组织型纤溶酶原激活物及其抑制剂与动脉粥样硬化的关系

组织型纤溶酶原激活物（tPA）和纤溶酶原激活物抑制剂（PAI）是纤溶系统外激活途径的重要活性物质,绝大多数由小血管内皮细胞合成。内皮细胞损伤和功能紊乱是动脉粥样硬化形成的重要始动环节。文章综述了内皮细胞产生的tPA和PAI与动脉粥样硬化和缺血性脑血管病之间的关系。     

胰岛素对血管平滑肌细胞增殖和组织型纤溶酶原激活剂及抑制物活性的影响

以体外培养的猪主动脉平滑肌细胞为实验对象，研究了不同浓度胰岛素对细胞增殖和组织型纤溶酶原激活剂琢抑制物活性的影响。细胞增殖检测采用氚标脱氧胸腺嘧啶核苷掺入法，组织型纤溶酶原激活剂及其抑制物活性测定采用底物显色法。结果发现胰岛素促进血管平滑肌细胞增殖，刺激纤溶酶原激活剂抑制物活性增加，均呈剂量依赖性。而组织型纤溶酶原激活剂活性在猪血管平滑肌细胞体外培养液中不存在，且与胰岛素的刺激与否及作用浓度、时间     

冠心病患者血浆脂蛋白(a)浓度与组织型纤溶酶原激活剂及抑制物活性的关系

为了了解冠心病患者血浆脂蛋白(a)浓度与组织型纤维蛋白溶解酶原激活剂及其抑制物活性的关系,进一步研究脂蛋白(a)促血栓形成的机理,本文应用酶联免疫吸附法测定20例冠心病患者与20名健康人脂蛋白(a)浓度,并以底物显色法测定其血浆组织型纤维蛋白溶解酶原激活剂及其抑制物活性。结果发现,冠心病组血脂蛋白(a)浓度和纤维蛋白溶酶原激活剂抑制物活性显著高于对照组,而纤维蛋白溶解酶原激活剂活性显著低于对照组;两组脂蛋白(a)浓度与纤维蛋白溶解酶原激活剂活性无关,而与纤维蛋白溶解酶原激活剂抑制物活性呈显著正相关。提示血浆高脂蛋白(a)浓度是冠心病的危险因素,冠心病患者纤溶与凝血功能失去平衡,促进了冠状动脉内血栓形成与动脉硬化的发展,进而导致和加重冠心病。     

冠心病患者血浆脂蛋白(a)浓度与组织型纤溶酶原激活剂及抑制物活性的关系

为了了解冠心病患者血浆脂蛋白（a）浓度与组织型纤维蛋白溶解酶原激活剂及其抑制物活性的关系，进一步研究脂蛋白（a）促血栓形成的机理，本文应用酶联免疫吸附法测定20例冠心病患者与20名健康人脂蛋白（a）浓度，并以底物显色法测定其血浆组织型纤维蛋白溶解酶原激活剂及其抑制物活性。结果发现，冠心病组血脂蛋白（a）浓度和纤维蛋白溶酶原激活剂抑制物活性显著高于对照组，而纤维蛋白溶解酶原激活剂活性显著低于对照组；两组脂蛋白（a）浓度与纤维蛋白溶解酶原激活剂活性无关，而与纤维蛋白溶解酶原激活剂抑制物活性呈显著正相关。提示血浆高脂蛋白（a）浓度是冠心病的危险因素，冠心病患者纤溶与凝血功能失去平衡，促进了冠状动脉内血栓形成与动脉硬化的发展，进而导致和加重冠心病。     

Clinical Implications of Elevated PAI-1 Revisited: Multiple Arterial Thrombosis in a Patient with Essential Thrombocythemia and Elevated Plasminogen Activator Inhibitor-1 (PAI-1) Levels with a Review of the Literature

Plasminogen activator inhibitor (PAI-1), a member of the serine protein family, is the most active in vivo inhibitor of fibrinolysis induced by plasminogen, tissue plasminogen activator (tPA), and urokinase type plasminogen activator (uPA). While the association between elevated PAI-1 and thrombogenesis has been well studied for several disease processes, including coronary disease, postoperative deep vein thrombosis (DVT), myocardial infarction, malignancy, and diabetes, few studies have concentrated on the correlation between elevated PAI-1 levels and thrombogenesis in patients with myeloproliferative disorders. Essential thrombocythemia (ET), a chronic myeloproliferative disorder, characterized by the overproduction of poorly functioning platelets, is associated with both thrombotic and hemmorhagic life-threatening complications. Although the events resulting in thrombogenesis in such patients may be multifactorial in nature, an association between elevated PAI-1 levels and thrombus formation has been proposed. Herein we present a patient diagnosed with ET complicated by multiple episodes of arterial thrombosis. Elevations in PAI-1 levels were documented repeatedly. The role of elevated PAI-1 when associated with other disease processes is also discussed.     

