Effect Of Plasminogen Activator Research Articles

Possible effects of plasminogen activator inhibitor-1 on promoting angiogenesis through matrix metalloproteinase 9 in advanced mycosis fungoides.

Mycosis fungoides (MF) progresses slowly before advancing to skin tumors followed by lymph node and visceral involvement. Among MF progression, stage IIB is an initial time point of tumor formation in MF. Since MF in tumor stage possess abundant blood vessels, it is important to evaluate the pro-angiogenic factors before and after MF in stage IIB. In this report, we investigated pro-angiogenic soluble factors in MF patients, as well as its pro-angiogenetic effects on tumor cells and stroma cells. We first evaluated the serum levels of pro-angiogenic factors in 9 MF patients without tumor formation and 8 MF patients with tumor formation. Among them, the serum MMP-9 and plasminogen activator inhibitors 1 (PAI-1) was significantly increased in MF with tumor formation compared in MF without tumor formation, leading to favorable formation of human dermal microvascular endothelial cells tube networks. Moreover, PAI-1 stimulation significantly increased the mRNA expression and protein production MMP-9 on monocytes derived M2 macrophages and HUT-78. Furthermore, since MMP-9 production from tumor cells as well as stromal cells is suppressed by bexarotene, we evaluate the baseline serum pro-angiogenic factors including MMP-9 in 16 patients with advanced cutaneous T cell lymphoma treated with bexarotene. The serum levels of MMP-2 and MMP-9 was significantly increased in bexarotene non-responded patients compared to responded patients. Our present study suggested the significance of MMP-9 and PAI-1 for the progression of MF stage toward to the tumor stage, and could be a therapeutic target in future.

Ameliorating effect of urokinase in bleomycin- induced pulmonary fibrosis in rats

Ameliorating effect of urokinase in bleomycin- induced pulmonary fibrosis in rats

A prospective audit evaluating use of urokinase in oncology patients with occluded central venous access devices.

This article reports the results of a single-site prospective audit evaluating the safety and effectiveness of urokinase (Syner-Kinase®) to restore patency in central venous access devices (CVADs) for cancer patients. CVADs are routinely inserted to allow the safe and timely administration of systemic anti-cancer therapies; therefore, catheter dysfunction can interrupt the treatment schedule and adversely affect patient outcome. The aim was to contribute to the development of evidence-based, standardised, best practice guidelines. Prospective data were collected from all patients (n=22) identified with an occluded CVAD, requiring use of Syner-Kinase to manage a persistent withdrawal occlusion or total occlusion, over a 6-month period. Findings revealed a single administration of Syner-Kinase for catheter occlusion clearance to be effective in 92% of cases. Results suggest that use of the thrombolytic agent is well-tolerated and an effective means of restoring patency for long-term CVADs in cancer patients.

Urokinase Attenuates Pulmonary Thromboembolism in an Animal Model by Inhibition of Inflammatory Response

Inflammatory response is an important determining factor for the mortality of patients with pulmonary thromboembolism. Inflammatory mediators can promote thrombus formation and increase hemodynamic instability. Urokinase is a commonly used drug for the treatment of PTE. The effect of urokinase on inflammatory reaction in PTE is still unclear. Our study was aimed at evaluating the effects of the intervention of urokinase and urokinase combined with aspirin in PTE rats. Results revealed that a large amount of infiltrated inflammatory cells surrounding the bronchus, vessels, and pulmonary mesenchyme, and even pulmonary abscess were observed in the PTE rats. CX3CL1/CX3CR1 coexpression, CX3CL1/NF-κB coexpression, and TXA2 were significantly higher. After treatment with urokinase, pulmonary embolism was partially dissolved and inflammatory cell infiltration was significantly reduced. The expression of TNNI3, BNP, D2D, PASP, PADP, PAMP, and TXA2, as well as CX3CL1/CX3CR1 coexpression and CX3CL1/NF-κB coexpression were significantly lowered. Aspirin showed no synergistic action. Therefore, these findings suggested the occurrence of inflammation during the process of PTE in rats. Urokinase treatment reduced the inflammatory response.

