子宫腺肌症与肿瘤转移相关基因之间关系的研究

目的：探讨肿瘤转移相关基因在子宫腺肌症发生中的作用。 方法： 采用免疫组织化学方法，对43例子宫腺肌症患者、22例对照组（正常子宫内膜）的nm23-H1、基质金属蛋白酶-2（MMP-2）、基质金属蛋白酶-9（MMP-9）、膜型1-基质金属蛋白酶（MT1-MMP）和基质金属蛋白酶组织抑制因子-1（TIMP-1）的表达进行研究。 结果： 子宫腺肌症中，MMP-2、MMP-9和MT1-MMP的表达水平明显高于对照组（P<0.01），nm23-H1和TIMP-1的表达水平无显著差异（P>0.05）。 结论： MMP-2、MMP-9和MT1-MMP在子宫腺肌症的发病过程中可能起重要的作用。     

基质金属蛋白酶-3基因多态性研究进展

基质金属蛋白酶-3（MMP-3）是MMPs家族中的重要成员之一，可降解细胞外基质中的多种成分，参与组织重构。MMP-3基因存在多态性位点，这些多态性位点会影响MMP-3的表达，从而影响疾病的发生和发展。目前研究发现MMP-3基因多态性可能与肿瘤、冠心病、子宫内膜异位症等多种疾病的发生和发展有关。     

妊娠期高血压疾病患者胎盘组织中基质金属蛋白酶-9（MMP-9）和整合素β 3

目的研究基质金属蛋白酶-9（MMP-9）和整合素β3（Integrin β3）在妊娠期高血压疾病患者胎盘组织中的表达,并探讨其与妊娠期高血压疾病发病的关系及两者的相关性。方法采用免疫组织化学染色（SP法）分别检测In-tegrinβ3、MMP-9在10例妊娠期高血压疾病患者及10例正常妊娠者胎盘组织中的表达。结果妊娠期高血压疾病组胎盘Integrinβ3表达明显高于正常妊娠组（P〈0.01）。妊娠期高血压疾病组胎盘MMP-9表达明显低于正常妊娠组（P〈0.01）,且随病情的加重MMP-9的表达有下降趋势,有统计学意义（P〈0.05）。结论本研究显示：与正常妊娠组比较妊娠期高血压疾病患者胎盘组织integrinβ3表达明显增加、MMP-9的表达明显减少,且随病情加重有减少趋势。表明integrinβ3、MMP-9可能参与妊娠期高血压疾病的发生和发展。     

基质金属蛋白酶-9及金属蛋白酶组织抑制因子-1在妊娠期高血压疾病患者胎盘组织中的表达

目的通过研究基质金属蛋白酶-9（MMP-9）及金属蛋白酶组织抑制因子-1（TIMP-1）在正常妊娠和妊娠期高血压疾病患者胎盘中的表达,探讨其与妊娠期高血压疾病发病机制的关系。方法收集山西医科大学第一医院产科和山西中医学院中西医结合医院产科住院分娩的产妇胎盘标本共142例,正常妊娠胎盘组织标本40例为对照组,妊娠期高血压疾病患者胎盘组织标本102例为病例组,通过免疫组织化学二步法,对MMP-9和TIMP-1在胎盘组织中的表达进行检测。结果1.MMP-9及TIMP-1在胎盘组织中的表达部位。在正常妊娠胎盘组织的滋养细胞、蜕膜细胞、间质细胞和血管内皮细胞胞浆中均可见MMP-9、TIMP-1的阳性表达,多为中度阳性和强阳性表达,但在妊娠期高血压疾病患者胎盘组织中,MMP-9未见间质细胞和血管内皮细胞有阳性表达,且表达者多为弱阳性。2.MMP-9在妊娠期高血压疾病患者中的阳性表达与正常妊娠组相比,差异有显著性（P〈0.05）,妊娠期高血压、子痫前期轻度、子痫前期重度组间比较差异有显著性（P〈0.05）。即妊娠期高血压疾病患者胎盘中MMP-9的表达显著低于正常妊娠,且随着妊娠期高血压疾病病情加重,MMP-9阳性表达呈明显减少趋势。3.TIMP-1在正常妊娠和妊娠期高血压疾病患者胎盘中的表达相比较,差异无显著性（P〉0.05）。结论MMP-9表达降低、MMP-9与TIMP-1的平衡状态改变可能与妊娠期高血压疾病发病有关,MMP-9及TIMP-1作为一对相互制约的因素在妊娠期高血压疾病发病中可能起重要作用,MMP-9有望成为妊娠期高血压疾病诊断及判断预后的新指标。     

