective inhibition of nitric oxide (NO) synthases with N(G)-nitro-L-arginine methyl ester (L-NAME; 4 mmol/L) decreases the effects produced by L-arginine. Lung MMP-2 and MMP-9 activities were determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis gelatin zymography. RESULTS: L-arginine at 0.5, 3, and 10 mmol/L attenuated APE-induced pulmonary hypertension by 25 to 42% (all p < 0.05). The protective effect of L-arginine was completely reversed by inhibition of NO synthesis with L-NAME. APE was associated with increased lung MMP-2 and MMP-9 activities (both p < 0.05). While L-arginine at 0.5 mmol/L produced no effect on MMPs, L-arginine 3 at mmol/L and 10 mmol/L attenuated the increases in MMP-2 and MMP-9 activities after APE (both p < 0.05). CONCLUSIONS: L-arginine attenuates APE-induced pulmonary hypertension through mechanisms involving increased NO synthesis and maybe attenuation of lung MMP-2 and MMP-9 activities.     

金属蛋白酶-9及其抑制物-1在实验性心动过速性心肌病中的变化

目的观察心动过速性心肌病(TIC)时金属蛋白酶(MMP)-9及其抑制剂(TIMP)-1的变化。方法对11只犬采用快速右房起搏建立TIC模型组,6只犬作假手术组(对照组)。应用超声心动图和心导管检查测量在窦性心律下的血流动力学数据。应用电子显微镜观察左室组织的超微结构改变。MMP-9及TIMP-1的相对变化通过免疫印迹法获得。结果8周后,与对照组相比,TIC组犬左室舒张末期容积及收缩末期容积均显著增加(P<0.05);左室射血分数在起搏1周后显著减小(P<0.05)。左室压力最大上升速率显著下降,最大下降速率绝对值显著下降(P<0.05和0.001),左室舒张末期压显著增大,左室松弛时间常数明显延长(P<0.05),二尖瓣血流频谱A波峰值流速和E波峰值流速均显著减小。心肌细胞超微结构发生变化,同时MMP-9增加,TIMP-1减少。结论快速右房起搏可制造TIC模型,TIC时MMP-9增加,TIMP-1减少。     

Expression of matrix metalloproteinase-13 and tissue inhibitor of metalloproteinase-1 in acute liver injury

BACKGROUND/AIMS: Matrix metalloproteinase-13, one of the principal neutral proteinases capable of cleaving native fibrillar collagens, is important in the degradation and remodeling of extracellular matrix. However, its precise expression in liver injury has not been characterized. We examined the kinetics of the expression of matrix metalloproteinase-13 and one of its specific inhibitors, tissue inhibitor of metalloproteinase-1, in acute liver injury in rats. METHODS: Acute liver injury was induced by administration of carbon tetrachloride or two different doses of D-galactosamine hydrochloride in Wistar rats. Hepatic matrix metalloproteinase-13 and tissue inhibitor of metalloproteinase-1 mRNA levels were then examined by Northern blotting. RESULTS: All rats survived after liver injury induced by carbon tetrachloride or low doses of D-galactosamine hydrochloride. However, rats died 5 days after induction of liver injury by high doses of D-galactosamine hydrochloride. In carbon tetrachloride-induced liver injury, matrix metalloproteinase-13 mRNA was transiently increased between 6 h and 1 day after injury. Tissue inhibitor of metalloproteinase-1 mRNA expression was increased between 6 h and 3 days after the peak of matrix metalloproteinase-13 expression. Similar patterns of matrix metalloproteinase-13 and tissue inhibitor of metalloproteinase-1 expression were observed in low-dose D-galactosamine hydrochloride-induced liver injury. In contrast, in high-dose D-galactosamine hydrochloride-induced liver injury, tissue inhibitor of metalloproteinase-1 expression peaked before matrix metalloproteinase-13 expression, which was increased 2 days after injury. Both mRNA levels continued to increase until death. CONCLUSIONS: Transient expression of matrix metalloproteinase-13, followed by that of tissue inhibitor of metalloproteinase-1, was observed during recovery from acute liver injury induced by carbon tetrachloride and low-dose D-galactosamine hydrochloride. In contrast, disordered expression of matrix metalloproteinase-13 was observed in fatal liver injury caused by high-dose D-galactosamine hydrochloride. These results indicate that matrix metalloproteinase13 plays an important role in the early phase of recovery from liver injury.     

