基质金属蛋白酶和组织金属蛋白酶抑制剂在大肠癌中的表达

目的　研究基质金属蛋白酶 (MMPs)及组织金属蛋白酶抑制剂 (TIMPs)在大肠癌中的表达特点 ,与肿瘤发生发展的关系 ,以及在肿瘤治疗中的应用前景。　方法　采用RT PCR方法测定 2 8例大肠癌患者肿瘤组织和周围正常粘膜的基质金属蛋白酶 2 (MMP 2 )、膜型 1 基质金属蛋白酶 (MT1 MMP)、基质溶素 (MMP 7)、组织金属蛋白酶抑制剂 2 (TIMP 2 )、组织金属蛋白酶抑制剂 3(TIMP 3)的mRNA表达状况 ,并将其结果与临床及病理学资料进行统计学分析。　结果　 (1) 2 7例患者肿瘤组织中MMP 7mRNA表达阳性 ,MMP 2、MT1 MMP、TIMP 2和TIMP 3在肿瘤组织和正常粘膜中均有高表达 ;(2 )肿瘤组织中MMP 7mRNA的表达水平与大肠癌患者的Dukes′分期相关 (P <0 0 1) ;(3)淋巴结阳性患者的肿瘤组织TIMP 2表达水平为 (1 2 5± 0 46 )明显高于淋巴结阴性患者的 (0 75± 0 41) ,差异有显著性意义 (P <0 0 1) ;(4)大肠癌患者癌周正常粘膜TIMP 3mRNA表达随患者Duke′s分期的进展和肿瘤浸润深度的增加而降低 (P <0 0 1) ;(5 )TIMPs与MMPs之间无明显相关关系 (P >0 1)。　结论　MMP 7可望成为诊断大肠癌的敏感指标 ;人工诱导TIMP 2、TIMP 3或阻断MMP 7、MMP 2、MT1 MMP的表达可能抑制肿瘤的浸润和转移 ,成为肿瘤治疗的新途径。     

基质金属蛋白酶2,9及金属蛋白酶组织抑制剂1在肾盂移行细胞癌中的表达及意义

目的 探讨基质金属蛋白酶2（MMP-2），9（MMP-9）及金属蛋白酶组织抑制剂1（TIMP-1）表达与肾盂移行细胞癌分级、分期及预后的关系。方法 采用免疫组化SP法检测117例肾盂移行细胞癌标本MMP-2，MMP-9发TIMP-1表达水平。患者中男97例，女20例。平均年龄59岁。肿瘤病理分级：G123例、G273例、G321例；TNM病理分期：Ta22例、T127例、T221例、T325例、T422例。结果 肾盂癌组织MMP-2表达阳性率81．2％（95例），MMP-9表达阳性率72．6％（85例），TIMP1表达阳性率72．6％（85例），阳性表达强度和阳性细胞分布不均匀，主要位于肿瘤细胞的胞质，随肿瘤分级、分期增加，MMP-2、MMP-9阳性表达率呈递增趋势，FL与预后相关，差异有统计学意义（P〈0．05）。TIMP-1阳性表达率随分级、分期增加呈递减趋势，但其差异无统计学意义（P〉0．05），TIMP-1表达强度与患者的生存时间无明显相关性。单因素方差分析发现MMP-9／TIMP-1比值与肿瘤临床病理分级、分期密切相关，随着分级、分期增加呈递增趋势（P〈0．05）。结论 MMP-2及MMP-9检测在肾盂癌病理分级、分期中有重要价值。MMP-2、MMP-9及MMP-9／TIMP-1比值在肾盂癌的预后判断中有重要意义。     

基质金属蛋白酶在胃癌组织中的表达

近年来的研究表明，基质金属蛋白酶（ｍａｔｒｉｘｍｅｔａｌｏｐｒｏｔｅｉｎａｓｅｓ，ＭＭＰｓ）能促进肿瘤的侵袭，而它们的活性可被其组织抑制物（ｔｉｓｕｅｉｎｈｉｂｉｔｏｒｓｏｆｍｅｔａｌｏｐｒｏｔｅｉｎａｓｅｓ，ＴＩＭＰｓ）所抑制［１］。本研究旨在了...     