MMP-2、MMP-9及EMMPRIN在子宫内膜异位症中的表达及临床意义

目的研究基质金属蛋白酶2（MMP-2）、基质金属蛋白酶9（MMP-9）、细胞外基质金属蛋白酶诱导因子（EMMPRIN）在子宫内膜异位症（EMs）的表达和意义。方法应用免疫组化二步法检测EMs患者异位内膜42例、在位内膜42例及正常内膜20例中的MMP-2、MMP-9、EMMPRIN的表达情况,并对它们的EMMPRIN、MMP-2、MMP-9蛋白表达水平进行相关性分析。结果 MMP-2、MMP-9、EMMPRIN在异位内膜组中阳性表达率分别为95.24%、92.86%和90.48%,显著高于在位内膜组、正常内膜组（P〈0.05）;而在位内膜组和正常内膜组差异无统计学意义（P〉0.05）。异位内膜组中,EMMPRIN分别和MMP-2,MMP-9呈正相关性（P〈0.01）。结论 MMP-2、MMP-9、EMMPRIN共同参与了子宫内膜异位症的发生发展;EMMPRIN可能通过促进MMP-2和MMP-9的合成与分泌发挥其作用。     

TGFβ1和MMP-9 mRNA在子痫前期胎盘中的表达及意义

目的通过检测子痫前期患者胎盘组织中TGFβ1和MMP-9 mRNA的表达，探讨其在子痫前期发病机制中的作用。方法用半定量逆转录聚合酶链反应（RT-PCR）技术检测正常妊娠（15例），子痫前期（24例）剖宫产后胎盘组织中TGFβ1和MMP-9基因在转录水平的表达。结果在重度子痫前期胎盘中TGFβ1 mRNA表达量升高；MMP-9 mRNA表达降低，与轻度子痫前期及正常组比较有明显意义。胎盘组织中TGFβ1的表达水平和MMP-9的表达水平呈负相关（P〈0．05）。结论子痫前期胎盘组织中TGFβ1、MMP-9在基因转录水平就发生异常而引起滋养细胞浸润不足，提示两者可能并共同参与子痫前期的发生和发展。     

子宫内膜异位症组织中MMP-2和MMP-9基因表达的意义

目的：探讨MMP-2和MMP-9在子宫内膜异位症发生中的作用。方法：采用免疫组织化学SP法研究25例子宫内膜异位症和22例正常子宫内膜组织中MMP-2及MMP-9的蛋白表达情况；采用RT-PCR法研究33例子宫内膜异位症的异位子宫内膜组织和30例正常子宫内膜组织中MMP-2和MMP-9基因的mRNA表达情况。结果：子宫内膜异位症组中的MMP-2和MMP-9的蛋白表达及mRNA表达均明显高于各自的正常子宫内膜对照组（P<0.05）。结论：MMP-2和MMP-9在子宫内膜异位症的发病过程中可能起重要的作用。     