Effectiveness of urokinase for salvaging occluded central venous access devices

Effectiveness of urokinase for salvaging occluded central venous access devices

Comparison of the effect of urokinase and batroxobin in the treatment of acute cerebral infarction

Objective To compare the efficacy and safety of urokinase and batroxobin in the treatment of acute cerebral infarction(ACI). Methods According to the digital table, 88 patients with ACI were randomly divided into two groups.The observation group(44 cases) was given thrombolytic therapy, the control group(44 cases) was given alteplase treatment.The treatment effects and safety were compared between the two groups. Results The NIHSS scores before treatment, 24h, 1 week and 2 weeks after thrombolysis had no statistically significant differences between the two groups(all P>0.05). After treatment for 1 month, 29 cases(65.9%) of nerve function good prognosis in the observation group, 28 cases(63.6%) in the control group, there was no significant difference between the two groups(χ2=0.049, P=0.958). In the control group, 1 case of cerebral hemorrhage, and occlusion in 1 case, 1 case of other adverse reactions(hematuria), the incidence rate of complications and adverse reaction was 6.82%(3/44). In the observation group, 2 cases of hemorrhage(including 1 case of cerebral hemorrhage and 1 case of gastrointestinal bleeding), 1 case of reperfusion injury and restenosis, 2 cases of other adverse reactions(including hematuria and allergic rash, each in 1 case), the incidence rate of complications and adverse reaction was 13.64%(6/44). There was no statistically significant difference in the incidence rate of complications and adverse reaction between the two groups(χ2=0.495, P=0.597). Conclusion Urokinase and alteplase in the treatment of ACI have considerable effect in improving the symptoms of patients with neurologic impairment, alteplase is slightly in terms of security advantages, but the price is relatively expensive, urokinase in the treatment of ACI in primary hospital is still desirable. Key words: Cerebral infarction; Urokinase; Alteplase

Organizing empyema induced in mice by Streptococcus pneumoniae: effects of plasminogen activator inhibitor-1 deficiency.

BackgroundPleural infection affects about 65,000 patients annually in the US and UK. In this and other forms of pleural injury, mesothelial cells (PMCs) undergo a process called mesothelial (Meso) mesenchymal transition (MT), by which PMCs acquire a profibrogenic phenotype with increased expression of α-smooth muscle actin (α-SMA) and matrix proteins. MesoMT thereby contributes to pleural organization with fibrosis and lung restriction. Current murine empyema models are characterized by early mortality, limiting analysis of the pathogenesis of pleural organization and mechanisms that promote MesoMT after infection.MethodsA new murine empyema model was generated in C57BL/6 J mice by intrapleural delivery of Streptococcus pneumoniae (D39, 3 × 107–5 × 109 cfu) to enable use of genetically manipulated animals. CT-scanning and pulmonary function tests were used to characterize the physiologic consequences of organizing empyema. Histology, immunohistochemistry, and immunofluorescence were used to assess pleural injury. ELISA, cytokine array and western analyses were used to assess pleural fluid mediators and markers of MesoMT in primary PMCs.ResultsInduction of empyema was done through intranasal or intrapleural delivery of S. pneumoniae. Intranasal delivery impaired lung compliance (p < 0.05) and reduced lung volume (p < 0.05) by 7 days, but failed to reliably induce empyema and was characterized by unacceptable mortality. Intrapleural delivery of S. pneumoniae induced empyema by 24 h with lung restriction and development of pleural fibrosis which persisted for up to 14 days. Markers of MesoMT were increased in the visceral pleura of S. pneumoniae infected mice. KC, IL-17A, MIP-1β, MCP-1, PGE2 and plasmin activity were increased in pleural lavage of infected mice at 7 days. PAI-1−/− mice died within 4 days, had increased pleural inflammation and higher PGE2 levels than WT mice. PGE2 was induced in primary PMCs by uPA and plasmin and induced markers of MesoMT.ConclusionTo our knowledge, this is the first murine model of subacute, organizing empyema. The model can be used to identify factors that, like PAI-1 deficiency, alter outcomes and dissect their contribution to pleural organization, rind formation and lung restriction.

Effect of urokinase on the outward permeability of blood-retinal barrier following local injection in rats

