Fibrinolytic Variables in Postmenopausal Women with Unstable Coronary Artery Disease

Objectives: Many women with typical anginal chest pain have normal coronary angiograms. The pathogenetic mechanisms behind the chest pain in these patients is unknown but may be due to altered fibrinolytic function enhancing thrombosis formation. We evaluated the two key components of the fibrinolytic system, tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) in women with clinical signs of unstable coronary artery disease (CAD). Methods and results: 158 patients with unstable CAD and 101 controls were examined. Of the patients 16% had normal vessels and 84% coronary atherosclerosis at coronary angiography. Mean plasma concentration of t-PA-ag, but not of PAI-1-act was higher in patients than in controls (t-PA-ag: 2.12 (2.05;2.19) vs. 1.98 (1.89;2.07), p<0.05; PAI-1-act: 1.55 (1.35;1.74) vs. 1.49 (1.24;1.73), p=n.s.). Patients with coronary atherosclerosis had significantly higher mean plasma levels of both t-PA-ag and PAI-1-act than patients with normal coronary vessels (t-PA-ag: 2.16 (2.08;2.33) vs. 1.94 (1.78;2.10), p<0.05; PAI-1-act: 1.68 (1.47;1.90) vs. 0.82 (0.43;1.21), p<0.01), and these differences were seen whether markers of myocardial damage were elevated or not. Mean plasma levels of PAI-1-act in patients with normal coronary vessels were even lower than in the control group (p<0.05). Almost all significant differences in mean plasma t-PA-ag and PAI-1-act disappeared after adjustments for known covariates. Conclusion: Our results indicate, regardless of myocardial marker elevation or not, an activated fibrinolytic system in postmenopausal women with unstable CAD and coronary atherosclerosis, but not in the same group of patients with normal coronary vessels. This argues against reduced fibrinolytic capacity in the latter patients and therefore against thrombosis formation as the cause of chest pain in these women. However, we cannot exclude that the differences can be an effect of inequality among some common risk factors between the groups.     

The Effect of Sleep/Wake State on Nocturnal Melatonin Excretion

Twenty-four hour patterns of urinary 6-sulphatoxymelatonin excretion were monitored in eight healthy adult subjects in two bed rest constant routines, one with normal nocturnal sleep and one with continuous wakefulness. The implementation of dim light "constant routines" enabled the effect of the sleep wake/state on melatonin to be tested without the confounding effects of body activity and normal room lighting. In both conditions 6-sulphatoxymelatonin excretion was significantly higher during the nighttime hours (2200-1000) than during the daytime hours (1000-2200) producing averages of 80% and 78.5% of the total 24 hour output in the sleep and wakeful conditions, respectively. The large differences between subjects in nocturnal melatonin excretion (38 to 150 nmol) were highly consistent between the two conditions. There were no differences between the nocturnal wakeful and sleep conditions in total nighttime melatonin excretion nor in the nighttime percentage of the 24 hour total melatonin excretions. Therefore, the sleep/wake state alone had no effect on nocturnal melatonin excretion. On the other hand, a significant correlation between the nighttime melatonin percentage and sleep length suggested the need to investigate further the relation between the amplitude of the melatonin circadian rhythm and sleep length and quality.     

The Role of the Fibrinolytic System in Corneal Angiogenesis

The plasminogen activation system has been implicated in angiogenesis and angiogenesis-dependent diseases such as cancer, atherosclerosis and ocular diseases. The identification and development of inhibitors of angiogenesis offer new possibilities for the treatment of these diseases. To clarify the role of proteins involved in the regulation of fibrinolysis during corneal angiogenesis, we have studied corneal vessel formation in mice deficient for urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), plasminogen, plasminogen activator inhibitor-1 (PAI-1) and thrombin-activatable fibrinolysis inhibitor (TAFI). Our results corroborate earlier findings that angiogenesis in the mouse cornea is dependent on PAI-1 and plasminogen. The absence of tPA, uPA or TAFI did not affect the formation of new vessels in the cornea.     

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.     