microRNA对基质金属蛋白酶2和基质金属蛋白酶9的调控及其在主动脉瘤发生发展中的作用

主动脉瘤(AA)是一种发病率和死亡率都很高的心血管疾病,且发病机制极其复杂。研究证实microRNA(miRNA)可以调节AA的多种病理生理过程,包括炎症、细胞外基质(ECM)重构、血管平滑肌细胞增殖和死亡等。基质金属蛋白酶2(MMP-2)和基质金属蛋白酶9(MMP-9)是MMP蛋白酶家族中的重要成员,同样在AA的上述病理生理过程中起着重要作用。近年来发现多种miRNA可通过直接或间接的方式调节AA中MMP-2和MMP-9的表达和活性,从而影响AA的发生发展。文章主要总结了miRNA对MMP-2、MMP-9的调控机制及其在AA病变中的作用,旨在为AA的诊断和治疗提供新思路。     

Plasma matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 as biomarkers of ulcerative colitis activity

AIM: Overexpression of mucosal metalloproteinases (MMP) has been demonstrated recently in inflammatory bowel disease. Their activity can be counterbalanced by the tissue inhibitor of metalloproteinases (TIMP). The aim of this study was to evaluate the effect of ulcerative colitis (UC) on MMP-1 and TIMP-1 plasma concentrations, as two possible biomarkers of the disease activity. METHODS: MMP-1 and TIMP-1 plasma concentrations were measured with an enzyme immunoassay in 16 patients with endoscopically confirmed active UC. RESULTS: Plasma concentrations of both MMP-1 (13.7 +/- 0.2 ng/ml) and TIMP-1 (799 +/- 140 ng/ml) were significantly elevated in UC patients in comparison to healthy controls (11.9 +/- 0.9 ng/ml and 220 +/- 7 ng/ml respectively). There was no correlation between TIMP-1 and MMP-1 concentrations (r=-0.02). TIMP-1 levels revealed significant positive correlations with scored endoscopic degree of mucosal injury, disease activity index and clinical activity index values as well as C-reactive protein concentration. There was no correlation between MMP-1 and laboratory, clinical or endoscopic indices of the disease activity. CONCLUSION: These results confirm the role of both MMP-1 and TIMP-1 in the pathogenesis of ulcerative colitis. However only TIMP-1 can be useful as a biomarker of the disease activity, demonstrating association with clinical and endoscopic pictures.     

金属蛋白酶-9及其抑制物-1在实验性心动过速性心肌病中的变化

目的观察心动过速性心肌病（TIC）时金属蛋白酶（MMP）-9及其抑制剂（TIMP）-1的变化。方法对11只犬采用快速右房起搏建立TIC模型组，6只犬作假手术组（对照组）。应用超声心动图和心导管检查测量在窦性心律下的血流动力学数据。应用电子显微镜观察左室组织的超微结构改变。MMP-9及TIMP-一1的相对变化通过免疫印迹法获得。结果8周后，与对照组相比，TIC组犬左室舒张末期容积及收缩末期容积均显著增加（P〈0．05）；左室射血分数在起搏1周后显著减小（P〈0．05）。左室压力最大上升速率显著下降，最大下降速率绝对值显著下降（P〈0．05和0．001），左室舒张末期压显著增大，左室松弛时间常数明显延长（P〈0．05），二尖瓣血流频谱A波峰值流速和E波峰值流速均显著减小。心肌细胞超微结构发生变化，同时MMP-9增加，TIMP-1减少。结论快速右房起搏可制造TIC模型，TIC时MMP-9增加，TIMP-1减少。     

Matrix metalloproteinase-9 and metalloproteinase-2 activity and expression is reduced by melatonin during experimental colitis

Abstract:  Matrix metalloproteinases (MMPs) are associated with matrix turnover in both physiological and pathological conditions. Several data indicate that MMPs play an important role in the pathogenesis of colitis. Various evidence has documented that the pineal secretory product melatonin exerts an important anti-inflammatory effect in different experimental models including colitis. However, no reports are available on the relationship between the activity and expression of MMPs and anti-inflammatory effect of melatonin. The aim of the present study was to evaluate whether melatonin prevents the experimental colitis in rats by regulating MMP-9 and MMP-2 activity and expression. Colitis was induced by intracolonic instillation of dinitrobenzene sulphonic acid (DNBS). Four days after DNBS administration, colon TNF- α production was associated with colon damage. Biochemical methods and zymography were used to analyse MMP-9 and MMP-2 activities in colon tissues from DNBS-injured rats. Our studies reveal that melatonin prevented colon injury and lipid peroxidation in rats at 4 days after DNBS-induced colitis. Melatonin also reduced proMMP-9 and MMP-2 activities that were induced in the colon tissues by DNBS administration. Reduced MMP-9 and MMP-2 activities were associated with reduced expression of TNF- α . We conclude that melatonin's ability to reduce DNBS-induced colon injury in rats is related to a reduction in proMMP-9 and MMP-2 activities and expression.     

