The molecular mechanisms of the thrombotic complications of atherosclerosis

Our evolving knowledge of the cellular and molecular mechanisms underlying atherosclerosis has helped uncover the underlying causes behind thrombotic complications of this disease. Most fatal coronary thrombosis result from fibrous cap rupture or superficial erosion. Recent research has established a role for matrix metalloproteinases in the regulation of aspects of plaque structure related to propensity to disrupt and provoke thrombosis. Inflammatory pathways impinge on proteinase activity and aspects of oxidative stress that may favour plaque disruption. Novel molecular imaging strategies may permit visualization of proteinase activity in vivo , providing a new functional window on pathophysiology.     

氨基葡萄糖对体外培养人软骨和滑膜细胞软骨寡聚基质蛋白分泌影响的比较

目的 比较氨基葡萄糖对体外培养软骨和滑膜细胞软骨寡聚基质蛋白(COMP)分泌的影响.方法 软骨细胞和滑膜细胞采自骨关节炎(OA)患者,采用分阶段酶消化法体外培养人软骨细胞和滑膜细胞,给予实验兔以氨基葡萄糖临床等效剂量灌胃后,抽取含药血清培养细胞.采用酶联免疫吸附试验(ELISA)检测药物对体外培养的人软骨细胞和滑膜细胞培养上清液中COMP的浓度.结果 体外培养滑膜细胞分泌的COMP浓度[(41.6±0.4)ng/ml]显著高于软骨细胞[(5.5±3.0)ng/ml](19＜0.05).氨基葡萄糖可显著增加体外培养软骨细胞的COMP分泌[(20.3±3.6)与(5.5±3.0)ng/ml,P＜0.05];而对体外培养滑膜细胞的作用较弱,可轻度减少COMP分泌[(36.6±1.3)与(41.6±0.4)ng/ml].结论 氨基葡萄糖含药血清可以促进体外培养软骨细胞分泌COMP,而对体外培养滑膜细胞无明显作用.     

基质金属蛋白酶抑制剂和肝纤维化关系的研究进展

基质金属蛋白酶抑制剂（TIMPs）是基质金属蛋白酶（MMPs）的特异性抑制剂,两者比例失常将导致细胞外基质合成和降解失去平衡,促进肝纤维化的形成。TIMPs表达的异常在肝纤维化形成过程中具有非常重要的作用,本文对TIMPs在肝纤维化形成中的变化及其对肝纤维化诊断、治疗等方面的作用作一综述。     

Phosphorylation of extracellular signal‐regulated kinase 1/2, p38 mitogen‐activated protein kinase and nuclear translocation of nuclear factor‐κB are involved in upregulation of matrix metalloproteinase‐9 by tumour necrosis factor‐α

Background: Upregulation of matrix metalloproteinase‐9 (MMP‐9) induced by tumour necrosis factor‐α (TNF‐α) is reportedly involved in a variety of non‐neoplastic and neoplastic diseases. In this study, we examined which signalling pathways are involved in TNF‐α‐induced MMP‐9 upregulation in cholangiocarcinoma (CC). Methods: We used two CC cell lines: HuCCT‐1 and CCKS‐1. Results: In an ex vivo study using HuCCT‐1 and CCKS‐1 cells, TNF‐α treatment induced MMP‐9 production and activation via interaction with TNF receptor‐1 (TNF‐R1) but not with TNF receptor‐2 (TNF‐R2), shown by zymography, and increased MMP‐9 promoter activity (luciferase assay). As for the signalling pathway, TNF‐α stimulation led to the phosphorylation of extracellular signal‐regulated kinase 1/2 (Erk1/2) and p38 mitogen‐activated protein kinase (p38MAPK) and translocation of nuclear factor κB (NF‐κB) (p65) into the nuclei. Inhibition studies using SB203580 (inhibitor of p38MAPK), U0126 (inhibitor of mitogen‐activated or extracellular signal‐regulated protein kinase 1/2) and MG132 (inhibitor of NF‐κB) showed that the phosphorylation of Erk1/2 and p38MAPK with activation of NF‐κB was closely related to MMP‐9 upregulation in both cell lines. Conclusion: These data suggest that TNF‐α/TNF‐R1 interaction leads to the phosphorylation of Erk1/2 and p38MAPK and nuclear translocation of NF‐κB, which is closely associated with the production and activation of MMP‐9 in cultured CC cells of HuCTT‐1 and CCKS‐1. Upregulation of MMP‐9 with NF‐κB activation may be involved in the tumour invasion of CC.     