Glycaemic Control,Smoking Habits and Diabetes Duration Affect the Extrinsic Fibrinolytic System in Type I Diabetic Patients but Microangiopathy Does Not

ABSTRACT The fibrinolytic system was studied in 43 type I diabetic patients with long duration of the disease, with or without evidence of microangiopathy, and in 26 control subjects. There were positive and independent correlations between tissue plasminogen activator (tPA) activity after venous occlusion and HbA_lc, and between triglycerides and plasminogen activator inhibitor (PAI-1) and tPA antigen concentrations before and after venous occlusion. The tPA activities both at rest and after venous occlusion were higher in the patients. There were no differences with regard to sex, hypertension or nephropathy for the levels of fibrinolytic variables in these patients. Subjects with retinopathy did not differ from those without retinopathy. Diabetes duration showed a significant negative association with tPA activity in multivariate regression analysis. Tobacco-smoking diabetics, as compared to non-smoking, had an increased tPA antigen release at venous occlusion, but also higher PAI-1 levels and reduced specific activity of the tPA protein. When assessed with the new specific assays now available, the fibrinolytic parameters appear to be specific indicators of endothelial dysfunction related to smoking and to degree of glycaemic control in type I diabetic subjects.     

脑梗死患者血浆纤溶指标的动态观察

目的　探讨脑梗死患者血浆中纤溶分子标志物———组织纤维蛋白溶酶原激活剂 (TPA)和纤溶酶原激活物抑制剂 (PAI 1)含量的动态变化及其临床意义。方法　采用酶免疫定量法对 30例首次急性脑梗死患者急性期和恢复期的血浆TPA和PAI 1含量进行测定 ,并选择 30名正常人作为对照。同时对比首次急性脑梗死 30例和再发脑梗死 2 8例急性期血浆TPA及PAI 1含量。结果　首次急性脑梗死患者恢复期的TPA低于急性期 ,高于正常对照组 ;PAI 1含量脑梗死恢复期明显高于急性期。再次发病急性脑梗死患者比首次发病急性脑梗死患者的PAI 1高。结论　PAI 1与脑梗死的发生与发展有着重要关系 ,应作为临床的重要危险因素对待。     

Regulation of tissue plasminogen activator in sickle cell anemia

Evidence of activation of the clotting system in individuals with sickle cell anemia (SCA) has been observed by several investigators. It has been suggested that the clotting and fibrinolytic systems may play a role in the pathophysiology of vaso-occlusion in SCA. We reported previously evidence of abnormal fibrinolytic activity as reflected in decreased releasable tissue plasminogen activator (t-PA) using a functional assay. We have examined the mechanism of the decreased functional releasable t-PA in individuals with SCA. We studied 12 patients with respect to releasable t-PA, fast acting inhibitor to t-PA (or PAI-1), and immunoreactive or antigenic t-PA. These SCA individuals were at their baseline states and not taking medications known to interfere with the fibrinolytic or clotting systems. We found that the mean releasable t-PA for the SCA individuals was 0.01 IU/ml of plasma with a standard error of mean (SEM) of 0.01. The mean releasable t-PA of 118 healthy normal controls was 0.70 IU/ml with SEM 0.10 (P less than .001). The mean level of fast-acting inhibitor to t-PA in unoccluded circulation of the SCA patients' plasma was 16.5 IU/ml with SEM of 3.54. The mean plasma levels of fast-acting inhibitor to t-PA in 56 healthy controls was 2.56 IU/ml with SEM of 0.29 (P less than .0001). The SCA patients had a mean baseline t-PA antigen level of 5.98 ng/ml with SEM of 1.72. The mean level of t-PA antigen of 78 healthy controls using the same technique was 4.3 ng/ml with SEM of 2.7 (not significant). The mean baseline functional t-PA for SCA individuals was 0.15 IU/ml with SEM 0.01 and the mean baseline functional t-PA for 118 controls was 0.17 IU/ml with SEM 0.10. These data suggest that the mechanism of decreased releasable t-PA in sickle cell anemia is related to an elevation of fast-acting inhibitor to t-PA and that antigenically t-PA is present in normal quantities in the baseline plasma in this population.     

Plasma Melatonin Exhibits a Diurnal Secretion in the Common Marmoset (Callithrix jacchus): Relationship to the Rest-Activity Cycle

The secretion of plasma melatonin exhibits a diurnal variation in the common marmoset (Callithrix jacchus jacchus) (n = 12) with mean values of 125.8 fmol/ml during darkness and below assay sensitivity (mean 70.5 fmol/ml) during the light period. Both melatonin secretion and the rest activity cycle appeared to be phase advanced with relation to the light dark cycle which is consistent with an endogenous circadian period (tau) of less than 24 h in this species.     