Background Retinal vascular recanalization is key to the treatment of retinal vascular occlusive disease.Studies confirmed that urokinase by intravitreal injection inhibits the expression of occludin protein at tight junction complexes among retinal capillary endothelial cells. Objective This study was to observe the effects of urokinase via eye local injection on the outward permeability of blood-retinal barrier by detecting the concentration of intravitreal Evans blue (EB). Methods Sixty healthy Sprague-Dawley (SD) rats were randomly assigned to four groups, and the right eyes of the rats were used as experimental eyes.Urokinase of 4 μl (350 U) and the equal volume of PBS (0.01 mol/L) was intravitreally injected separately in the intravitreal urokinase group and the intravitreal PBS group, and 10 μl urokinase (1 000U) and the equal volume of PBS was injected via retrobulbar tissue respectively as the retrobulbar urokinase group and the retrobulbar PBS group.Twenty-four hours after injection of drugs, 0.5% EB 4 μl was intravitreally injected.Four hours later, the rats were sacrificed and the right eyeballs were excised for the extraction and drying.EB was extracted from dried vitreous by formamide.Then, the concentration of EB in formamide was determined by a formamide extraction-ultraviolet spectrophotometry method to calculate the concentration of EB in vitreous.The use and care of experimental animals followed the Regulations for the Administration of Affair Concerning Experimental Animals by State Science and Technology Commission (2011 version). Results The rat vitreous body showed the light blue color in intravitreal urokinase group and the retinal vessels were visible under the microscope, and that in the retrobulbar urokinase group presented blue color.However, in the intravitreal and retrobulbar PBS group, rat vitreous exhibited the deeper blue color and retinas were invisible.Absorbance of EB in formamide was 0.181±0.008, 0.450±0.017, 0.330±0.009 and 0.436±0.012 in the intravitreal urokinase group, intravitreal PBS group, retrobulbar urokinase group and retrobulbar PBS group, respectively.The intravitreal EB concentrations in the intravitreal urokinase group were (0.266±0.014)g/L, which was lower than (0.667±0.026)g/L, (0.496±0.015)g/L and (0.657±0.017)g/L of the intravitreal PBS group, retrobulbar urokinase group and retrobulbar PBS group, showing significant different among the four groups (F=100.406, P<0.01), and the intravitreal urokinase group showed the lowest value in comparison with other three groups (all at P<0.01). Conclusions Local application of urokinase around eye can augment the outward permeability of blood-retinal barrier in rats. Intravitreal assay of EB after intravitreal injection is a feasible approach to the determination of outward permeability of blood-retinal barrier. Key words: Urokinase; Intravitreal injection; Evans blue; Blood-retinal barrier; SD rats

Urokinase stimulates production of matrix metalloproteinase-9 in fibroblasts with involvement of reactive oxygen species.

In cultured fibroblasts, urokinase stimulated expression of MMP-9 and generation of ROS, while antioxidant ebselen abolished the stimulating effect of urokinase on MMP-9 expression. sTNF-α produced similar and more pronounced stimulating effect. The data showed that urokinase could regulate MMP-9 expression via ROS generation in fibroblasts, which can play an important role in stimulation of their migration and development of constrictor (negative) vascular remodeling due to thickening of the adventitia.

Children with Nephrotic Syndrome Suffer from Cerebral Venous Thrombosis

Hypercoagulability is a common complication in children with nephrotic syndrome and may cause venous thrombosis. This study explored the effectiveness of urokinase and low-molecular-weight (LMW) heparin used in conjunction in seven children with nephrotic syndrome complicated by intracranial venous thrombosis. The urokinase dose was 2,000-4,000 u/kg/day initially, with a pulse dose of 20,000-40,000 u given within 15-30 minutes and the remainder was pump-infused. From day 2, a dose of 2,000 u/kg/day was infused via the pump, and the total course duration was 3 to 7 days. During treatment, thrombin time (TT) and activated partial thromboplastin time (APTT) were tested three times per week, and particular attention was given to any bleeding. LMW heparin was used at a dosage of 100-120 anti-Xa IU/kg once or twice per day, given by abdominal subcutaneous injection for two weeks. The antiplatelet drug, dipyridamole 3-5 mg/kg, was also given orally two or three times per day for three months. In this study, the early use of urokinase, LMW heparin and anti-platelet drugs had good effect, the need for preventive therapy and early diagnosis of this complication in nephrotic syndrome should be given wider clinical consideration.

Effects of plasminogen activator inhibitor-1-specific RNA aptamers on cell adhesion, motility, and tube formation.

