Levels of tissue-type plasminogen activator and plasminogen activator inhibitor 1 in disseminated intravascular coagulation syndrome

Since disseminated intravascular coagulation (DIC) may directly reflect the abnormal regulation of the fibrinolytic system by endothelial cells, we have measured the levels of tissue-type plasminogen activator (t-PA), type 1 PA inhibitor (PAI-1) and t-PA . PAI-1 complex which is formed as a result of interaction on the two factors, in the plasma of patients with DIC (n = 51) and healthy controls (n = 42). Antigens of t-PA, PAI-1 and t-PA . PAI-1 complex were significantly increased in the DIC plasma (36.4 +/- 25.1, 106.8 +/- 54.7 and 46.6 +/- 34.5 ng/ml, respectively) compared with those in normal plasma (8.5 +/- 4.3, 54.4 +/- 21.2 and 8.6 +/- 3.5 ng/ml, respectively). The molar ratio of t-PA to PAI-1 was much higher in the DIC plasma (1:3) than in normal plasma (1:6), which caused enhancement of the whole fibrinolytic activity in the DIC plasma. These changes resulted in significant consumption of plasminogen, alpha 2-plasmin inhibitor (alpha 2-PI) and a significant increase of plasmin . alpha 2-PI complex (PPI) and D-dimer. These results suggest that t-PA and its specific inhibitor PAI-1 both of which are secreted from endothelial cells into blood, play an important role on the progress of DIC.     

Tissue plasminogen activator and plasminogen activator inhibitor-1 in human choledochal bile

Fibrinolytic properties have been detected in animal and human gallbladder (GB) bile. Plasminogen activator inhibitor-1 (PAI-1) has been reported in greater concentration in GB stone bile and may be a nucleating factor in the pathogenesis of GB stone formation. It is unknown whether or not human choledochal bile has similar properties, which could have a role in choledocholithiasis. The aims of this study were to determine the presence of fibrinolytic properties of human choledochal bile and to compare those properties among normal, acalculous, and calculous-infected choledochal bile. Tissue plasminogen activator (t-PA) and PAI-1 of choledochal bile were measured by enzyme linked immunosorbent assay in patients with cholangitis due to acalculous bile duct obstructions (n = 9), choledocholithiasis with cholangitis (n = 20), and normal bile (n = 7). The t-PA concentration of choledochal bile was no different among the three groups (acalculous-infected bile, median 4.61 ng/ml, and calculous-infected bile, 4.61 ng/ml, versus normal bile, 7.33 ng/ml). PAI-1 was detected in choledochal bile in significantly greater concentrations in patients with acalculous cholangitis due to bile duct obstructions and choledocholithiasis with cholangitis (acalculous-infected bile, median 0.36 ng/ml, and calculous-infected bile, 0.1 ng/ml, versus normal bile, 0.02 ng/ml, p < 0.05), but the bile concentration of PAI-1 was no different between the acalculous and calculous-infected choledochal bile. Human choledochal bile possesses t-PA and PAI-1. PAI-1 was present in greater concentrations in both acalculous and calculous-infected choledochal bile. Increased levels of PAI-1 may be an epiphenomenon of cholangitis rather than a factor in the pathogenesis of choledocholithiasis.     

Plasminogen activator and plasminogen activator inhibitor activities in a reference population

The influence of age, gender, and aspirin ingestion on plasma levels of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) activities was studied in a reference population of 35 men and 35 women between the ages of 20 and 65 years. The t-PA values (mean +/- SD) in the women before and after 5 minutes of venous occlusion were 3.8 +/- 1.4 and 7.8 +/- 4.4 micrograms/L, respectively; in men these values were 3.3 +/- 1.2 and 8.8 +/- 8.9 micrograms/L. Men had higher mean PAI levels than did women (5.0 vs. 2.5 kU/L). T-PA showed an inverse relationship to PAI in both sexes. There was a negative correlation of t-PA levels with age, whereas PAI levels were positively correlated. The ingestion of a single dose of aspirin (650 mg) did not alter PAI or t-PA activities. This study indicates that factors such as age and sex may need to be considered when reference populations are developed for clinical studies of fibrinolysis.     