改良溶解圈纤溶酶原激活物测定法及其在革兰氏阴性菌中的应用

本研究建立的测定纤溶酶原激活物（Ｐｌａ）的纤维蛋白溶解圈法，不仅简单易行，而且具有很高的敏感性和特异性。检测灵敏度较原来的普通溶解圈法提高了大约５００倍，能检出２．５×１０－５ＩＵ的尿激酶（ＵＫ）活力。本方法特别适用于低Ｐｌａ含重的定性定量检测，如革兰氏阴性菌纤溶酶原激活物的测定。应用此方法，本研究首次证明了伤寒和鼠伤寒杆菌具有纤溶酶原激活物的活性，１０Ｄ鼠伤寒菌的Ｐｌａ活性相当于４×１０－２ＩＵＵＫ；１ＯＤ伤寒菌的Ｐｌａ活性相当于５×１０－３ＩＵＵＫ。     

AMI患者尿激酶与组织型纤溶酶原激活剂治疗结果的对比

比较31例尿激酶(UK)及14例组织型纤溶酶原激活剂(t-PA)静脉溶栓辅以阿斯匹林及肝素治疗急性心肌梗塞(AMI)的疗效.t-PA组与UK组相比较:血管再通率分别为78.6%与58.1%(P>0.05);脑、消化道及呼吸道出血并发症在t-PA组稍多,而UK组以局部皮肤出血较多.血管再通组心力衰竭、严重性心律失常、室壁瘤及梗塞后心绞痛的发生率较低,但两组间均无显著性差异;再通组病人心脏破裂的发生明显低于未再通组(0与17.6%P<0.05).本研究提示静脉t-PA溶栓治疗血管再通率高于静脉UK,有条件者可以首选t-PA.溶栓再通可以减少心力衰竭、室壁瘤、心梗后再缺血的发生,特别是心脏破裂的发生,从而改善病人的预后.     

rt-PA在血脑屏障氧糖剥夺体外模型中对神经细胞保护的研究

目的 观察重组组织型纤溶酶原激活剂(rt-PA)在体外血脑屏障氧糖剥夺模型中对神经细胞的影响,探讨rt-PA对脑缺血神经元的保护作用.方法 利用Transwell培养小室为支架,构成以人血管上皮细胞为基础的体外血脑屏障模型;利用厌氧培养箱及无糖培养液,建立体外缺血缺氧模型;在体外缺血缺氧模型基础上,采用组织培养技术,培养神经细胞,并在缺血缺氧条件下,使用MTT法进行检测不同剂量rt-PA对神经细胞活性的影响.结果 分别在氧糖剥夺实验(OGD)及非OGD条件下,在不同rt-PA药物的浓度作用下,低浓度(0.312 5 μg/mL)对非OGD条件下神经细胞的生长有促进作用,在OGD条件下,低浓度(0.625 μg/mL,0.312 5 μg/mL)对神经细胞同样具有保护作用.结论 rt-PA可能对脑缺血后神经细胞存在保护作用,并与rt-PA的剂量相关,在OGD条件下,低剂量rt-PA对神经细胞的保护作用更为显著.     

Association between Plasma Levels of Plasminogen Activator Inhibitor-1 and Colorectal Neoplasms

Background/Aims

Plasminogen activator inhibitor-1 (PAI-1) is important for tumor growth, Invasion, and metastasis. In this study, we investigated the relationship between plasma levels of PAI-1 and colorectal adenomas.

Methods

We reviewed the medical records of 3,136 subjects who underwent colonoscopy as a screening exam. The subjects were classified into a case group with adenomas (n=990) and a control group (n=2,146). Plasma PAI-1 levels were categorized into three groups based on tertile.

Results

The plasma levels of PAI-1 were significantly higher in adenoma cases than in controls (p=0.023). The prevalence of colorectal adenomas increased significantly with increasing levels of PAI-1 (p=0.038). In the adenoma group, advanced pathologic features, size, and number of adenomas did not differ among the three groups based on tertiles for plasma PAI-1 levels. Using multivariate analysis, we found that plasma level of PAI-1 was not associated with the risk of colorectal adenomas (p=0.675). Adjusted odds ratios for colorectal adenomas according to increasing plasma levels of PAI-1 were 0.980 (95% confidence interval [CI], 0.768 to 1.251) for the second-highest plasma level and 1.091 (95% CI, 0.898 to 1.326) for the highest level, compared with the lowest levels.