基质金属蛋白酶家族在颅脑损伤患者中表达水平的变化

目的 探讨颅脑损伤(TBI)患者基质金属蛋白酶(MMPs)和基质金属蛋白酶抑制剂(TIMPs)水平之间的关系以及与临床预后的相关性.方法 收集颅脑损伤患者30例,并分为轻重两组,分别留取24、72、120 h内脑脊液及静脉血,10例健康体检者为对照组,用双抗体夹心酶联免疫吸附试验(ELISA)法检测MMPs和TIMPs水平.结果 本实验检测到MMP-9在颅脑损伤患者组脑脊液中24 h内达到高峰[(71.34±13.93) μg/L],可以持续72 h.TIMP-1在120 h内可达高峰[(162.24±17.15) μg/L],相对第72小时及第24小时内差异有统计学意义(P＜0.05).颅脑损伤患者与对照组的MMP-9、MMP-2、TIMP-1及TIMP-2无论脑脊液还是血液中的表达差异均有统计学意义(P＜0.05).重度TBI患者组的MMP-9在脑脊液水平显著高于轻度TBI患者组.颅脑损伤患者组伤后MMP-9 (24 h)含量与TIMP-1(120 h)含量呈正相关(P＜0.01).结论 MMPs和TIMPs在颅脑损伤患者脑脊液和血浆中增加,TIMP-1和MMP-9呈正相关,MMP-9可以作为预测颅脑损伤患者临床预后的指标.     

基质金属蛋白酶在腹主动脉瘤组织中的表达

目的探查基质金属蛋白酶类（MMPs）在腹主动脉瘤（AAA）组织中产生的源泉。方法采用间质胶原酶（MMP-1）和明胶酶以MMP-9）的mRNA探针在20例AAA组织及4例正常人腹主动脉组织的切片上行原位杂交实验结果MMP-1及MMP-9在巨噬细胞、平滑肌细胞和淋巴细胞均有表达,其中巨噬细胞的MMPs表达强烈。结论MMPs在AAA的形成和扩张中发挥重要作用,炎性细胞是产生MMPS的主要源泉,并影响问质细胞的MMPS表达。     

基质金属蛋白酶及其抑制剂与骨肉瘤

寻找新方法,提高骨肉瘤(OS)治愈率,已成为骨科研究的重点.多个基因参与OS的发生发展,基质金属蛋白酶(MMP)与MMP组织抑制剂(TIMP)平衡紊乱在OS中起重要作用.MMP表达与肿瘤分级或侵袭性相关,且与复发或转移风险相关;TIMP表达与较弱的肿瘤侵袭行为及良好预后相关,其中以明胶酶(MMP-2、MMP-9)及TIMP-2、TIMP-1与OS关系最密切.明胶酶和MT1-MMP过表达多提示OS预后不良.尽管MMP-9、TIMP-1有不同作用,对疾病不同时期有重要意义,但都可作为OS不良预后的标记物,对高危病人更好地划分亚型有意义.抑制MMP治疗OS有潜在可行性.该文就MMP及TIMP在OS研究中的进展作一综述.     

基质金属蛋白酶及其抑制剂和增殖细胞核抗原在大肠肿瘤中的表达及意义

大肠癌患者根治术后约半数死于转移和 (或 )复发。基质金属蛋白酶 (matrixmetalloproteinases,MMPs)中MMP9可水解基底膜 (basementmembrane,BM)和细胞外基质 (extracellularmatrix ,ECM)中IV型胶原等多种成分 ,金属蛋白酶组织抑制剂 (tissueinhibitorofmetalloproteinase,TIMP1)可特异抑制其活性。增殖细胞核抗原 (proliferativecellnuclearantigen ,PCNA)是DNA多聚酶δ辅助蛋白 ,三者均与肿瘤密切相关。一、资料与方法大肠腺癌标本 5 2例 ,大肠腺瘤标本15例 (7例管状腺瘤 ,8例绒毛状腺瘤 ) ,正常上皮组织 10例 ,均经病理学证实。…     