Neutralization of plasminogen activator inhibitor-1 (PAI-1) by activated protein C is species-dependent

The interaction of bovine and human activated protein C (APC) with type-1 plasminogen activator inhibitor (PAI-1) was studied in a cell-free system. Human plasma and a preparation of PAI-1 obtained from human endothelial cell cultures were used as sources of PAI-1. Bovine APC was able to neutralize PAI-1 inhibitory activity present in both sources in a dose-dependent manner; the concentration of bovine APC required to produce 50% (C₅₀) neutralization of endothelial PAI-1 (0.5nM) was 4 μg/ml (64nM). Moreover, when complexes between tissue plasminogen activator (t-PA, 60ng/ml, 0.84nM) and PAI-1(18.8ng/ml, 0.35nM) were incubated with bovine APC, the amount of such complexes decreased as a function of the concentration of added APC (C₅₀ = 2 μ/ml, 32 nM), and a concomitant increase in the amount of residual t-PA activity was observed. This effect was due to the formation of APC⊎PAI-1 complexes as detected by immunoblotting with monoclonal antibodies directed against PAI-1. By this mechanism bovine APC prevented the initial reaction between PAI-1 and t-PA and interfered with the stability of complexes between t-PA and PAI-1. The latter observation suggests that complexes between t-PA and PAI-1 may dissociate in the presence of bovine APC. In contrast with these findings, when the experiments were performed in an entirely human homologous cell-free system, human APC did not form a complex with PAI-1 and no effect either on PAI-1 or on the stability of preformed t-PA ⊎ PAI-1 complexes was observed. The results indicate that the neutralization of PAI-1 by APC is a phenomenon induced by interspecies molecular interactions.     

Tissue plasminogen activator, plasminogen activator inhibitors, and activator-inhibitor complex in liver disease.

AIMS--To identify the relative contribution of plasminogen activators, particularly tissue plasminogen activator (t-PA) and specific plasminogen activator inhibitors (PAI-1, PAI-2), to the fibrinolytic changes associated with various types of liver disease or severe chemical and physical damage to the liver. METHODS--Platelet rich (PRP) and platelet poor plasma (PFP) from patients with alcoholic cirrhosis, primary biliary cirrhosis, hepatic malignancy, or paracetamol overdose, or who were undergoing partial hepatectomy or liver transplantation, were assayed for t-PA, PAI-1, t-PA-PAI-1 complex and PAI-2 antigen values using specific enzyme linked immunosorbent assays (ELISAs) developed in this laboratory. RESULTS--Appreciable increases in the plasma concentration of t-PA, PAI-1, and t-PA-PAI-1 were seen in patients with alcoholic cirrhosis, primary biliary cirrhosis, and hepatic malignancy. Liver damage due to paracetamol overdose and partial hepatectomy both resulted in a striking increase in plasma PAI-1 concentration, although concentrations of t-PA and t-PA-PAI-1 complex were less affected. Concentrations of t-PA, PAI-1, and t-PA-PAI-1 complex returned to near normal values after successful liver transplantation in a patient with chronic active hepatitis. PAI-2 was also detected in several patients with chronic liver disorders. CONCLUSIONS--Haemorrhage due to fibrinolytic bleeding is commonly associated with liver disease. The patients studied here all had appreciable increases in circulating t-PA antigen concentrations. This was associated with increased concentrations of PAI-1 antigen and t-PA-PAI-1 complex and the balance between activator and inhibitor did not result in systemic plasmin generation. Reduced PAI-1 activity in cirrhosis or a critical difference in the ratio of t-PA to PAI-1 concentrations may explain the enhanced plasminogen activator activity previously noted in cirrhosis but not metastatic disease. Reduced hepatic clearance of t-PA and t-PA-PAI-1 complex due to impaired liver function may account for increased concentrations of free and complexed t-PA.     

Tissue plasminogen activator and plasminogen activator inhibitor in patients with liver cirrhosis

The behaviour of tissue plasminogen activator (t-PA) and t-PA inhibitor (PAI) was studied in patients with decompensated liver cirrhosis. t-PA antigen showed a 3-fold significant increase with respect to healthy volunteers. t-PA activity in these patients did not significantly differ from that found in the controls, but the specific activity of t-PA was significantly lowered by 63%. PAI activity was significantly reduced in cirrhosis (−67%), while PAI-1 antigen was increased by 24%. Venous occlusion of the arm for 20min induced similar increases of t-PA antigen both in normal subjects and cirrhotic patients. These findings show that the total amount of t-PA is enhanced in liver cirrhosis, with no increase of t-PA activity due to the capacity of PAI to bind increased circulating t-PA antigen. The increased total amount of t-PA in cirrhotic patients could be explained in terms of a reduced clearance by the hepato-endothelial system.     