Fibrinolytic characteristics and their significance in malignant, tuberculous and cirrhotic pleural and ascitic fluids

The fibrinolytic characteristics and clinical pathological significance of pleural and ascitic fluid were studied in patients with malignant tumour, tuberculosis or liver cirrhosis. Urokinase plasminogen activator (uPA) and urokinase plaminogen activator receptor (uPAR) levels were measured by enzyme-linked immunoadsorbent assay and tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), plasminogen (Plg), plasmin (Pl) and alpha(2) plasmin inhibitor (alpha(2)PI) by colorimetric assay. uPA and uPAR levels were higher in malignant tumour and tuberculosis compared with liver cirrhosis, whereas tPA levels were significantly higher in liver cirrhosis and malignant tumour than in tuberculosis patients. Tuberculosis patients showed statistically higher PAI-1, Plg and Pl concentrations than malignant tumour patients, which, in turn, were higher than those in liver cirrhosis patients. alpha(2)PI levels were markedly higher in malignant tumour and liver cirrhosis than in tuberculosis. In the malignant tumour group, only uPA level was significantly different between the samples that contained cancer cells and those that did not. We found significant differences between the fibrinolytic characteristics in pleural and ascitic fluid in patients with malignant tumour, tuberculosis and liver cirrhosis. The analysis of several fibrinolytic parameters could help to determine the quality of pleural and ascitic fluid, and also to further understand the pathological processes of these diseases.     

Effects of humic acid on the viability and coagulant properties of human umbilical vein endothelial cells

We have previously shown that humic acid (well-water humic acid, HA, and synthetic humic acid, SHA) enhances cell surface expression of tissue factor (TF). Here we report that incubation of human umbilical vein endothelial cells (HUVEC) for 2 hr with HA or SHA cause a rapid rise in TF mRNA levels, as shown by Northern blot analysis. To understand the cytotoxic and fibrinolytic effects of HA and SHA on cultured HUVEC, the cells were treated with varying concentrations of HA and SHA for various periods of time. Both HA and SHA (10–200 μg/ml) inhibited the viability of subconfluent HUVEC, cultured in the presence or absence of 20% FBS (Fetal Bovine serum) in the culture medium, in a dose-dependent manner. Both HA and SHA induced surface changes in the HUVEC as revealed by scanning electron micrography (SEM). However, protocatechuic acid, the monomer of SHA, did not significantly inhibit cell growth, and showed a cytotoxic effect only at 200 μg/ml. Furthermore both HA and SHA stimulated HUVEC to produce plasminogen activator inhibitor (PAI-1) and tissue plasminogen activator (t-PA) in a dose and time dependent fashion; the amount of PAI-1 produced was found to exceed that of t-PA. The monomer of SHA did not have this stimulatory effect. These results distinctly suggest that in addition to the inhibition of viability HA is involved in TF induction and PAI-1 synthesis in HUVEC and these may be some of the plausible mechanisms underlying the thrombotic disorders in Blackfoot disease. © 1996 Wiley-Liss, Inc.     

缺血性脑血管病纤溶活性和血清同型半胱氨酸含量测定的临床意义

目的　探讨缺血性脑血管病 (ICVD)患者血浆纤溶活性和血清同型半胱氨酸 (Hcy)含量的变化及其临床意义。方法　入选ICVD患者 86例 (ICVD组 ) ,根据病情又分为短暂脑缺血发作 (TIA)组 14例 ,脑梗死组 72例 ,并入选非脑血管病患者 4 3例作为对照组 ,分别采用产色法测定血浆纤溶酶原 (Plg)、组织型纤溶酶原激活物 (t PA)、纤溶酶原激活抑制物 1(PAI 1)活性 ,荧光偏振光法测定血清Hcy,电化学发光法测定叶酸 ,同时常规测定血脂水平。结果　ICVD组 ,TIA患者和脑梗死患者血浆Plg、t PA活性均较对照组显著降低 (P <0 .0 5 )。ICVD组血清Hcy水平较对照组明显升高 (P <0 .0 1) ,t PA活性降低和高Hcy对ICVD的发生均有显著作用。结论　t PA活性降低和高Hcy分别是ICVD的独立危险因素     