基质金属蛋白酶及其抑制剂在肾脏病中的作用

在各种肾脏疾病的基础研究中 ,基质金属蛋白酶 (ｍａｔｒｉｘｍｅｔａｌｌｏｐｒｏｔｅｉｎａｓｅｓ ,ＭＭＰｓ)及其抑制剂 (ｔｉｓｓｕｅｉｎｈｉｂｉｔｏｒｏｆｍａｔｒｉｘｍｅｔａｌｌｏｐｒｏｔｅｉｎａｓｅｓ,ＴＩＭＰｓ)的作用越来越受到重视 ,因大多数肾脏疾病病理表现中 ,均有不同程度的细胞外基质 (ＥｘｔｒａｃｅｌａｒＭａｔｒｉｘ,ＥＣＭ)异常增多 ,ＭＭＰｓ及ＴＩＭＰｓ之间精密的平衡关系在ＥＣＭ转换中起重要作用。本文就这一方面的研究近况做一简述。　　 1　基质金属蛋白酶及其抑制剂研究简介1 .1　ＭＭＰｓ　是ＥＣＭ降…     

基质金属蛋白酶及其抑制因子在边缘系统胶质瘤中的表达

目的探讨基质金属蛋白酶(MMPs)MMP2、MMP9及其组织抑制因子(TIMPs)TIMP2在边缘系统胶质瘤侵袭过程中的作用。方法利用免疫组织化学方法检测MMP2、MMP9及TIMP2在35例高、低级别胶质瘤和20例脑膜瘤中的表达。结果①MMP2及MMP9在高级别胶质瘤中的表达明显高于低级别胶质瘤,在低级别胶质瘤中的表达明显高于脑膜瘤,差异有显著性。②TIMP2在高级别胶质瘤中的表达明显低于低级别胶质瘤,在低级别胶质瘤中的表达明显低于脑膜瘤,差异有显著性。结论①MMP2及MMP9的表达与胶质瘤的恶性程度有关,可能成为胶质瘤恶性程度和预后的判断指标。②TIMP2是MMP2的抑制因子,两者之间失衡是促进胶质瘤侵袭的重要因素之一。     

基质金属蛋白酶13抑制剂在骨关节炎治疗中的现状与展望

骨关节炎(OA)是一种以关节软骨的变性、破坏及骨质增生为特征的慢性关节病.基质金属蛋白酶13(MMP13)是在骨关节炎发生发展过程中的一种关键介质,而MMP13抑制剂则能够通过对MMP13的抑制作用起到保护软骨细胞的作用.本文简要回顾了目前在临床工作和基础研究中被人们所关注的各种MMP13抑制剂,横向对比其优劣性,对未...     

The role of polyphosphates in the sequestration of matrix metalloproteinases

This study outlines the potential of a novel therapeutic dressing for the management of chronic wounds. The dressing incorporates polyphosphate, a non toxic compound with a number of beneficial characteristics in terms of wound healing, in a foam matrix. The aim of this study was to identify the potential of polyphosphate incorporated in the foam dressing to sequester the activity of matrix metalloproteinases (MMPs) and proteases derived from Pseudomonas aeruginosa. Methods used included gelatin zymography and milk‐casein agar plate analysis. Results have shown that this dressing is effectively capable of reducing the levels of MMP‐2 and MMP‐9 in both their active and latent forms using an in vitro model. The dressing also demonstrated the compound's potential in the regulation of P. aeruginosa derived proteases.     

A critical role for matrix metalloproteinases in liver regeneration

BACKGROUND: Matrix metalloproteinases (MMPs), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) are mediators of liver regeneration. To determine whether MMPs are required for normal hepatic regeneration, we performed 67% hepatectomies on mice treated with a broad-spectrum MMP-inhibitor, and assessed the effect on liver regeneration and urinary MMP activity. METHODS: Mice were subjected to sham operations, 67% hepatectomy, or 67% hepatectomy plus treatment with the broad-spectrum MMP inhibitor Marimastat. Urine collected preoperatively and for 8 d postoperatively was tested for MMP-2 and MMP-9 activity using zymography. Serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin, TNF-alpha, IL-6, and hepatocyte growth factor levels were measured. Liver sections were analyzed by CD31 immunohistochemistry and microvessel density. Mitotic index and proliferating cell nuclear antigen labeling index were determined. RESULTS: The mean regenerating liver weight on postoperative day 8 was 0.72 +/- 0.01 grams for the hepatectomy Marimastat group, and 0.83 +/- 0.02 grams for the hepatectomy control group (P < 0.001). Urinary MMP-9 activity was elevated during hepatic regeneration, and decreased on postoperative day 8 when the liver returned to its preoperative mass. In contrast, urine from hepatectomy Marimastat mice, in which liver regeneration was successfully inhibited, showed consistently low levels of MMP-2 and MMP-9 activity. The hepatectomy Marimastat group also exhibited elevated serum IL-6 levels on post-operative day 8, while serum TNF-alpha soluble receptor II levels were unchanged. Hepatocyte growth factor levels were not significantly different between the control hepatectomy and hepatectomy Marimastat groups at days 2, 4, and 8. Liver microvessel density was reduced in the hepatectomy Marimastat group at day 4. Mitotic index and proliferating cell nuclear antigen index were significantly decreased in the Marimastat hepatectomy group at post-operative day 2. CONCLUSIONS: The broad-spectrum MMP-inhibitor Marimastat inhibits liver regeneration. Microvessel density is reduced at day 4. Furthermore, urinary MMP-9 is elevated during liver regeneration, and this effect is not observed when regeneration is inhibited by the broad-spectrum MMP-inhibitor Marimastat.     

