纤溶酶原激活物抑制剂-1与肝纤维化

肝纤维化形成过程中,主要以细胞外基质沉积为主要病理特征.目前研究表明有很多因素参与细胞外基质沉积,纤溶酶原激活物抑制剂-1在此过程中发挥着重要作用,本文就纤溶酶原激活物抑制剂-1参与纤维化的机制作一综述.     

纤溶酶原激活物抑制剂-1在肝纤维化中的作用

肝纤维化是肝脏对慢性损伤的一种修复反应,是慢性肝病共有的病理改变,其特征是以胶原为主的细胞外基质(ECM)在肝内过多沉积.目前研究证实,纤维蛋白溶解系统(纤溶系统),特别是尿激酶型纤溶酶原激活物(uPA)及其主要抑制物纤溶酶原激活物抑制剂-1(PAI-1)与肝纤维化关系密切.PAI-1可阻止uPA激活纤溶酶原,降低基质金属蛋白酶(MMP)活性导致ECM在肝内过多沉积.本文就PAI-1在纤维化疾病特别是肝纤维化中的作用作一综述.     

肝硬化患者纤溶酶原激活物以及基质金属蛋白酶抑制剂蛋白表达

[目的]探讨肝纤维化不同分级α-平滑肌肌动蛋白(α-SMA)、基质金属蛋白酶1(MMP-1)、基质金属蛋白酶抑制剂1(TIMP-1)蛋白表达以及血浆尿激酶型纤溶酶原激活物(uPA)、纤溶酶原激活物抑制剂1(PAI-1)变化在肝纤维化发生发展中的意义.[方法]慢性肝病患者37例,依据病理变化分为0～4级,其中1级8例,2级9例,3级7例,4级13例;正常对照组6例.免疫组化法测定肝组织α-SMA、MMP-1、TIMP-1蛋白表达.ELISA法测定血浆uPA、PAI-1、转化生长因子β1(TGF-β1)变化.并同时检测血透明质酸、血清清蛋白、凝血酶原时间及其活动度、胆红素改变.[结果]随着肝纤维化的发展,肝组织α-SMA、MMP-1、TIMP-1蛋白表达以及血浆uPA、PAI-1、TGF-β1水平逐渐增加.在肝纤维化3、4级α-SMA、TIMP-1蛋白表达、血浆PAI-1水平增加尤为明显,而血浆uPA水平、肝组织MMP-1蛋白表达差异无统计学意义,表现为uPA、MMP-1相对不足.在肝纤维化4级血浆TGF-β1与α-SMA蛋白表达呈正相关(P＜0.05),α-SMA蛋白表达与PAI-1、TIMP-1蛋白表达呈正相关(均P＜0.05).[结论]肝组织TIMP-1蛋白表达以及血浆PAI-1在肝硬化发展过程中发挥着重要作用.抑制TGF-β1的早期激活,抑制肝星状细胞激活与PAI-1过度表达,适当增加MMP-1表达,可能有助于增加肝细胞外基质降解,从而延缓肝硬化的发生发展.     

实验性肝纤维化大鼠肝组织中纤溶酶原激活物抑制剂-1分布与表达

为动态观察肝纤维化大鼠模型肝组织中PAI-1的分布和表达,采用CC l4制备肝纤维化大鼠模型进行观察试验。通过对模型肝组织进行PAI-1免疫组化染色和采用图文分析系统检测PAI-1面密度。结果如下:PAI-1阳性染色主要分布在肝纤维化活跃的汇管区、肝组织变性坏死处;PAI-1面密度随注射CC l4时间的延长而递增(3周0.1356±1.052E-2;6周0.1979±1.191E-2;9周0.2321±2.159E-2,P<0.05),与α-SMA阳性细胞数、胶原面积、HPY含量变化一致;停止注射四氯化碳3周时PAI-1面密度明显下降(7.966E-2±5.587E-3)低于6周时(P<0.05),与α-SMA阳性细胞数变化一致,而胶原面积、HPY含量与9周时相同,无明显下降。肝组织中PAI-1的表达与星状细胞活化有关,可反映肝纤维化的进展,但不能反映肝纤维化程度。     

纤溶酶原激活物抑制剂-1与肾间质纤维化

肾间质纤维化(RIF)是各种慢性肾脏疾病发展到终末期肾病的共同归路.纤溶酶原激活物抑制剂(PAI)的表达及活性异常在RIF病变中发挥着至关重要的作用.该文就PAIs系统在RIF发生发展过程中的作用做一综述.     