机械牵张对兔角膜成纤维细胞细胞外基质基因表达的影响

目的 研究机械牵张与白介素-1β（IL-1β）联合作用对兔角膜成纤维细胞细胞外基质相关基因表达的影响。方法 对原代提取的兔角膜成纤维细胞进行牵张幅度15%、频率0.1 Hz的周期性牵张12、24、36 h,同时给予IL-1β处理,采用实时荧光定量PCR检测细胞基质金属蛋白酶（MMPs）、基质金属蛋白酶的组织抑制剂（TIMP-1）和I型胶原α1（Collagen Iα1）mRNA表达变化水平。结果 IL-1β单独作用可以诱导角膜成纤维细胞MMP-1、MMP-3和MMP-9 mRNA表达;MMP-1和MMP-3 mRNA表达随时间而降低,MMP-9、TIMP-1、Collagen Iα1 mRNA则随时间而增加;IL-1β与机械牵张联合作用使MMP-1、MMP-3、MMP-9 mRNA表达水平上调,TIMP-1和Collagen Iα1 mRNA表达下调,且具有时间依赖。单独机械牵张使Collagen Iα1 mRNA表达下降,IL-1β与机械牵张联合作用使其表达进一步下调,且具有时间依赖性。结论 机械牵张与炎性因子联合作用可加剧角膜组织破坏,促进角膜膨隆的发生发展。     

AQP4,MMP-2及MMP-9在高血压性脑出血后脑水肿中的早期表达

目的：探讨水通道蛋白4（AQP4）及基质金属蛋白酶2，9（MMP-2，MMP-9）表达在高血压性脑出血后早期脑水肿发生中的作用。方法：应用免疫组织化学方法检测高血压性脑出血患者出血后24h内血肿周围脑组织中AQP4及MMP-2、MMP-9的表达。结果：高血压性脑出血患者血肿周围有明显的脑动脉硬化和脑水肿发生，正常对照组中未发现明显的MMP-2，MMP-9阳性表达，AOP4可见少量表达，而在高血压性脑出血组出血24h内AQP4，MMP-2及MMP-9则见明显表达（P〈0．01），尤其是AQP4的阳性表达升高更为显著，在小血管及神经胶质细胞中均见大量表达。结论：AQP4、MMP-2及MMP-9的早期上调表达与高血压性脑出血后脑水肿的发生具有密切的关系。尤其是AQP4的表达在早期脑水肿的发生、发展中具有重要的作用。     

胎盘MMP-2、MMP-9及微血管密度在子痫前期发病的初步研究

目的 探讨基质金属蛋白酶（MMP）-2、MMP-9和微血管密度在妊娠高血压疾病患者胎盘中表达及其临床意义。方法 选取2019年1月至2020年12月上海市嘉定区妇幼保健院住院分娩的重度子痫前期、子痫前期、妊娠高血压患者及正常产妇（对照组）各30例。采用免疫组化法检测各组胎盘组织中MMP-2、MMP-9表达水平,并H-E染色再进行微血管密度计数,分析胎盘MMP-2、MMP-9、微血管密度与妊娠高血压疾病程度的关系。结果 4组胎盘MMP-2与MMP-9阳性表达比较（P<0.05）,其表达均随病情加重呈递减趋势;重度子痫前期组、子痫前期组与对照组比较（P<0.05）。4组胎盘微血管密度计数比较,差异有显著性（P<0.05）,其计数随病情加重呈递减趋势;重度子痫前期组、子痫前期组、妊娠高血压组与对照组比较（P<0.05）。胎盘MMP-2、MMP-9、微血管密度与妊娠高血压疾病程度均呈负相关（P<0.05）。结论 胎盘MMP-2、MMP-9及微血管密度计数在妊娠高血压疾病患者胎盘组织中异常表达可作为胎盘的生物学指标,评估病情严重程度。     

Content of matrix metalloproteinase-8 and matrix metalloproteinase-9 in oral fluid of patients with chronic generalized periodontitis

The content of MMP-8 and MMP-9 in oral fluid of 145 patients (95 women and 50 men, 18-52 years) was measured by enzyme immunoassay. We examined 63 subjects with the intact periodontium and 82 patients with chronic generalized periodontitis (25 patients with mild disease, 45 patients with moderate disease, and 12 patients with severe disease). All patients were examined during the remission of chronic periodontitis and did not have clinical signs of associated somatic diseases. No significant differences were found in the content of MMP-8 and MMP-9 in oral fluid from periodontitis patients and subjects with the intact periodontium. The content of MMP-8 an MMP-9 in oral fluid of patients with severe periodontium was slightly higher than that in other patients and subjects with the intact periodontium. The depth of the periodontal pocket was shown to be the most reliable clinical sign for the state of periodontal tissues. A strong correlation was revealed between this criterion and MMP-9 content in oral fluid.     