Effects of the Magenstrasse and Mill operation for obesity on plasma plasminogen activator inhibitor type 1, tissue plasminogen activator,fibrinogen and insulin

Plasminogen activator inhibitor 1 (PAI-1), tissue plasminogen activator (t-PA), fibrinogen and insulin were measured in 43 patients 3 years after they had undergone the Magenstrasse and Mill (MM) procedure and in 43 morbidly obese (MO) patients. Mean plasma PAI-1 was 61 ng/ml in the MO group compared to 30 ng/ml in the MM group (p < 0.0001); mean plasma t-PA was 10 ng/ml in the MO group compared to 7 ng/ml in the MM group (p < 0.001). Mean fibrinogen was 3.6 g/l in the MO group compared to 3.2 g/l in the MM group (p < 0.05). Mean plasma insulin levels were 32 U/ml in the MO group compared to 15 U/ml in the MM group. These changes suggest that use of the MM procedure may reduce mortality and morbidity from coronary heart disease in these high-risk obese patients.     

Cerebrospinal fluid plasminogen activator inhibitor-1 in patients with neurological disease.

AIM: To study cerebrospinal fluid (CSF) concentrations of plasminogen activator inhibitor type-1 (PAI-1) in patients with neurological disease. METHODS: CSF PAI-1 concentrations were measured in 51 patients with neurological disease and 20 reference subjects using an ELISA. The patient group comprised three patients with viral meningitis, 20 with encephalitis, nine with acute lymphoblastic (n = 7) and myeloid (n = 2) leukaemia (with central nervous system involvement), and 19 with multiple sclerosis. RESULTS: Raised PAI-1 concentrations were observed in patients with leukaemia, encephalitis and multiple sclerosis. There was no difference in the mean concentrations of PAI-1 in patients with meningitis when compared with the reference subjects. The highest mean (SEM) PAI-1 concentration was found in patients with leukaemia (1.28 (0.36) ng/ml), and the next highest in those with encephalitis (1.19 (0.20) ng/ml). these values were much higher than those in patients with viral meningitis. In a previous report, raised CSF tissue-type plasminogen activator (tPA) activities were detected in patients with multiple sclerosis, leukaemia and encephalitis, with mean activities in decreasing order. PAI-1 concentrations in the same patients were the reverse of their corresponding tPA activities, being higher in those with leukaemia and encephalitis, than in patients with multiple sclerosis. There was no association between CSF PAI-1 concentrations and age in either patients or controls. Similarly, there was no association between CSF PAI-1 concentrations and urokinase-type plasminogen activator (uPA). CONCLUSIONS: Raised CSF PAI-1 concentrations may be used as a non-specific marker of neurological disease. Moreover, PAI-1 may play an important role in regulating the functions tPA, and probably uPA, in CSF.     

Tissue plasminogen activator and plasminogen activator inhibitor type 1 gene polymorphism in patients with gastric ulcer complicated with bleeding

Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) may be involved in the pathogenesis of peptic ulcers through suppression of fibrinolysis. This study was designed to investigate associations of t-PA and PAI-1 genes with clinical features of the patients with bleeding gastric ulcers. Eighty-four patients with peptic ulcers and 100 controls were studied between January 1998 and April 2000. We used polymerase chain reaction and endonuclease digestion to genotype for 4G/5G polymorphism in the promoter region of the PAI-1 gene and the Alurepeat insertion/deletion (I/D) polymorphism in intron h of the t-PA gene. Various clinical features, including lesion site, bleeding event, recurrence of ulcer, and rebleeding, were assessed using a multiple logistic regression model. The genotype distributions of both the t-PA and PAI-1 genes did not differ between the patient and control groups. The occurrence of the I/D or D/D genotype of t-PA was significantly higher in cases of duodenal ulcer (adjusted OR=4.39, 95% CI=1.12-17.21). When a dominant effect (i.e., 4G/4G or 4G/5G versus 5G/5G) of the 4G allele was assumed, the PAI-1 4G/4G genotype was independently associated with rebleeding after hemostasis (adjusted OR=5.07, 95% CI=1.03-24.87). Our data suggest that t-PA gene polymorphism is associated with duodenal ulcers, and that the PAI-1 gene may be a risk factor leading to recurrent bleeding after initial hemostasis.     