转化生长因子β1刺激肝星状细胞中纤溶酶原激活物抑制剂1表达

肝星状细胞(HSC)的激活是肝纤维化发生的中心环节.活化的HSC大量增殖,并合成以胶原为主的细胞外基质(ECM)沉积在肝内.转化生长因子(TGF)β是激活HSC并促进其增殖的最重要细胞因子之一,可促进ECM产生,导致并加速肝纤维化的发生和发展.本实验拟通过免疫细胞化学法检测纤溶酶原激活物抑制剂(PAI)1在HSC中的定位,逆转录聚合酶链反应(RT-PCR)及免疫细胞化学法等研究TGF β1促进PAI 1 mRNA和蛋白质的表达,探讨PAI 1在肝纤维化发生和发展中的作用.     

α-平滑肌肌动蛋白表达及血浆转化生长因子β1变化在肝纤维化发生发展中的作用

目的 测定肝纤维化不同分级α-平滑肌肌动蛋白(α-SMA)、尿激酶型纤溶酶原激活物(uPA)、纤溶酶原激活物抑制剂-1(PAI-1)蛋白表达及血浆转化生长因子β_1(TGF β_1)变化,以探讨其在肝纤维化发生发展中的意义。方法 慢性肝病患者37例,依据肝组织HE、VG染色分为0～4级,其中1级8例,2级9例,3级7例,4级13例。6例正常肝组织为正常对照组。免疫组织化学法测定肝组织α-SMA、uPA、PAI-1蛋白表达变化。ELISA法测定血浆TGF β_1变化。检测血透明质酸。结果 肝纤维化S_(1～4)级肝组织α-SMA表达分别为(4.2±0.5)％、(5.5±0.7)％、(7.9±0.5)％、(9.7±0.7)％,uPA分别为(4.0±0.5)％、(4.8±0.5)％、(5.0±0.5)％、(4.8±0.4)％,PAI-1分别为(4.7±0.4)％、(7.0±0.4)％、(8.9±0.3)％、(11.9±0.3)％,且随肝纤维化分级增加血浆TGF β_1水平也逐渐增加。在肝纤维化S_3、S_4级,α-SMA、PAI-1蛋白表达以及血浆TGF β_1水平增加尤为明显,而uPA仅轻微增加,表现为uPA相对不足。结论 肝组织α-SMA、uPA、PAI-1蛋白表达以及血浆TGF β_1变化在肝纤维化发生发展过程中发挥着重要作用,抑制TGF β_1的早期激活,抑制肝硬化晚期PAI-1过度表达,可能有助于抑制肝星状细胞的激活、增加肝细胞外基质降解,从而有助于延缓肝硬化的发生发     

纤溶酶原激活物抑制剂-1与动脉粥样硬化

摘要纤溶酶原激活物抑制剂-1可能是动脉粥样硬化的危险因素，它通过影响动脉附壁血栓形成、内皮再生、新内膜形成和基质沉积等环节参与动脉粥样硬化。     

尿激酶型纤溶酶原激活物及其抑制物与肝纤维化

肝纤维化是肝脏对慢性损伤的一种修复反应,以细胞外基质(ECM)在肝内过多沉积为特征。尿激酶型纤溶酶原激活物(uPA)及其抑制物(PAI)是调节基质金属蛋白酶(MMP)活性和ECM降解的关键因素。uPA通过uPA-纤溶酶-MMP级联反应途径,最终可产生活化的纤溶酶和MMP,后两者是降解ECM的重要物质。因而调控uPA的表达,可能为肝纤维化的治疗提供新的途径。     

PAI-1与代谢综合征

血浆纤溶酶原激活物抑制剂(PAI)-1是纤溶系统的主要调控因子。近年研究发现,PAI- 1的升高是代谢综合征的一个核心特征,与肥胖、胰岛素抵抗、2型糖尿病、心血管疾病、脂代谢紊乱和高血压等密切相关,甚至可能影响内脏脂肪的蓄积。因此,对PAI—1的直接抑制不仅为降低心血管危险因素提供新的治疗策略,也对治疗肥胖、胰岛素抵抗及2型糖尿病等有益。     

Dynamic expression of extracellular signal-regulated kinase in rat liver tissue during hepatic fibrogenesis

INTRODUCTION Mitogen-activated protein kinase (MAPK) pathway is an important intracellular signal transduction system[1], and extracellular signal-regulated kinase 1 (ERK1) is the critical and classical pathway of MAPK and plays an important role in sever…     

纤溶酶原激活物抑制剂1与静脉血栓栓塞性疾病

纤溶酶原激活物抑制剂1是纤维蛋白溶解系统的一个成分.许多研究发现血浆纤溶酶原激活物抑制剂1水平和基因多态性与静脉血栓栓塞性疾病的发生有显著的关系.     