Imbalanced matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 activities in patients with thromboangiitis obliterans

The pathogenic mechanisms of thromboangiitis obliterans (TAO) are not entirely known and the imbalance of matrix metalloproteinases (MMPs) plays a role in vascular diseases. We evaluated the MMP-2 and MMP-9 circulating levels and their endogenous tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in TAO patients with clinical manifestations. The study included 20 TAO patients (n = 10 female, n = 10 male) aged 38-59 years under clinical follow-up. The patients were classified into two groups: (1) TAO former smokers (n = 11) and (2) TAO active smokers (n = 9); the control group included normal volunteer non-smokers (n = 10) and active smokers without peripheral artery disease (n = 10). Patient plasma samples were used to analyze MMP-2 and MMP-9 levels using zymography, and TIMP-1 and TIMP-2 concentrations were determined by enzyme-linked immunosorbent assays. The analysis of MMP-2/TIMP-2 and MMP-9/TIMP-1 ratios (which were used as indices of net MMP-2 and MMP-9 activity, respectively) showed significantly higher MMP-9/TIMP-1 ratios in TAO patients (p < 0.05). We found no significant differences in MMP-2/TIMP-2 ratios (p > 0.05). We found higher MMP-9 levels and decreased levels of TIMP-1 in the TAO groups (active smokers and former smokers), especially in active smokers compared with the other groups (all p < 0.05). MMP-2 and TIMP-2 were not significantly different in patients with TAO as compared to the control group (p > 0.05). In conclusion, our results showed increased MMP-9 and reduced TIMP-1 activity in TAO patients, especially in active smokers compared with non-TAO patients. These data suggest that smoke compounds could activate MMP-9 production or inhibit TIMP-1 activity.     

The role of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in cryptogenic organizing pneumonia

BACKGROUND: The processes observed in interstitial lung disease are associated with the production, deposition, and proteolysis of the extracellular matrix (ECM), which may lead to irreversible pulmonary structural remodeling or to appropriate repair without fibrosis. Matrix metalloproteinases (MMPs) and a tissue inhibitor of metalloproteinases (TIMPs) are known to regulate remodeling of the ECM and thus to be important in the process of lung fibrosis. Pulmonary structures are extensively remodeled in usual interstitial pneumonia (UIP), whereas severe architectural remodeling is minimally present in cryptogenic organizing pneumonia (COP). However, not much is known about the roles of MMP-9 and/or TIMP-1 in COP. METHODS: Levels of MMP-9, TIMP-1 and the molar ratio of MMP-9/TIMP-1 in BAL fluids were investigated in 11 patients with UIP, in 8 patients with COP, and in 10 control subjects. We checked the levels of MMP-9 and TIMP-1 by means of enzyme immunoassay, and the hydrolytic activity of MMP-9 in BAL fluids was measured by gelatin zymography. Further, we evaluated the expression of MMP-9 and TIMP-1 in lung tissue by immunohistochemistry. RESULTS: The concentrations of MMP-9 and TIMP-1 were significantly increased in patients with UIP and were even higher in patients with COP compared with control subjects. The levels of MMP-9 and TIMP-1 were significantly higher in patients with COP than in patients with UIP. The molar ratio of MMP-9/TIMP-1 was significantly higher in patients with COP than in control subjects. In patients with COP, the concentration of MMP-9 significantly correlated with the number of neutrophils and lymphocytes. Zymographic analysis revealed that the activity of the 92-kd pro-MMP-9 was increased in patients with UIP and was even higher in patients with COP, compared with control subjects. CONCLUSIONS: These data suggest that overproduction of MMP-9 and TIMP-1, and an imbalance between MMP-9 and TIMP-1, may have a role as diagnostic references in COP.     

Expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 in recurrent chronic rhinosinusitis with nasal polyposis

Matrix metalloproteinase (MMP) is involved in the upper airway remodeling process. We hypothesized that MMP had an additive effect on the formation of recurrent nasal polyp. We also investigated the association between the functional promoter polymorphism of MMPs and the intensity of labeling index. Expressions of MMP-2 and MMP-9 were assessed via immunohistochemical staining and compared between different groups, including recurrent nasal polyps, nonrecurrent nasal polyps, and control nasal mucosa. Two promoter functional single-nucleotide polymorphisms (rs3918242 for MMP-9 and rs243865 for MMP-2) were selected to correlate with staining intensity. Expression of MMP-9 was significantly enhanced in gland for recurrent nasal polyp (p = 0.016) and nonrecurrent nasal polyp (p = 0.005) compared to the control. MMP-2 positivity was significantly increased in surface epithelium for recurrent nasal polyp (p = 0.004) compared to the control (p = 0.061). However, there was no significant difference in MMP-9 and MMP-2 expressions between recurrent and nonrecurrent nasal polyps. Genetic polymorphism of MMP-2 and MMP-9 functional promoters was not associated with the intensity of labeling index. These results suggested that up-regulation of MMP-9 in gland and MMP-2 in surface epithelium was characteristic of both recurrent and nonrecurrent nasal polyps. Pathogenesis of recurrent nasal polyps may involve a mechanism other than MMP.