Tissue plasminogen activator and placental plasminogen activator inhibitor in human gingival fluid

Gingival crevicular fluid (GCF) is an extracellular exudate protecting periodontal tissue. Pathological changes in the periodontium are reflected in the composition of GCF. Crevicular fluid was collected from healthy volunteers on Millipore^® filter disks, and eluted at 100-fold dilution. The samples were tested for fibrinolytic activity and the presence of the plasminogen activators, t-PA and u-PA, and the specific plasminogen activator inhibitors, PAI-1 and PAI-2. In the diluted samples, t-PA was found at concentrations of 4–33 gmg/l, and PAI-2 at concentrations of 19–84 μg/l, whereas u-PA and PAI-1 were hardly detectable. Analyses of parotid and whole saliva yielded no evidence of gingival fluid contamination from these sources. The fibrinolytic activity of gingival fluid was completely quenched both by antibodies against t-PA and by PAI-2, indicating the presence of t-PA in its two chain form which is more susceptible to inhibition. This inhibition by PAI-2 may serve a regulatory purpose and prevent excessive proteolysis and tissue destruction.     

Detection of specific forms of plasminogen activator inhibitor type 1-by monoclonal antibodies

Monoclonal antibodies to plasminogen activator inhibitor type-1 (PAI-1) were generated and characterised for their ability to inhibit PAI-1 interaction with tissue plasminogen activator (t-PA) and urokinase (u-PA) and detection of the various forms of PAI-1 (native, complexed, and degraded) by immunoblotting. Mab17 inhibited both complex formation between PAI-1 and t-PA/u-PA and PAI-1 activity in a dose dependent manner by 90%. Mab 25 was much less effective, blocking complex formation less than 30% and PAI-1 activity less than 20%. The Kds of Mab 17 and Mab25 were 2.8×10⁻¹¹ M and 2.6×10⁻¹⁰ M, respectively. Following SDS-PAGE and immunoblotting, Mab 17 detected native PAI-1 only; PAI-1 in complex and the t-PA/u-PA degraded form of PAI-1(M_r=42000) did not react with this antibody. In contrast, Mab25 detected all three forms of PAI-I although the affinity for the native form appeared to be greater than Mab 17 or the PAI-1 polyclonal employed. Despite these differences, both monoclonal antibodies immunoprecipitated native and degraded PAI-1 equally as well. These results suggest that the epitope of Mab 17 is associated with the reactive site of PAI-1 and that this region is either missing or not accessible in the cleaved form or in complex.     

The activation of plasminogen by tissue plasminogen activator is not enhanced by different heparin species as assessed in vitro with a solid-phase fibrin method

The aim of this study was to evaluate the effect of several heparin species (standard heparin, heparin of low molecular weight: IC 831422, heparin of high affinity for antithrombin III: IC 831435, and heparin of low affinity for antithrombin III: IC 831436) on the different steps of the fibrinolytic mechanism i.e., interaction of tissue-type plasminogen activator (t-PA) with plasminogen activator inhibitor-1 (PAI-1), binding of t-PA and plasmin(ogen) to fibrin and activation of plasminogen on the fibrin surface, in the presence of plasma proteins and factors that modulate fibrinolysis. Fibrinolytic and plasmin amidolytic activities were measured in the presence and absence of heparin. The spectrophotometric assays were performed in the presence and absence of solid-phase fibrin using selective chromogenic substrates for plasmin and saturating concentrations of plasminogen.The overall fibrinolytic activity, the amidolytic activity of mixtures of t-PA or urokinase with plasminogen in the absence of fibrin, the binding of t-PA and plasmin(ogen) to fibrin and the t-PA/PAI-1 interaction were not modified by heparin. In contrast, the activation of plasminogen by fibrin-bound t-PA decreased as a function of the concentration of heparin. Although this effect was not significant at concentrations usually used in routine heparin therapy (0.1 to 1 iu/ml) it might have some relevance when heparin is injected in bolus doses.In conclusion, by using a solid-phase fibrin method which allows the analysis of t-PA/PAI-1 balance, data were obtained indicating that the heparin species tested here neither competed with fibrin for the binding of t-PA, nor potentiated the activation of plasminogen at the fibrin surface.     