Plasminogen activator inhibitor-1 gene polymorphisms in pre-eclampsia

Pre-eclampsia (P-EC) is a multisystem disorder of pregnancy, characterized by new-onset hypertension and proteinuria. Deregulation of the coagulation cascade and hypofibrinolysis appear to play a central role in the development of this disease. After a brief review of the genetic basis of P-EC and the role of genes encoding proteins involved in coagulation, we focus on polymorphisms of the plasminogen activator inhibitor (PAI-1) gene. The most relevant association studies between PAI-1 gene polymorphisms and P-EC are reviewed. Results indicate that the 4G/4G genotype of the -675 4G/5G polymorphism represents a weak risk factor for P-EC.     

Plasminogen activator inhibitor-1 and vitronectin promote vascular thrombosis in mice

Occlusive thrombosis depends on the net balance between platelets, coagulation, and fibrinolytic factors. Epidemiologic information suggests that plasminogen activator inhibitor-1 (PAI-1), a central regulator of the fibrinolytic system, plays an important role in determining the overall risk for clinically significant vascular thrombosis. Vitronectin (VN), an abundant plasma and matrix glycoprotein, binds PAI-1 and stabilizes its active conformation. This study assessed the role of PAI-1 and VN expression in the formation of occlusive vascular thrombosis following arterial or venous injury. The common carotid arteries of 17 wild-type (WT) mice and 8 mice deficient in PAI-1 were injured photochemically while blood flow was continuously monitored. WT mice developed occlusive thrombi at 52.0 +/- 3.8 minutes (mean +/- SEM) following injury; mice deficient in PAI-1 developed occlusive thrombosis at 127 +/- 15 minutes (P <.0001). Mice deficient in VN (n = 12) developed vascular occlusion 77 +/- 11 minutes after injury, intermediate between the values observed for WT mice (P <.03) and mice deficient in PAI-1 (P <.01). PAI-1 and VN also affected the time to occlusion after injury to the jugular vein. Three WT mice developed occlusive venous thrombosis an average of 39.7 +/- 1 minutes following the onset of injury, whereas the jugular veins of 4 mice deficient in PAI-1 and 4 deficient in VN occluded 56.7 +/- 5 and 58.7 +/- 2 minutes, respectively, following injury (P <.04 and P <.01 compared to WT mice). These results suggest that endogenous fibrinolysis and its regulation by PAI-1 and VN have important roles in the development of occlusive vascular thrombosis after vascular injury. (Blood. 2000;95:577-580)     

Increased expression of plasminogen activator and plasminogen activator inhibitor during liver fibrogenesis of rats: role of stellate cells.

BACKGROUND/AIMS: Plasminogen activators and plasminogen activator inhibitors are important regulators of the balance between the proteolytic and antiproteolytic activities that determine extracellular matrix turnover. We examined the expression of plasminogen activator-plasmin system components in experimental liver fibrosis of rats. METHODS: Liver fibrosis was produced in rats by injecting carbon tetrachloride for 6 to 12 weeks. Gene expression for plasminogen activator inhibitor-1 (PAI-1), urokinase and tissue plasminogen activators (uPA and tPA), urokinase plasminogen activator receptor (uPAR), and transforming growth factor-beta1 (TGF-beta1) was examined by Northern analysis. Western analysis was performed to detect protein expression of PAI-1, uPA and uPAR. An immunohistochemical study was performed to detect the localization of PAI-1. Additionally, primary cultured liver cells were examined by Northern and Western analyses for this protein with or without prior incubation with TGF-beta1. RESULTS: At 6 weeks, when fibrosis had occurred, uPA and uPAR mRNAs had increased 2.8-fold and 1.8-fold, respectively; PAI-1 and tPA mRNA levels were unchanged. At the cirrhotic stage (9 to 12 weeks), mRNA levels for PAI-1, uPA, uPAR and tPA were all increased. Western analysis also showed increased uPA and uPAR expressions in fibrotic liver, and increased PAI-1, uPA and uPAR expressions in cirrhotic liver. PAI-1 protein was also demonstrated immunohistochemically along sinusoids, vessels, and bile duct cells of normal and fibrotic liver. In liver cell cultures, Kupffer cells, hepatocytes, and especially stellate cells, expressed PAI-1. Expression was enhanced in stellate cells cultured from fibrotic or cirrhotic liver or stimulated in vitro with TGF-beta1. CONCLUSION: Though increased uPA and uPAR may act on matrix degradation in fibrotic liver, increased PAI-1 together with uPA, uPAR and tPA are associated with overall inhibition of matrix degradation in cirrhotic liver. Hepatic stellate cells are an important source of PAI-1 during liver fibrosis.