高血压患者凝血酶原及纤溶酶原激活物和其抑制物测定

目的探讨正常人各年龄组间和高血压病人血纤溶指标的差异及其意义。方法用发色底物法分别时≤３９岁（ｎ＝４９），４０～５９岁（ｎ＝１４９），≥６０岁（ｎ＝６４）各组健康人和高血压组（ｎ＝５６）的血纤溶活性指标凝血酶原（ＰＬＧ），组织型纤溶酶原激活物（ｔ－ＰＡ）和纤溶酶原激活物抑制物（ＰＡＩ）进行测定。结果≥６０岁组和高血压组的ＰＬＧ和ｔ－ＰＡ明显低于５９岁以下各组（Ｐ＜０．００１），ＰＡＩ则明显高于５９岁以下各组（Ｐ＜０．００１）。结论健康老人（≥６０岁）和高血压病人纤溶活性降低。     

The role of strict metabolic control by insulin infusion on fibrinolytic profile during an acute coronary event in diabetic patients

BACKGROUND: Many clinical and laboratory observations give support to the hypothesis that strict metabolic control by insulin infusion during acute coronary events may improve the ischemic damage and prognosis. HYPOTHESIS: We investigated the impact of intensive insulin treatment on fibrinolytic parameters during an acute ischemic myocardial event (unstable angina or acute myocardial infarction) in patients with type 2 diabetes mellitus. METHODS: The study group consisted of 48 type 2 diabetic patients, of whom 24 were randomized to conventional therapy plus intensive insulin treatment (Group 1) and 24 to conventional therapy only (Group 2). The two groups were comparable according to gender, age, body mass index, waist:hip ratio, duration of diabetes, previous antidiabetic treatment, type of ischemic events, concomitant therapy, and the classic risk factors for coronary disease. Insulin-treated patients were excluded from the study. Plasma levels of fibrinogen, tissue plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1) were measured on admission and discharge. Fibrinogen (fibr) was measured using the photometric method. PAI-1 and t-PA were measured by enzyme-linked immunosorbent assays. RESULTS: T-PA increased in both groups during hospitalization (t-PA(admission) vs. t-PA(discharge): Group 1: 15.42 +/- 4.4 ng x ml(-1) vs. 21.2 +/- 5.74 ng x ml(-1), p = 0.000037; Group 2: 14.47 +/- 6.31 ng x ml(-1) vs. 19.18 +/- 6.88 ng x ml(-1), p = 0.001). On the other hand, fibr and PAI-1 levels increased remarkably in controls (Group 2, fibr(admission) vs. fibr(discharge): 2.98 +/- 1.04 g x l(-1) vs. 3.59 +/- 1.01 g x l(-1), p = 0.002, and PAI-1admission vs. PAI-1 discharge: 30.6 +/- 17.34 ng x ml(-1) vs. 40.62 +/- 23.48 ng x ml(-1), p = 0.003). This finding was not observed in the intensive insulin treatment group (Group 1, fibr(admission) vs. fibr(discharge): 2.87 +/- 0.73 g x l(-1) vs. 2.67 +/- 0.72 g x l(-1), p = 0.101, and PAI-1 admission vs. PAI-1 discharge: 30.75 +/- 15.81 ng x ml(-1) vs. 27.75 +/- 6.43 ng x ml(-1), p = 0.484). CONCLUSION: Intensive insulin treatment during an acute coronary event improves fibrinolytic profile in patients with diabetes mellitus. This is a possible mechanism for the reduced short- and long-term mortality in diabetic patients treated with intensive insulin treatment protocol.     

芪龙胶囊对急性脑梗死患者的疗效观察

目的探讨芪龙胶囊治疗急性脑梗死的疗效及作用机制。方法急性脑梗死患者100例,随机分为2组,对照组50例进行常规治疗,治疗组50例在常规治疗基础上同时给予口服芪龙胶囊治疗,比较2组患者治疗前后欧洲脑卒中量表评分、日常生活活动能力量表评分,血浆血栓素B_2(TXB_2)、6-酮-前列环素(6-Keto-PGF1a)及组织型纤溶酶原激活剂(t-PA)、纤溶酶原激活物抑制剂1(PAI-1)的变化。结果治疗组和对照组患者治疗后欧洲脑卒中量表评分和日常生活活动能力量表评分较治疗前明显升高(P<0.01);治疗组患者治疗后,欧洲脑卒中量表评分和日常生活活动能力量表评分较对照组明显升高,差异有统计学意义(P<0.05)。治疗组患者治疗后TXB_2、PAI-1含量较对照组明显下降,6-Keto-PGF1a、t-PA含量较对照组明显升高,差异有统计学意义(P<0.01)。结论芪龙胶囊可明显改善临床疗效,具有促纤溶及抑制血小板活化的作用。     