The serine protease inhibitor (serpin) plasminogen activator inhibitor-1 (PAI-1) is associated with the pathophysiology of several diseases, including cancer and cardiovascular disease. The extracellular matrix protein vitronectin increases at sites of vessel injury and is also present in fibrin clots. Integrins present on the cell surface bind to vitronectin and anchor the cell to the extracellular matrix. However, the binding of PAI-1 to vitronectin prevents this interaction, thereby decreasing both cell adhesion and migration. We previously developed PAI-1-specific RNA aptamers that bind to (or in the vicinity of) the vitronectin binding site of PAI-1. These aptamers prevented cancer cells from detaching from vitronectin in the presence of PAI-1, resulting in an increase in cell adhesion. In the current study, we used in vitro assays to investigate the effects that these aptamers have on human aortic smooth muscle cell (HASMC) and human umbilical vein endothelial cell (HUVEC) migration, adhesion, and proliferation. The PAI-1-specific aptamers (SM20 and WT15) increased attachment of HASMCs and HUVECs to vitronectin in the presence of PAI-1 in a dose-dependent manner. Whereas PAI-1 significantly inhibited cell migration through its interaction with vitronectin, both SM20 and WT15 restored cell migration. The PAI-1 vitronectin binding mutant (PAI-1AK) did not facilitate cell detachment or have an effect on cell migration. The effect on cell proliferation was minimal. Additionally, both SM20 and WT15 promoted tube formation on matrigel that was supplemented with vitronectin, thereby reversing the PAI-1's inhibition of tube formation. Collectively, results from this study show that SM20 and WT15 bind to the PAI-1's vitronectin binding site and interfere with its effect on cell migration, adhesion, and tube formation. By promoting smooth muscle and endothelial cell migration, these aptamers can potentially eliminate the adverse effects of elevated PAI-1 levels in the pathogenesis of vascular disease.

A Combined Treatment with Taurine and Intra-arterial Thrombolysis in an Embolic Model of Stroke in Rats: Increased Neuroprotective Efficacy and Extended Therapeutic Time Window

Combination treatment may target different pathophysiological events following cerebral ischemia thus enhancing the efficacy of treatment in thromboembolic stroke. Taurine confers a neuroprotective effect in the mechanical stroke model. This effect has not been assessed in an embolic stroke model. Here, we sought to evaluate the neuroprotective effect of taurine alone and in combination with thrombolytic therapy to investigate whether combined administration would extend the therapeutic time window without increasing the hemorrhagic transformation in a rat embolic stroke model. Rats were subjected to right embolic middle cerebral artery occlusion and then randomly assigned to the following groups: saline treatment alone at 4h, urokinase, taurine treatment alone at 4, 6, or 8h, and the combination of taurine and urokinase at 4, 6, or 8h after the insult. Brain infarct volume, neurobehavioral outcome, regional cerebral blood flow, intracranial hemorrhage incidence were observed and evaluated. Posttreatment with taurine at 4 or 6h, urokinase at 4h or in combination at 4, 6, or 8h significantly reduced infarct volume and improved neurobehavioral outcome. The combination treatment had better neurobehavioral outcome and smaller infarction volume than urokinase or taurine treatment alone. The clinical outcome correlated well with infarct volume. Together, the present study suggests that administration of taurine after stroke is neuroprotective, seemingly because it reduces the reperfusion damage of urokinase, leading to widen the therapeutic window for the thrombolytic effect of urokinase to 8h. Thrombolysis can also enhance the neuroprotective effect of taurine. The reduction of inflammatory response, neuron death and inhibition of blood brain barrier (BBB) disruption may underlie the beneficial effects of combination of taurine and urokinase in the treatment of embolic stroke.

Clinical research in the effects of urokinase on acute cerebral infarction in very early stage

Objective To study the effects of thrombolysis for the treatment of acute cerebral infarction (ACI) in early stage (within 6 hours after onset) in hospital, and to demonstrate the benefit of urokinase in the treatment of acute cerebral infarction. Method The patients with cerebral infarction treated with UK within 3hours after onset in the emergency department were enrolled as the study group, and those treated with thrombolytics in the neurological unit over the same period were taken as the control group. Results The average time from onset of ACI to starting thrombolytic therapy was 45 minutes in the study group and 80 minutes in the control group.The number of patients treated with thrombolysis within 3 hours was 39 ( 14.4% ) in the study group and 29 (10.5%) in the control group. There were significant differences in the scores of the National Institutes of Health Stroke Scale (NIHSS) after thrombolytic therapy and in Bathel index of complete or nearly complete recovery rate between two groups. The length of hospital stay was shorter in patients of the study group than that in the control group. Conclusions The thrombolytic treatment with urokinase employed to the patients in the early stage of acute cerebral infarction leads to better outcomes than that in the later stage. Key words: Emergency; Thrombolytic therapy; Cerebral infarction; Urokinase

Application and nursing about urokinase for the treatment of thrombosis in arteriovenous fistula in hemodialysis patients