MS CT在食管癌诊断中的价值及其征象与MMP-2表达的相关性分析

目的探讨多层螺旋CT（MSCT）在食管癌诊断中的价值及其征象与食管癌组织MMP-2表达的关系。方法对59例经胃镜活检证实的食管癌患者于放疗前行MSCT检查,同时应用免疫组化SP法检测59例食管癌组织和41例癌旁组织中MMP-2表达情况,分析食管癌MSCT征象与MMP-2表达的关系。结果MSCT扫描诊断食管癌57例,与病理诊断结果符合率为96．6％;癌组织和癌旁组织中MMP-2表达阳性率分别为59．32％、31．71％（P=0．007）;食管癌组织MMP-2表达与MSCT所示浸润深度、气管／支气管受侵、主动脉受侵、椎前三角受侵、颈部淋巴结转移、纵隔淋巴结转移均有明显相关性。结论MSCT对食管癌及其淋巴结、远处脏器转移诊断准确率高,且其征象与MMP-2表达密切相关,对明确食管癌治疗方案起重要作用。     

女性压力性尿失禁患者阴道壁组织中MMP-13、MMP-14和TIMP-1的表达变化及意义

目的探讨女性压力性尿失禁（SUI）患者阴道壁组织中基质金属蛋白酶13、14（MMP-13、14）和组织基质金属蛋白酶抑制剂-1（TIMP-1）的表达变化及意义。方法收集30例女性SUI患者的阴道壁组织（SUI组）、30例盆腔器官脱垂患者（POP）的阴道壁组织（POP组）、30例无SUI及POP患者的阴道壁组织（对照组）,采用免疫组化SP法检测这三组的MMP-13、MMP-14、TIMP-1。结果MMP-13、MMP-14在POP组、SUI组中的表达明显高于对照组（P均〈0.05）,TIMP-1在POP组、SUI组的表达明显低于对照组（P均〈0.05）;SUI组MMP-13的表达与TIMP-1表达呈负相关（r=-0.281,P〈0.05）,MMP-14与TIMP-1的表达呈负相关（r=-0.381,P〈0.05）,MMP-13与MMP-14的表达呈正相关（r=0.992,P〈0.05）。结论女性SUI患者阴道壁组织中MMP-13、14表达增加,TIMP-1表达减少,导致胶原降解增加,从而诱发SUI。     

慢性心力衰竭患者心肌细胞外基质含量的变化及螺内酯干预

目的:探讨慢性心力衰竭(心衰)患者心肌细胞外基质的变化及螺内酯的治疗作用.方法:将 61例慢性心衰患者随机分为对照组30例和螺内酯组31例,两组患者给予相同的常规基础治疗,螺内酯组加用螺内酯20 mg/d.两组在治疗开始前及治疗后 3个月和 6个月应用放射免疫分析方法测定血清心肌细胞外基质Ⅲ型前胶原、Ⅳ型前胶原及透明质酸含量,同时做超声心动图测定左心室收缩和舒张功能参数,并按Lipkin法行 6分钟步行实验,按NYHA心功能分级评定.结果:①所有患者上述心肌细胞外基质含量均明显增高,且与左心室射血分数呈负相关(P均＜0.01),治疗6个月后以螺内酯组下降更明显(P＜0.01);②治疗 6个月后,螺内酯组左心室射血分数,二尖瓣舒张早期流速(VE)与二尖瓣舒张晚期流速(VA)之比VE/VA及6分钟步行距离均比对照组显著提高(P＜0.01,P＜0.05).结论:心肌细胞外基质的变化与心衰病程进展明显相关,慢性心衰患者在接受常规治疗的同时长期应用小剂量醛固酮拮抗剂-螺内酯能更完全抑制肾素-血管紧张素-醛固酮系统,抑制心肌细胞外基质重塑,减轻心肌纤维化,改善心功能,提高生活质量.     