Polyethylene wear particles do not induce inflammation or gelatinase (MMP-2 and MMP-9) activity in fibrous tissue interfaces of loosening total hip arthroplasties

In vitro and in vivo studies have suggested that polyethylene wear particles are the main cause for osteolysis in prosthetic loosening. Elevated amounts of proteases including gelatinases (or matrix metalloproteinases MMP-2 and MMP-9) have been found in fibrous tissue interfaces of loosened total hip arthroplasties suggesting that proteolysis plays a role in osteolysis. The presence of proteases does not mean that they are active, because activity of proteases is highly regulated at the post-translational level. We investigated whether the activity of two major proteases that are active extracellularly and have been associated with loosening, MMP-2 and MMP-9, is involved in loosening of non-cemented hip implants with polyethylene acetabular components. Eight interface tissues retrieved during revision were studied with light and electron microscopy and by in situ zymography to localize MMP-2 and MMP-9 activity in combination with immunohistochemistry to localize MMP-2 and MMP-9 proteins. All interface tissues contained large amounts of polyethylene wear particles, either in large accumulations or dispersed in the extracellular matrix or intracellularly in fibroblasts. Particles were not encountered in association with MMP-2 or MMP-9 activity or leukocytes. Inflammation was never found. MMP-9 activity was restricted to macrophages and MMP-2 activity was restricted to microvascular endothelial cells mainly outside areas where particles were present. Our data indicate that wear particles do not induce activation of leukocytes or MMP-2 or MMP-9 activity. Therefore, aseptic loosening may not be particle induced but initiated by other mechanisms such as mechanical stress.     

Cisplatin-induced kidney injury in the rat: l-carnitine modulates the relationship between MMP-9 and TIMP-3

Renal interstitial fibrosis is a major complication of cisplatin treatment, due to the increased accumulation of extracellular matrix (ECM) proteins whose remodeling is important for the development of normal tissues; indeed, its malfunction might play a role in the etiology of various diseases.Biopharmacological evaluations suggest that l-carnitine can prevent cardiac metabolic damage caused by doxorubicin, as well as can inhibit cisplatin-induced injury in the kidney and in the small intestine, without any interference with the drug's antitumoral properties. Since the glomerular basement membrane and the mesangial matrix constitute the ECM of the renal glomerulus, we examined the localization and expression of MMP-9 and TIMP-3 in normal rat kidney and the changes in their expression over a period of time by treatment with cisplatin, with and without l-carnitine. MMP-9 immunoreaction in cisplatin-treated rat kidney tissue suggests an involution of the basal membrane, an alteration of ECM components and low glomerular function, due to the increased thickness of the mesangium. Our results suggest that the matrix remodeling by MMP-9 and TIMP-3, in the later stages, can play an important role in the development of glomerular sclerosis and interstitial fibrosis after cisplatin treatment. It can also be postulated that l-carnitine protects from cisplatin injury, by modulating the relationship between MMP-9 and TIMP-3.     

MMP-2、MMP-9与Ⅳ型胶原在大肠癌中的表达及其相关性研究

目的: 研究大肠癌中MMP-2、 MMP-9与IV型胶原的表达及其相关性.方法: 对30例Dukes'B、 C期大肠癌患者的癌组织和正常组织进行IV型胶原、 MMP-2、 MMP-9的免疫组织化学检测, 并进行相关性分析.结果: IV型胶原在大肠癌组织中的表达明显降低; MMP-2、 MMP-9在大部分正常大肠组织中均未见表达, 仅少数见到有阳性表达, 而在癌组织中表达明显增强.IV型胶原评分与MMP-9表达之间呈负相关.结论: 大肠癌组织中IV型胶原的表达明显降低, MMP-9对大肠癌中IV型胶原的降解起着重要作用.     