Hemostasis Parameters Disturbances in Healthy Individuals with Prehypertension

Prehypertension (PH) seems to be related to increased cardiovascular risk in healthy normotensive subjects, while essential hypertension is associated with hemostasis balance disturbances. The aim of our study was to examine the impact of PH on hemostasis parameters in healthy individuals with PH and to compare the findings with those of healthy normotensives with normal blood pressure (NBP) levels. This study was performed in 204 (96 M, 108 F) subjects who attended our hypertension clinic. Seventy-eight (36 M, 42 F) subjects with PH, mean age 52 ± 5 years, and body mass index (BMI) 23 ± 1.5 kg/m² made up group A, and 126 (60 M, 66 F) subjects with NBP, mean age 53 ± 6 years, and BMI 23.2 ± 1.4 kg/m² without any history of cardiovascular disease or diabetes mellitus made up group B. Systolic blood pressure and diastolic blood pressure were measured in three sequential visits, which were performed by the same trained nurse. Serum lipid levels, fibrinogen (F), thrombomodulin (TM), and plasminogen activator inhibitor-1 antigen, and tissue plasminogen activator antigen were determined in the whole population. Plasminogen activator inhibitor-1 antigen and tissue plasminogen activator antigen levels were significantly higher in the PH group as compared with normotensives, while in PH subjects, significantly higher plasma levels of F and TM were found compared with normotensive group. The two groups were matched for age, sex, BMI, and serum lipid levels. Our findings indicate that PH is associated with hemostasis disturbances predisposing to hypercoagulability and impaired fibrinolysis. This observation may be of prognostic value for future cardiovascular events in this group and needs further investigation.     

动脉粥样硬化性疾病患者血浆纤溶活性的变化及与血脂的关系

为观察动脉粥样硬化性疾病患得血浆纤维性的变化及其与血脂的关系，本实验分别采用发色底物法，酶联免疫吸附测定法和酶法对３１例动脉硬化疾病，患者血浆纤溶活性和血脂水平进行了测定，它们的相关性进行了分析。     

Hypofibrinolysis in patients with hypercoagulability: The roles of urokinase and of plasminogen activator inhibitor

The prevalence of abnormalities of fibrinolysis in patients with venous thromboembolism is as yet unknown. Defined abnormalities include congenital dysfunction and deficiency of plasminogen, and probably impaired plasminogen activation secondary to elevated levels of plasminogen activator inhibitor type 1 (PAI-1) or to impaired release of tissue plasminogen activator (tPA). In this preliminary study, we analyzed plasma samples from 21 patients for whom an investigation for possible thrombophilia was requested. Twenty of the patients had venous thromboembolism, and one had arterial thrombosis at an early age. Two patients had deficiency of protein C or protein S, but no other recognized biochemical disturbances related to thrombophilia were identified. Patient samples and plasma from 25 normal controls were assayed for tPA activity, PAI-1 activity, and urokinase (uPA) activity and antigen. tPA activity and antigen were not significantly different in patients than in controls. PAI-1 activity was significantly greater in patients (P < 0.0001). uPA activity was not different in the two groups. However, uPA antigen was significantly reduced in patients compared to controls (P = 0.001). These data suggest that hypofibrinolysis leading to a risk of thrombosis may be caused not only by elevated PAI-1 activity but also by reduced total uPA concentration. © 1993 Wiley-Liss, Inc.     