胸腔镜下早期肺癌根治术的临床疗效探讨

【摘要】 目的 探讨胸腔镜下行肺叶切除淋巴结扩清术在肺癌治疗中的安全性、有效性及适应证。方法 2009年8月至2012年8月行全胸腔镜下肺癌根治术83例,其中男性47例,女性36例,平均年龄55.5岁。手术均通过3个胸腔镜操作孔完成,肺叶切除及淋巴结清扫的操作方法和顺序与常规开胸手术大致类似。 结果 本组83例手术均顺利完成,手术时间70~380 min,术中出血80~900 mL,术后胸管引流2~14 d。术中术后未发生严重并发症及死亡病例,中转开胸3例。术后病理结果:腺癌53例,鳞癌28例,肉瘤样癌2例。术后随访平均6.7个月,3例腺癌病人术后3~9个月发生肝转移、脑转移,其余无复发。结论 全胸腔镜下肺癌根治术是可行的,在有效性、彻底性、安全性方面可达到传统开胸手术同样的根治效果,是早期非小细胞肺癌的一种安全、有效、可行的手术治疗方法。     

肺癌组织中p16基因mRNA表达及其临床意义

目的　检测肺癌组织中p16基因mRNA的表达情况 ,探讨p16基因在肺癌发生发展过程中的作用。方法　应用逆转录 聚合酶链反应 (RT PCR)方法检测肺癌组织中p16基因mRNA的表达。结果　肺良性疾病组织、癌周正常肺组织p16基因mRNA表达高于肺癌组织 ,差异有显著性 (P分别 <0 .0 5 ) ;小细胞肺癌p16基因mRNA阳性率 (10 0 %)高于非小细胞肺癌 (4 6.0 %)P <0 .0 5 ;临床Ⅰ、Ⅱ期p16基因mRNA阳性率 (75 .0 %)高于临床Ⅲ、Ⅳ期 (3 4.1%) ,P <0 .0 5 ;无淋巴结转移的病例p16基因mRNA阳性率 (73 .3 %)高于有淋巴结转移的病例 (3 3 .3 %) ,P <0 .0 5 ;高、中分化病例组p16基因mRNA表达阳性率 (5 4.5 %)与低分化病例组 (4 4 .0 %)之间差异无显著性 (P >0 .0 5 )。结论　p16基因的异常改变可能参与了非小细胞肺癌发生发展过程 ,p16基因mRNA的表达检测作为一种辅助指标。     

In vitro and in vivo studies on matrix metalloproteinases interacting with small intestine submucosa wound matrix

Small intestine submucosa (SIS), a bioactive extracellular matrix (ECM) containing critical components of the ECM including collagens, proteoglycans, and glycosaminoglycans, has been widely used for wound healing. The purpose of this study was to investigate the interaction between SIS and matrix metalloproteinases (MMPs). MMP-1, MMP-2, and MMP-9 displayed different binding affinities, indicated by a loss in activity in solution upon incubation with SIS at 53·8%, 85·9%, and 36·9% over 24 hours, respectively. A cell migration study was conducted to evaluate the effects of MMPs and SIS on keratinocytes. The results indicated that MMPs inhibit keratinocyte migration in vitro, and that the inhibition can be significantly reduced by pre-incubating the MMP solution with SIS. To evaluate activity in vivo a diabetic mouse wound healing study was conducted. Biopsy samples were collected on different days for analysis of MMP levels by gelatin zymography. MMP activity was found to be attenuated by SIS treatment on day 3 after wounding. On day 7, the attenuation became less significant indicating that the MMP binding ability of SIS had become saturated. SIS was able to reduce MMP activity immediately, and may reduce the inhibitory effects of MMPs on keratinocyte migration.     