Regulation of matrix metalloproteinase-9 in endometrium during the menstrual cycle and following administration of intrauterine levonorgestrel

Remodelling of endometrial tissues is fundamental to the cyclical changes that occur during the menstrual cycle, implantation and, in the absence of pregnancy, at menstruation. The enzyme matrix metalloproteinase-9 (MMP-9) is recognized as important in these processes but its regulation is not well defined. These studies have demonstrated that MMP-9 activity is present in the endometrium and exhibits cyclical changes in its distribution in the glandular and stromal cells. MMP-9 protein is present throughout the cycle with highest expression, as determined by semiquantitative analysis of specific MMP-9 immunoreactivity, in glandular cells during the mid secretory phase. A similar distribution was observed in first trimester decidua. In women with a levonorgestrel intrauterine system (LNG-IUS), which delivers high local concentrations of progestagen to the uterine cavity, MMP-9 is highly expressed in both endometrial glandular and stromal cells, and in the vasculature (in endothelial and perivascular cells). It can be concluded that MMP-9 is stimulated directly or indirectly by progesterone. Furthermore, MMP-9 may play a role in the remodelling of the endometrium that occurs during the menstrual cycle and in the aetiology of the morphological changes and breakthrough bleeding associated with long-term progestagen administration via a LNG-IUS.     

Immunolocalization of MMP-2 and MMP-9 in human rheumatoid synovium

Matrix metalloproteinase (MMP)-2 and MMP-9, two important members of the matrix metalloproteinase family, have been shown critical contributions in intra-tumor angiogenesis and invasion of tumor progression, and they might also play important roles in the angiogenesis as well as the pannus formation of rheumatoid arthritis (RA). In the present study, we used the immunohistochemistry, the immunofluorescence staining and the con-focal scanning methods to characterize the immunolocalization of MMP-2 and MMP-9 in RA synovium tissues. Our results showed that both MMP-2 and MMP-9 immunostaining could be found in synoviocytes and vascular endothelial cells. Moreover, our con-focal scanning also showed that MMP-2 could be found in infiltrating CD14⁺ monocytes and CD68⁺ macrophages, and MMP-9 could be found in infiltrating CD68⁺ macrophages in RA synovium tissues, while weak or negative staining of these two MMPs could be found in infiltrating CD20⁺B cells and CD3⁺T cells in RA synovium. Thus, our finding suggests that both MMP-2 and MMP-9 expressed by synoviocytes as well as certain infiltrating immune cells role importantly in the angiogenesis in RA progression.     

Activation of neutrophil collagenase in periodontitis

Neutrophil collagenase (matrix metalloproteinase 8 [MMP-8]) is an important mediator of tissue destruction in inflammatory diseases. Studies of anaerobic periodontal infections have shown that active MMP-8 in gingival crevicular fluid is associated with the degradation of periodontal tissues in progressive periodontitis whereas the latent enzyme is predominant in gingivitis. Since the activation of MMP-8 appears to be a crucial step in periodontitis, we have examined the activation of MMP-8 in gingival crevicular fluid samples by using a soluble biotinylated collagen substrate. Analysis of gingival crevicular fluid in periodontitis, gingivitis, and controls revealed sixfold (P < 0.001)-higher levels of active collagenase in periodontitis (n = 12) samples compared to gingivitis (n = 17) samples, which exhibited low levels of activity, while controls (n = 25) showed no activity. After gingival crevicular fluid was collected, no further activation of latent collagenase occurred in vitro. Although both MMP-1 and MMP-8, but not MMP-13, could be detected by immunoblots, blocking antibodies to MMP-1 showed that collagenase activity was largely contributed by MMP-8, which was localized to the matrix of diseased tissues. The MMP-8 in gingival crevicular fluid migrated primarily as a 60-kDa form with smaller amounts of a 78-kDa species, whereas MMP-8 isolated from peripheral neutrophils migrated at 70 and 89 kDa, corresponding to active and latent forms of the enzyme, respectively. Most of the MMP-8 in the 60- and 70-kDa bands selectively bound to tissue inhibitor of metalloproteinase 2 and collagen, indicating that most, but not all, of the enzyme in these bands was in an activated form. However, the amounts of the 78- and 60-kDa forms from gingival crevicular fluid in different samples did not correlate (r2 = 0.028) with the latent and active enzyme measured by collagenase assay. Collectively, these studies have identified distinct forms of latent and active MMP-8 in gingival crevicular fluid that appear to result from a unique activation mechanism that occurs in periodontitis. The complexity of MMP-8 activation is further indicated by the presence of latent, activated, and superactivated forms of MMP-8 in the 60- and 70-kDa bands obtained from gingival crevicular fluid and neutrophil samples, respectively.     