Effects of imidapril therapy on endogenous fibrinolysis in patients with recent myocardial infarction

Background: Treatment with an angiotensin-con verting enzyme (ACE) inhibitor in patients with myocardial infarction has been shown to modify endogenous fibrinolysis. Hypothesis: We investigated the effects of the ACE inhibitor imidapril on endogenous fibrinolysis in association with the serum ACE activity. Methods: In a randomized, double-blind, placebo-controlled study beginning 4 weeks after uncomplicated myocardial infarction, 15 patients received imidapril (5 mg daily) (imidapril group) and another 15 received placebo therapy (placebo group) for 4 weeks. Blood sampling was performed before the start of administration and on Days 3, 7, and 28 after the start of administration. Serum ACE activity and plasma fibrinolytic variables [plasminogen activator inhibitor (PAI) activity, plasminogen activator inhibitor type 1 (PAI-1) antigen level, and tissue type plasminogen activator (TPA) antigen level] were measured. Results: There was no difference between the imidapril and placebo groups in serum ACE activity or plasma fibrinolytic variables before administration. Serum ACE activity decreased significantly on Days 3, 7, and 28 in the imidapril group. The decrease of PAI activity and PAI-1 antigen levels was significantly less on Days 7 and 28, but not on Day 3. The TPA antigen level in the imidapril group was unchanged. None of the parameters in the placebo group was changed. Conclusion: The ACE inhibitor imidapril modified fibrinolysis, but the effects occurred after the inhibition of serum ACE activity.     

Potential antithrombotic and fibrinolytic properties of the angiotensin converting enzyme inhibitors

Summary As a class of therapeutic agents, the ACE inhibitors have proven to have long-term mortality benefit when used after myocardial infarction and among patients with symptomatic congestive heart failure. Clinical trial data also indicate that the use of ACE inhibitors is associated with reduced rates of recurrent coronary thrombosis, an observation that raises the possibility that the renin-angiotensin system may be directly involved in the thrombotic process and that the ACE inhibitors may have valuable fibrinolytic and/ or antithrombotic effects. Recent in vitro and in vivo studies of angiotensin II and its interactions with the fibrinolytic system, particularly with the primary inhibitor of intravascular fibrinolysis, plasminogen activator inhibitor type 1 (PAI-1), provide substantial support for this hypothesis. In addition, a series of cross-sectional studies have described a genetic linkage between a common ACE gene polymorphism (DD) and the prevalence of clinical cardiovascular events, an intriguing finding as this polymorphism may account for much of the population variability in plasma ACE levels. Taken together, the totality of available clinical and experimental findings support the possibility of a direct linkage between the ACE system and vascular thrombosis that merits further prospective evaluation.Dr. Ridker is the recipient of a Clinician Scientist Award from the American Heart Association. Dr. Vaughan is the recipient of a Clinical Investigator Award from the United States Veterans Administration.     

氨氯吡咪对大鼠慢性阻塞性肺疾病模型病理改变的影响

目的观察尿激酶型纤溶酶原激活物（u-PA）抑制剂氨氯吡咪对大鼠慢性阻塞性肺疾病（COPD）模型病理及病理生理改变的影响，探讨u-PA系统成分在COPD发病中的作用。方法健康Wistar大鼠24只随机分为3组：正常对照组、模型组和氨氯吡咪组。7周后检测各组大鼠的肺功能，支气管肺泡灌洗液（BALF）细胞计数及分类，天狼猩红染色观察支气管肺组织的胶原沉积，免疫组化染色观察u-PA、u-PA受体、纤溶酶原激活物抑制物1（PAI-1）的蛋白定位和表达。结果模型组大鼠的呼气阻力显著高于对照组和氨氯吡咪组，0．3s用力呼气容积／用力肺活量、呼气峰流速均显著低于对照组和氨氯吡咪组；模型组大鼠的BALF中自细胞总数、中性粒细胞、单核细胞和巨噬细胞构成比显著高于对照组和氨氯吡咪组；模型组大鼠以I型胶原为主的细胞外基质在气道壁过度沉积，胶原面积显著高于对照组和氨氯吡咪组；模型组大鼠支气管肺组织u-PA、u-PA受体和PAI-1蛋白表达的平均吸光度值[（0．166±0．010）、（0．158±0．024）和（0．171±0．012）]显著高于对照组[（0．137±0．015）、（0．122±0．009）和（0．144±0．005）]及氨氯吡咪组[（0．126±0．004）、（0．120±0．010）和（0．122±0．004）]，且u-PA受体蛋白表达与中性粒细胞构成比呈显著正相关。结论应用u-PA抑制剂氨氯吡咪可显著减轻COPD大鼠的气道炎症和病理结构改变，u-PA系统成分是COPD气道炎症和组织重塑环节中具有关联作用的重要物质。