基质金属蛋白酶及抑制剂在心肌梗死后心室重构中的作用

目的　研究大鼠心肌梗死后外源性基质金属蛋白酶抑制剂 (多西环素 ,Doxycycline)在心室重构中的作用。方法　 70只SD大鼠随机分为对照组 (10只 )、手术对照组 (9只 )、心肌梗死后 1天组 (10只 )、心肌梗死后 1周组 (10只 )、心肌梗死后 2周组 (8只 )、心肌梗死后 4周组 (7只 )、治疗 2周组 (8只 )和治疗 4周组 (8只 ) ,采用免疫组织化学、酶谱法、免疫印迹 (WesternBlotting)、逆转录 聚合酶链反应 (RT PCR)和AcusonSequoia 5 12超声心动图仪分别测定胶原含量 ,Ⅰ Ⅲ胶原比例、基质金属蛋白酶 2 ,9(MMP 2 ,9)蛋白和mRNA的变化规律及心功能。结果　多西环素治疗后 ,胶原含量明显减少 ,Ⅰ Ⅲ胶原比例下降得以改善 (P <0 .0 5 ) ,MMP 2 ,9蛋白和mRNA在心肌梗死后活性减少 ,基质金属蛋白酶组织抑制剂 1蛋白含量和mRNA转录无明显变化 ,治疗组心功能在术后 4周得以改善。结论　多西环素治疗后MMP 2 ,9的mRNA转录减少 ,MMP 2 ,9活性降低 ,胶原含量减少 ,Ⅰ Ⅲ胶原比例恢复 ,这些影响可能是其改善心肌梗死后心室重构的机制之一。     

益气活血解毒方和血府逐瘀胶囊抑制再狭窄中细胞外基质的对比研究

目的比较益气活血解毒方和血府逐瘀胶囊抑制再狭窄中细胞外基质的作用特点.方法用电刺激兔颈总动脉,喂饲高脂饲料,再用球囊原位扩张造成动脉粥样硬化再狭窄模型,病理取材,HE、Masson染色及平滑肌细胞肌动蛋白α-SM-actin免疫组化分析和图像分析.结果益气活血解毒方能显著减少内膜增生,尤其是降低血管局部胶原含量的作用最显著.而血府逐瘀胶囊可明显降低血清转化生长因子(TGF-β)的含量,也可减少血管局部的胶原含量.同时两组对内膜平滑肌细胞数均无影响.结论两种中医治则治法对再狭窄均有一定程度的抑制作用,但二者作用的病理环节有所不同.     

Serum markers detect the presence of liver fibrosis: a cohort study

BACKGROUND & AIMS: Histologic examination of a liver biopsy specimen is regarded as the reference standard for detecting liver fibrosis. Biopsy can be painful and hazardous, and assessment is subjective and prone to sampling error. We developed a panel of sensitive automated immunoassays to detect matrix constituents and mediators of matrix remodeling in serum to evaluate their performance in the detection of liver fibrosis. METHODS: In an international multicenter cohort study, serum levels of 9 surrogate markers of liver fibrosis were compared with fibrosis stage in liver biopsy specimens obtained from 1021 subjects with chronic liver disease. Discriminant analysis of a test set of samples was used to identify an algorithm combining age, hyaluronic acid, amino-terminal propeptide of type III collagen, and tissue inhibitor of matrix metalloproteinase 1 that was subsequently evaluated using a validation set of biopsy specimens and serum samples. RESULTS: The algorithm detected fibrosis (sensitivity, 90%) and accurately detected the absence of fibrosis (negative predictive value for significant fibrosis, 92%; area under the curve of a receiver operating characteristic plot, .804; standard error, .02; P < .0001; 95% confidence interval, .758-.851). Performance was excellent for alcoholic liver disease and nonalcoholic fatty liver disease. The algorithm performed equally well in comparison with each of the pathologists. In contrast, pathologists' agreement over histologic scores ranged from very good to moderate (kappa = .97-.46). CONCLUSIONS: Assessment of liver fibrosis with multiple serum markers used in combination is sensitive, specific, and reproducible, suggesting they may be used in conjunction with liver biopsy to assess a range of chronic liver diseases.