t-PA activity, antigen and PAI-1 antigen levels in blood obtained from the patients with cerebral infarction

Tissue plasminogen activator (t-PA) produced by endothelial cells exerts a powerful effect on the course of thrombosis, embolism, or arteriosclerosis. However, the fluctuations of fibrinolytic system in the patients with cerebral infarction (CI), have yet to be demonstrated. This study was designed to investigate t-PA activity, t-PA antigen and plasminogen activator inhibitor-1 (PAI-1) antigen levels in the CI patients. The mean t-PA activity, t-PA antigen and PAI-1 levels in patients were 0.53 +/- 0.64 IU/ml, 10.9 +/- 5.2 ng/ml and 23.0 +/- 14.9 ng/ml, and the normal ranges were 0.02-0.28 IU/ml, 1.0-7.0 ng/ml and 5.3-45.0 ng/ml, respectively. Almost all the patients were plotted out to the abnormal range by scattergrams relating t-PA activity to t-PA antigen, and no daytime fluctuations of the above three parameters in the patients differed from those in normal controls. When CI patients were followed up to the 8th hospital day, abnormal fluctuations were also observed. Consequently we suggest that this information may help to attain the more progressive treatment or the preventive therapy of CI.     

Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 levels in acute myocardial infarction

The cause of the circadian variation in the incidence of acute myocardial infarction (AMI) has not been identified. Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) have opposing effects on thrombi. Hence, the extent of the clot, the size of the infarct and outcome of patients could depend on t-PA and PAI-1 levels. In an effort to elucidate the pathophysiologic basis of circadian variation of AMI, we investigated the presence of a possible corresponding circadian variation in the levels of endogenous t-PA and PAI-1 in patients diagnosed to have AMI and the effects of hypertension, diabetes and site of the infarct on these levels. We estimated the levels of t-PA and PAI-1 in platelet-poor plasma of 42 patients with AMI on admission, using the enzyme-linked immunosorbant assay. Although not statistically significant, patients having an AMI in the morning hours had the highest t-PA:PAI-1 ratio. The normal circadian variation in PAI-1 levels was lost in patients with AMI, probably due to the disease process. Also, the t-PA levels in hypertensive patients were significantly lower than in nonhypertensives. PAI-1 levels were also significantly lower in patients with anteroseptal than in inferior and anterolateral AMI. This relationship between the fibrinolytic potential and the site of infarction needs further study. Furthermore, t-PA levels on admission were significantly lower in survivors and may have a predictive value in determining the outcome.     

Increase of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) in plasma after thrombolytic therapy of patients with myocardial infarction. A randomised,placebo-controlled study

Based on recent studies we hypothesised that the marked generation of thrombin in patients who undergo coronary thrombolysis was associated with substantial deviations of endogenous tissue-type plasminogen activator (t-PA) and the plasminogen activator inhibitor type 1 (PAI-1) in plasma.In the present placebo-controlled study we observe in 20 patients treated with recombinant t-PA (rt-PA) a marked increase (p<0.001) of antigen concentrations in plasma of endogenous t-PA and PAI-1 during the first 12h after initiation of treatment. The concentrations of endogenous t-PA and PAI-1 in plasma correlated significantly (p<0.05) with an estimate of generated thrombin in vivo, determined as plasma concentrations of thrombin-antithrombin III complexes. We conclude that the generation of coagulant activity following coronary thrombolysis is associated with an increased synthesis and/or release of endogenous t-PA and PAI-1, which suggests that the procoagulant condition involves an altered functional state of the vascular endothelium.     

Human gender differences in fibrinolytic responses to exercise training and their determinants