血管内皮生长因子和基质金属蛋白酶-9的表达与胰腺癌侵袭转移的关系

目的 :研究血管内皮生长因子 (VEGF)与基质金属蛋白酶 - 9(MMP - 9)在胰腺癌中的表达与胰腺癌侵袭转移的关系。方法 :采用免疫组化ABC法对 30例胰腺癌手术切除标本的VEGF及MMP- 9蛋白表达进行检测。结果 :VEGF和MMP - 9在胰腺癌组织中的阳性表达率分别为 83 3 % (2 5/ 30 )和60 % (1 8/ 30 ) ,在正常胰腺组织中分别为 45 % (9/ 2 0 )和 2 5 % (5/ 2 0 ) ,癌组织与正常组织间存在显著差异 (P <0 0 5) ;VEGF和MM - 9的阳性表达率与胰腺癌的侵袭转移显著相关。结论 :VEGF和MMP - 9在胰腺癌生长、侵袭和转移过程中起着重要的作用 ,对预测胰腺癌复发、转移具有一定的意义     

Implication of extracellular matrix metalloproteinases in the course of chronic inflammatory airway diseases

Matrix metalloproteinases (MMPs) are major proteolytic enzymes that are involved in extracellular matrix (ECM) turn over. MMP-2 (gelatinase A) and MMP-9 (gelatinase B) cleave type IV collagen, which is an important constituent of basement membrane. These enzymes play an important role in normal tissue homeostasis, but imbalance between MMPs and their tissue inhibitors (TIMPs) is thought to be a critical factor in regulating tissue remodeling. MMP-2 is produced by fibroblasts, endothelial, and epithelial cells, while MMP-9 is mainly produced by inflammatory cells. The role of MMPs was investigated through biochemical analysis or in situ expression, in the pathogenesis of two chronic inflammatory airway diseases, asthma and nasal polyposis. Both are characterized with the accumulation of active inflammatory cells, matrix remodeling and epithelial changes. Increased levels of MMP-9 and TIMP-1 were found in asthmatic subjects and NP. In NP, MMP-9 expression was detected in epithelial, endothelial and inflammatory cells. In this setting, MMP-9 could play a crucial role in the transmigration of basement membrane components by inflammatory cells leading to inflammatory cell accumulation and maintenance of inflammation in airway. Moreover, MMP-9 may contribute to cell migration, an important mechanism involved in the repair of the respiratory epithelium.     

Genetic association between matrix metalloproteinase MMP-9 and MMP-3 polymorphisms and Japanese sporadic Alzheimer's disease

Recent studies suggested that matrix metalloproteinases (MMPs) might play an important role in the pathophysiology of Alzheimer's disease (AD). MMP-9 and MMP-3 are reported to degrade amyloid beta and have several functional polymorphisms associated with other common diseases. Four common polymorphisms in each of MMP-9 and MMP-3 were examined in AD cases and normal control individuals. Common polymorphisms of MMP-9, rs3918248, rs2664538, rs2250889 and rs2274756 showed no association with risk for AD. We observed strong linkage disequilibrium (LD) between rs2664538 and rs2250889 in our Japanese samples. The polymorphisms of MMP-3; 5A/6A insertion polymorphism in the promoter, rs3025079, rs520540 and rs679620 also did not influence risk for AD. LD of the 5A/6A polymorphism with rs679620 was relatively strong. These results suggest that the common polymorphisms of MMP-9 and MMP-3 investigated here are not associated with AD.