Conclusions

These results suggest that elevated plasma PAI-1 levels are not associated with the risk of colorectal neoplasms.     

纤溶酶原激活物抑制剂-1与心血管疾病

纤溶酶原激活物抑制剂-1是纤溶系统的主要调节因子,通过抑制纽织型纤溶酶原活化剂影响血浆纤溶和凝血系统的平衡,引起或者加速心血管疾病的发生发展。纤溶酶原激活物抑制剂-1对心血管疾病的诊断、预后,尤其对冠心病的诊断、分型、危险分层、预后及经皮冠状动脉介入治疗后的再狭窄的判断有重要指导意义。心血管疾病相关的的辅助检查中,纤溶酶原激活物抑制剂-1将提供一种新的选择。     

阿加曲班治疗急性缺血性脑卒中疗效及应用时机的临床研究

目的观察急性缺血性脑卒中后不同时间段应用阿加曲班的临床疗效。方法随机选取我院发病24h内的急性缺血性脑卒中患者80例,根据发病6～12h和13～24h 2个时间段应用阿加曲班,将患者分为A组28例,B组52例。7d后进行美国国立卫生研究院脑卒中量表(NIHSS)评分,以判定临床疗效。结果与治疗前比较,2组治疗后NIHSS评分明显降低,差异有统计学意义(P<0.05)。2组临床疗效比较差异无统计学意义(P>0.05)。结论阿加曲班治疗急性缺血性脑卒中有临床疗效。发病24h内不同时间应用对临床疗效无影响。     

人组织型纤维蛋白溶解酶原激活剂cDNA在牛血管内皮细胞中的表达

利用基因生组技术，将人组织型纤维蛋白溶解酶原激活剂cDNA与逆转录病毒载体LNSX重组后转染至病毒包装细胞．其分泌的重组逆转录病毒颗粒再用来感染NIH3T3细胞和牛血管内皮细胞，经G418筛选，二周后计数存活的阳性细胞克隆数，得到病毒滴度为4×10~8cfu／L。计算转染效率为6×10~8克隆/gDNA/10~6细胞。在含人纤维蛋白原和凝血酶的纤维蛋白板上点样并用标准品作对照，发现经逆转录病毒感染的重组内皮细胞和包装细胞．分泌的细胞培养液，在纤维蛋白板上显示有大小不一的溶圈。使用发包底物法也测得含人组织型纤维蛋白溶解酶原激活刘cDNA转基因内皮细胞培养液的分泌活性．正常的内皮细胞则由于分泌量少而在敏感度以下．使用特异性的免疫组织化学杂色并经图像分析证实，人组织型纤维蛋白溶解酶原激活剂基因在牛的血管内皮细胞中得到表达。说明人组织型纤维蛋白溶解酶原激活剂基因的cD-NA已正确转入牛的血管内皮细胞中，为将来进行基因治疗展示了良好的应用前景．     

人组织型纤维蛋白溶解酶原激活剂cDNA在牛血管内皮细胞中的表达

利用基因生组技术,将人组织型纤维蛋白溶解酶原激活剂cDNA与逆转录病毒载体LNSX重组后转染至病毒包装细胞.其分泌的重组逆转录病毒颗粒再用来感染NIH3T3细胞和牛血管内皮细胞,经G418筛选,二周后计数存活的阳性细胞克隆数,得到病毒滴度为4×10~8cfu/L。计算转染效率为6×10~8克隆/gDNA/10~6细胞。在含人纤维蛋白原和凝血酶的纤维蛋白板上点样并用标准品作对照,发现经逆转录病毒感染的重组内皮细胞和包装细胞.分泌的细胞培养液,在纤维蛋白板上显示有大小不一的溶圈。使用发包底物法也测得含人组织型纤维蛋白溶解酶原激活刘cDNA转基因内皮细胞培养液的分泌活性.正常的内皮细胞则由于分泌量少而在敏感度以下.使用特异性的免疫组织化学杂色并经图像分析证实,人组织型纤维蛋白溶解酶原激活剂基因在牛的血管内皮细胞中得到表达。说明人组织型纤维蛋白溶解酶原激活剂基因的cD-NA已正确转入牛的血管内皮细胞中,为将来进行基因治疗展示了良好的应用前景.     

Association of Plasminogen Activator Inhibitor-1 Gene Polymorphism with Inflammatory Bowel Disease in Iranian Azeri Turkish Patients

Background/Aim:

Previous studies have shown the association of some genetic factors, such as Plasminogen activator inhibitor type-1 (PAI-1) 4G/5G polymorphism, with the development of inflammatory bowel disease (IBD). We aimed to study this polymorphism as a risk factor in IBD patients in this cohort.