Objective To observe the effects of urokinase in the treatment of thrombosis in hemodialysis patients with arteriovenous fistulae and to discuss simple, safe and effective methods of thrombolysis. Methods Local injections of urokinase were applied in 23 hemodialysis patients for 43 times to treat thrombosis in fistula, then the effects were observed, and the changes between before treatment and after treatment of several index, such as activated partial thromboplastin time( APTT), Fibrinogen( Fbg), international normalized ratio (INR), Prothrombin Time (PT), thrombin time(TT) were compared. Results The thrombolytic therapies were used in 23 cases for 43 times in total, in which 33 times (76.7% ) received success, and there were no severe complications occurred. The effectiveness was related to the duration of thrombosis. There were no significant differences in comparison of APTT, Fbg, INR, PT, TT before and after urokinase administration. Conclusions Urokinase was effective in thrombolytic therapy for hemodialysis patients with thrombosis in arteriovenous fistula. Key words: Hemodialysis; Arteriovenous fistulae; Thrombolysis; Thrombus; Nursing

Effect of urokinase on hemorheology in the treatment of acute myocardiai infarction

Objective To study the therapeutic effects of urokinase in the treatment of acute myocardiai in-farction(AMI) and its effect on the changes of hemorheological.Methods 96 patients with AMI were divided into the group treatment with urokinase and the control group.blood samples taken from every group before treatment and three hours after therapy were derected.Results The recanalization rate was significantly higher in the group treatment with urokinase than control group.CK and CKMB significantly improved after treatment with urokinase than control.The indexes of hemorheology in the patients with AMI were abnormal,which were improved after intravenous onjection with urokinase.Conclusion Early using of urokinase in AMI could improve the indexes of hemorheology sign-ficently,and it could shrink the area of infarction,recover reperfusion rate and reduce mortality rate. Key words: Urokinase; Thrombolysis; Myocardiai infarction; Hemorheology

Effect of plasmin, plasminogen activators and a plasmin inhibitor on bovine in vitro embryo production

In the present study, four experiments were conducted to investigate the possible effects of plasminogen activators (urokinase-type plasminogen activator (u-PA) and tissue-type plasminogen activator (t-PA)), plasmin, and a plasmin inhibitor (epsilon-aminocaproic acid (epsilon-ACA)) on different stages of bovine in vitro embryo production (IVP). The concentrations of these modifiers in IVP media were conditioned according to the plasminogen activator activity of bovine preovulatory follicular fluid. Media were modified in a single phase of IVP with an 18 h or 24 h incubation for in vitro maturation (IVM) and a 24 h or 48 h incubation for the IVF or in vitro culture (IVC), respectively. After IVM the oocytes were either fixed and stained or underwent IVF and IVC. The main findings were: (1) plasmin added to the 18 h IVM medium increased maturation rate without affecting fertilisation or embryo development rates; (2) t-PA added to the IVF medium significantly increased cleavage; (3) u-PA added to the IVC medium significantly increased embryo development rates; (4) the efficiency of all phases of IVP was reduced after the addition of epsilon-ACA; and (5) plasminogen addition had no effect in any IVP phase tested. We conclude that the members of the plasminogen activator-plasmin system contribute in different ways to bovine IVM, IVF and IVC.

Tyk2 mediates effects of urokinase on human vascular smooth muscle cell growth

The urokinase (uPA)/uPA receptor (uPAR) system plays a role in the response of the vessel wall to injury, presumably by modulating vascular smooth muscle cell (VSMC) functional behaviour. The Jak/Stat signaling pathway has been implicated to mediate the uPA/uPAR-directed cell migration and proliferation in VSMC. We have therefore investigated the underlying molecular mechanisms, which remained not completely understood. In particular, we aimed at identification of the kinase involved in the signaling cascade leading to Stat1 phosphorylation by uPA and its impact on VSMC growth. We performed expression in VSMC of kinase-deficient mutant forms of the Janus kinases Jak1 and Tyk2 and used different cell culture models imitating the response to vascular injury. We provide evidence that Tyk2, but not Jak1, mediates uPA-induced Stat1 phosphorylation and VSMC growth inhibition and suggest a novel function for Tyk2 as an important modulator of the uPA-directed VSMC functional behaviour at the place of injury.