Endurance exercise training improves fibrinolysis, but this training-induced adaptation may differ somewhat between men and women. We sought to determine whether the potential gender differences in training-induced changes in selected fibrinolysis measures were related to changes in adiposity and/or plasma lipoprotein lipid levels. Seventeen men and 28 women, 50-75 years old, who were generally overweight to obese, were assessed for plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (t-PA) activity, t-PA antigen and plasma lipoprotein-lipid levels, and body composition before and after 6 months of endurance exercise training while on a low-fat diet. At baseline, there were no differences in fibrinolytic measures between the men and women. Baseline levels of these fibrinolytic markers in both men and women were primarily related to other fibrinolytic measures and body composition, with a smaller contribution from plasma high-density lipoprotein cholesterol (HDL-C) levels. Exercise training reduced t-PA antigen levels in both men and women, but the reduction was significantly greater in men (-1.6 +/- 0.3 versus -0.5 +/- 0.2 ng ml(-1), P = 0.007). Exercise training decreased PAI-1 activity more in men than in women (-2.6 +/- 1.4 versus +0.9 +/- 0.9 IU ml(-1), P = 0.03). Men and women both showed increased t-PA activity with exercise training to the same extent (+0.38 +/- 0.12 versus +0.36 +/- 0.24 U ml(-1)). The changes in fibrinolytic measures with exercise training in men and women were correlated with changes in other fibrinolytic measures, although in men abdominal fat changes were a strong predictor of fibrinolytic changes with training. These findings suggest that training-induced improvements in endogenous fibrinolysis markers are somewhat greater in men compared to women and may be more strongly associated with abdominal obesity in men.     

Expression of urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, and plasminogen activator inhibitor-1 and -2 in hepatocellular carcinoma

It has become more and more clear in recent decades that the plasminogen activation system, which includes urokinase-type plasminogen activator (uPA), urokinase-type plasminogen activator receptor (uPAR), plasminogen activator inhibitor (PAI)-1 and PAI-2, plays a very important role in the aggressiveness of cancer. Using immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), the expression of these four components of the uPA system was analyzed in 19 cases of hepatocellular carcinoma (HCC) and 18 cases of the adjacent non-cancer tissues which all had chronic active hepatitis with liver fibrosis or liver cirrhosis. Four cases of normal liver tissues, as controls for immunohistochemical stains, were obtained from the hepatectomized liver of patients with metastatic cancer in the liver. The positive rates of uPA, uPAR, PAI-1 and PAI-2 for immunohistochemical stains in cancer tissues were 78.9, 68.4, 57.9 and 31.6%, respectively. Positive signals were mainly distributed in the cytoplasm of the cancer and in stromal cells. Moreover, the strong stains were chiefly located in the invasive front of the cancer cells. No specific stain was detected in four cases of normal liver tissues. In ELISA, there were significant differences between cancer and non-cancer tissues in concentration of uPA, uPAR and PAI-1 (P < 0.0003, 0.0024 and 0.01, respectively), but there was no significant difference in that of PAI-2 (P = 0.37). These results suggest that uPA, uPAR and PAI-1 are related to invasion of HCC.     

Induction of the plasminogen activator system by mechanical stimulation of human bronchial epithelial cells

Mechanical stimulation of the airway epithelium, as would occur during bronchoconstriction, is a potent stimulus and can activate profibrotic pathways. We used DNA microarray technology to examine gene expression in compressed normal human bronchial epithelial cells (NHBE). Compressive stress applied continuously over an 8-h period to NHBE cells led to the upregulation of several families of genes, including a family of plasminogen-related genes that were previously not known to be regulated in this system. Real-time PCR demonstrated a peak increase in gene expression of 8.0-fold for urokinase plasminogen activator (uPA), 16.2-fold for urokinase plasminogen activator receptor (uPAR), 4.2-fold for plasminogen activator inhibitor-1 (PAI-1), and 3.9-fold for tissue plasminogen activator (tPA). Compressive stress also increased uPA protein levels in the cell lysates (112.0 versus 82.0 ng/ml, P = 0.0004), and increased uPA (4.7 versus 3.3 ng/ml, P = 0.02), uPAR (1.3 versus 0.86 ng/ml, P = 0.007), and PAI-1 (50 versus 36 ng/ml, P = 0.006) protein levels in cell culture media. Functional studies demonstrated increased urokinase-dependent plasmin generation in compression-stimulated cells (0.0090 versus 0.0033 OD/min, P = 0.03). In addition, compression led to increased activation of matrix metalloproteinase (MMP)-9 and MMP-2 in a urokinase-dependent manner. In postmortem human lung tissue, we observed an increase in epithelial uPA and uPAR immunostaining in the airways of two patients who died in status asthmaticus compared with minimal immunoreactivity noted in airways from seven lung donors without asthma. Together these observations suggest an integrated response of airway epithelial cells to mechanical stimulation, acting through the plasminogen-activating system to modify the airway microenvironment.