肺隔离药物灌注治疗肺癌临床研究

目的　探讨肺隔离药物灌注(ILP)治疗晚期肺癌的临床疗效。方法　对3 9例不可切除的肺癌、肺功能不能耐受肺切除手术者或多发性转移性肺癌患者进行肺隔离药物灌注化疗,即建立与体循环完全隔离的受累肺/肺叶的体外循环并以阿霉素灌注,灌注起始浓度为6mg/L ,心泵流量(2 0 0±5 0 )ml/min分,维持平均肺动脉压在2 0～2 5mmHg(1mmHg =0 .13 3kPa) ,常温(3 7℃)灌注,持续转流45min。结果　(1)灌注前后生命体征平稳,ILP术后1hMPaP、PVR及PAP升高,PaO2 降低,但循环稳定。(2 )灌注时肺隔离完全,能达到有效的肺内血药浓度[(4 .0 5±1.0 4)mg/L～(4 .19±0 .3 3 )mg/L]。(3 )肿瘤细胞坏死率97.9%。(4 )全组肿瘤治疗总有效率89.7%。(5 )术后1年生存率76.9%。(6)术后并发症主要是肺损伤,但阿霉素起始灌注浓度在6mg/L时肺损伤是可逆的。结论　ILP直接通过肺动脉灌注给药,能大幅度提高局部化疗药物的浓度,提高患者的1年生存率,是治疗晚期肺癌的一种可供选择的有效方法之一     

大鼠肺移植术后早期肺组织ICAM-1表达的变化

目的　研究大鼠肺移植术后早期肺组织细胞间粘附分子 1(ICAM 1)表达的变化。方法　用免疫组织化学 (SABC)法及设置内参照的半定量RT PCR方法 ,对移植肺获再灌注及通气 4h后肺组织的ICAM 1蛋白及其mRNA表达水平进行观察。实验组 (n =6 )肺经低钾右旋糖酐液 4℃保存12h后 ,行同种异体左肺原位移植。对照组 (n =6 )充分游离左侧肺动、静脉及支气管。免疫组织化学检测结果按阴性 (- )、可疑 (± )、弱阳性 ( )、阳性 ( )、强阳性 ( )进行记录。PCR产物电泳后扫描记录条带密度。结果　移植肺肺泡上皮及肺血管内皮细胞免疫着色显著较对照组深 (P<0 .0 1)。其ICAM 1mRNA与β actinmRNART PCR扩增产物相对密度值亦显著高于对照组 ,分别为 0 .873± 0 .0 44和 0 .44 2± 0 .0 37,P <0 .0 1。结论　肺移植术后早期肺组织ICAM 1表达上调 ,这种上调与ICAM 1mRNA增强有关。     

Interaction of periosteal explants with articular chondrocytes alters expression profile of matrix metalloproteinases

Periosteal tissue is a source of growth factors and of osteochondral progenitor cells which makes it suitable for implantation in chondral defects as known in autologous chondrocyte implantation. The aim of this study was to determine the interaction between periosteal tissue and articular chondrocytes with respect to catabolic effectors such as matrix metalloproteinases (MMPs) and IL‐6. Human articular chondrocytes were cultured for up to 28 days as micromass pellets in coculture either with physical contact to periosteal explants or allowing paracrine interactions only. Expression, secretion, and activation of MMPs and IL‐6 were analyzed in chondrocytes, periosteum, and culture supernatants. Both coculture conditions influence gene expression levels of MMPs and IL‐6 in a time‐, culture‐, and tissue‐dependent manner. Coculturing of periosteum with chondrocytes promotes gene expression and secretion of IL‐6. In periosteum, physical contact inhibits MMP‐2 and MMP‐13 gene expression while paracrine coculture induces expression of IL‐6, MMP‐2, ‐7, and ‐13. Pro‐MMP‐2, ‐7, and ‐13 were detected in supernatants of all culture regimens whereas pro‐MMP‐9 was secreted from periosteum only. As a balanced amount of MMP activity is likely required to achieve sufficient integration of the regenerate tissue with the surrounding healthy cartilage, an exceeding expression of proteinases might result in degradation, hypertrophy or rejection of the graft. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:1576–1585, 2010