Effects of urokinase and low-molecular-weight heparins calcium in 62 cases of acute cerebral infarction

目的 探讨尿激酶(uK)联合低分子肝素钙治疗进展性脑梗死的疗效和安全性.方法 对发病6h后病情继续发展的急性脑梗死患者62例,随机分为治疗组和对照组,治疗组首剂给予尿激酶30万U,第2、3天各20万U分别溶于生理盐水100ml中静滴,30min内滴完;UK滴注后6h给予低分子肝素钙5000IU脐周皮下注射.连用1周.同时给予胞二磷胆碱、25%甘露醇、阿司匹林等常规药物治疗.对照组除不采用UK外,其余治疗与治疗组相同.结果 治疗组疗效优于对照组(P＜0.01).治疗组治疗后24h、72h、14d神经功能状态评分较治疗前明显改善(P＜0.01),病情进展控制较好,而对照组虽有改善但差异无统计学意义(P＞0.05).结论 UK联合低分子肝素钙治疗进展性急性脑梗死疗效肯定,安全性好。

The effectiveness of urokinase in treatment of pleural effusion in children

Purpose : Pleural effusion is a common complications of pediatric bacterial pneumonia. Intrapleural administration of fibrinolytic agents such as urokinase have been used in the management of complicated parapneumonic effusions. But the safety and effectiveness of intrapleural urokinase instillations in children has not been confirmed. The aim of this study is to evaluate the safety and effectiveness of intraperitoneal urokinase in children. Methods : We reviewed a total of 29 children diagnosed as parapneumonic effusion with septation by chest CT or chest ultrasonography. We divided them into two groups. Fourteen children treated with urokinase after thoracostomy (Group A) were compared with 15 children treated only with thoracostomy (Group B). The urokinase, 3,000 IU/kg/day, was injected into the pleural cavity twice a day. Results : There was no statistical difference in sex and age between the two groups. Total drainage volume during thoracostomy in group A and B was 375.5 mL and 350.0 mL, respectively. It was not statistically significant. But the amounts of pleural fluid of group A on day 1, day 2 and day 3 were 102.5 mL, 100.0 mL, and 70.0 mL respectively and those of group B on day 1, day 2 and say 3 were 120.0 mL, 50.0 mL and 15.0 mL respectively. To compare group A with group B in the amounts of drainage volume on day 1 was not statistically significant, but the amounts of drainage volumes on day 2 and day 3 in group A were statistically more significant than group B (Day 1 P=0.371, Day 2 P=0.049, Day 3 P=0.048, respectively). The duration of fever, antibiotics, thoracostomy and total hospital days. Were not statistically significant between the two groups. But the frequency of complications in Group A was statictically significantly lower than in group B. Conclusion : Intrapleural instillation of urokinase facilitates the drainage of loculated pleural effusions, especially during the first 3 days, and it could reduce complications, such as pleural thickening, surgical managements, re-positioning of tube and re-thoracostomy. So intrapleural urokinase injection was and effective and safe treatment of pleural effusion in children (P=0.014).

Urokinase Induces Matrix Metalloproteinase-9/Gelatinase B Expression in THP-1 Monocytes via ERK1/2 and Cytosolic Phospholipase A2 Activation and Eicosanoid Production

Objective: Urokinase-type plasminogen activator (uPA) regulates cell migration and invasion by pericellular proteolysis and signal transduction events. We characterized the mechanisms by which uPA regulates matrix metalloproteinase-9 (MMP9) function in THP-1 monocytes. Methods and Results: In THP-1 monocytes, MMP9 production induced by urokinase was completely inhibited by the ERK1/2 inhibitor, PD98059, but not by the p38 mitogen-activated protein kinase inhibitor, SB202190. A dominant negative MEK1 adenovirus also blocked MMP9 expression. The effect of urokinase was completely suppressed by genistein and by herbimycin A indicating that tyrosine kinase(s) are required for MMP9 production. Bisindolylmaleimide, a protein kinase C (PKC) inhibitor, did not decrease MMP9 expression suggesting that PKC activation is not required. Key roles for cytosolic phospholipase A₂ (PLA2) and eicosanoid production were shown by complete inhibition with methyl arachidonyl fluorophosphonate (an inhibitor of cytosolic PLA2), and indomethacin (a cyclooxygenase inhibitor), with no effect of monoalide, a secretory PLA2 inhibitor. uPA stimulated phosphorylation of cytosolic PLA2. Conclusions: Induction of MMP9 by uPA in THP-1 monocytes is via a pathway involving MEK1-ERK1/2-mediated activation of cytosolic PLA2 and eicosanoid generation. These data suggest important roles for eicosanoids in monocyte migration induced by uPA and MMP9.