Patients and Methods:

One hundred and fifteen IBD patients and 95 healthy controls were selected from Iranian Azeri Turks and -6754G/5G polymorphism of PAI-1 gene was tested by polymerase chain reaction using allele-specific primers confirmed by sequencing.

Results:

There was no significant difference of PAI-1 polymorphism between IBD patients and the control group (P > 0.05). Furthermore, these data showed no significant difference between Crohn''s disease and ulcerative colitis patients. However, 4G/4G homozygotes have reduced probability to progression of loss of appetite, whereas 5G/5G genotypes have increased risk for development of chronic diarrhea without blood, nausea, and loss of appetite.

Conclusions:

Although our study showed no significant association of PAI-1 polymorphism between patients and control group, the carriers of 4G/4G genotype and 4G allele had reduced risk for the progression of IBD features in this cohort.     

Enhanced clearance of Abeta in brain by sustaining the plasmin proteolysis cascade

The amyloid hypothesis states that a variety of neurotoxic beta-amyloid (Abeta) species contribute to the pathogenesis of Alzheimer's disease. Accordingly, a key determinant of disease onset and progression is the appropriate balance between Abeta production and clearance. Enzymes responsible for the degradation of Abeta are not well understood, and, thus far, it has not been possible to enhance Abeta catabolism by pharmacological manipulation. We provide evidence that Abeta catabolism is increased after inhibition of plasminogen activator inhibitor-1 (PAI-1) and may constitute a viable therapeutic approach for lowering brain Abeta levels. PAI-1 inhibits the activity of tissue plasminogen activator (tPA), an enzyme that cleaves plasminogen to generate plasmin, a protease that degrades Abeta oligomers and monomers. Because tPA, plasminogen and PAI-1 are expressed in the brain, we tested the hypothesis that inhibitors of PAI-1 will enhance the proteolytic clearance of brain Abeta. Our data demonstrate that PAI-1 inhibitors augment the activity of tPA and plasmin in hippocampus, significantly lower plasma and brain Abeta levels, restore long-term potentiation deficits in hippocampal slices from transgenic Abeta-producing mice, and reverse cognitive deficits in these mice.     

Relationship between Serum Soluble Urokinase Plasminogen Activator Receptor Level and Steroid Responsiveness in FSGS

Background and objectives

Soluble urokinase plasminogen activator receptor (suPAR) was initially proposed as a pathogenic and predictive biomarker of primary FSGS, but the findings were controversial. This study aimed to clarify the clinical implications of suPAR.

Design, setting, participants, & measurements

The study enrolled 109 patients with biopsy-proven primary FSGS who were administered prednisone between January 2011 and May 2013 and followed up for 6–24 months (median duration of follow-up, 12 months). Ninety-six healthy volunteers, 20 patients with minimal-change disease (MCD), and 22 patients with membranous nephropathy (MN) served as controls. Serum suPAR levels were measured using ELISA.

Results

suPAR levels in patients with FSGS (median, 3512 [interquartile range (IQR), 2232–4231] pg/ml) were significantly higher than in healthy controls (median, 1823 [IQR, 1563–2212] pg/ml; P<0.001), patients with MCD (median, 1678 [IQR, 1476–2182] pg/ml; P<0.001), and patients with MN (median, 1668 [IQR, 1327–2127] pg/ml; P<0.001). With 3000 pg/ml used as a threshold, suPAR levels were elevated in 48.6% of patients with FSGS, in contrast to 5% of patients with MCD and 4.5% of those with MN. suPAR levels were independently associated with steroid response in patients with FSGS (odds ratio, 85.02; P=0.001). Patients who were sensitive to steroids had significantly higher suPAR levels than nonsensitive patients (median, 3426 [IQR, 2670–5655] pg/ml versus 2523 [IQR, 1977–3460] pg/ml; P=0.001). A suPAR level of 3400 pg/ml was chosen as the optimal cutoff value for steroid response. At the 6-month follow-up in 84 patients with FSGS, suPAR levels were significantly decreased in those with suPAR level ≥3400 pg/ml (median, 4553 [IQR, 3771–6120] pg/ml versus 3149 [IQR, 2278–3953]; P=0.002) but were unchanged in patients with suPAR level <3400 pg/ml (median, 2359 [IQR, 2023–2842] pg/ml versus 2490 [IQR, 1916–3623] pg/ml; P=0.09).

Conclusions

suPAR is specifically elevated in some patients with FSGS, which differs from the finding in patients with MCD and MN. A suPAR assay may help predict steroid response in patients with primary FSGS.