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PubMedDate not supplied

Cytotoxicity of viscoelastics on cultured corneal epithelial cells measured by plasminogen activator release.

BACKGROUND: Plasminogen activator has been shown to be released by epithelial cells following corneal injury. The demonstration of the release of plasminogen activator from cultured corneal epithelial cells has been used for developing a cytotoxicity test, the Corneal Epithelial Plasminogen Activator test, which compares changes in the level of plasminogen activator in tissue culture media following chemical exposure as an index of chemical injury. METHODS: Cultured rabbit corneal epithelial cells were exposed to varying concentrations of several viscoelastics for 1 hour. Release of plasminogen activator into the tissue culture media following exposure to the viscoelastic agent was studied as an index of chemical injury. RESULTS: The least cytotoxicity to cultured rabbit epithelium was associated with those viscoelastic agents containing methylcellulose. A 1-hour exposure to most concentrations of methylcellulose and chondroitin sulfate (Phacote) and methylcellulose (Occucoat) demonstrated release of greater amounts of plasminogen activator than was seen following a similar exposure to balanced salt solution, suggesting the greatest protective effect of these two viscoelastics. In contrast, sodium hyaluronate and chondroitin sulfate (Viscoat) showed decreased amounts of plasminogen activator release after a 1-hour exposure to cultured corneal epithelial cells demonstrating cytotoxicity. Polyacrylamide (Orcolon) and most diluted preparations of sodium hyaluronate (Healon and Healon Yellow) showed only mild reductions in the release of plasminogen activator, whereas undiluted sodium hyaluronate preparations were nearly as cytotoxic as Viscoat. CONCLUSIONS: This study suggests that viscoelastic agents containing methylcellulose (Phacote and Occucoat) may be most protective of the corneal epithelium during ophthalmic surgery. The clinical success of several dilute viscoelastic solutions as tear substitutes was corroborated by the lack of cytotoxicity seen in this study. Viscoat and undiluted sodium hyaluronate preparations showed the greatest cytotoxicity to cultured rabbit corneal epithelium.

Acrylic Resins↗
PubMed1993

PAM, a novel plasminogen-binding protein from Streptococcus pyogenes.

The ability of group A streptococci to bind human plasminogen and plasmin has attracted interest, because it could provide the bacteria with a mechanism for invasion. M or M-like proteins account for the binding of several plasma proteins to group A streptococci. To investigate whether M or M-like proteins were responsible for the binding of plasminogen to group A streptococci, acid-extracted material from a type M53 streptococcal isolate was tested for its ability to bind plasminogen. Indeed, a 42-kDa plasminogen-binding protein was solubilized. Two oligonucleotides homologous with conserved sequences in known M protein genes were used as primers in the polymerase chain reaction, with chromosomal DNA from the M53 isolate. When cloned and expressed in Escherichia coli, a resulting fragment encoded a 43-kDa plasminogen-binding protein. Nucleotide sequence determination of the gene fragment revealed an open reading frame encoding a polypeptide of 43,580 Da, which matched the amino-terminal amino acid sequence of the plasminogen-binding protein extracted from M53 streptococci. The DNA sequence data also proved the relationship of the encoded protein, named PAM, to the M proteins. The plasminogen-binding domain was mapped to the amino-terminal third of PAM. Plasminogen absorbed by M53 streptococci or by immobilized PAM could be activated by streptokinase. The results provide further evidence of the diversity of the M protein family and suggest a new mechanism whereby these proteins contribute to the virulence of group A streptococci.

Amino Acid Sequence↗
PubMed1977

[Plasminogen content of human fibrinogen preparations from different sources (author's transl)].

In connection with fibrinolytic therapy, it is of interest to know how much plasminogen is contained in different commercially available figrinogen preparations. This problem was investigated with the aid of a semiquantitative determination of plasminogen. The determined plasminogen content was compared with plasminogen concentration of pooled human plasma. Using the ratio of plasminogen to fibrinogen, and fixing the plasminogen content of human plasma arbitrarily at 100%, the proportion of plasminogen in fibrinogen from Immuno is 134%, fibrinogen from Behringwerke contains 13.7%, and Kabi-fibrinogen contains 2.71% plasminogen.

Fibrinogen↗
PubMed2003

Inhibition of cell surface mediated plasminogen activation by a monoclonal antibody against alpha-Enolase.

Localization of plasmin activity on leukocyte surfaces plays a critical role in fibrinolysis as well as in pathological and physiological processes in which cells must degrade the extracellular matrix in order to migrate. The binding of plasminogen to leukocytic cell lines induces a 30- to 80-fold increase in the rate of plasminogen activation by tissue-type (tPA) and urokinase-type (uPA) plasminogen activators. In the present study we have examined the role of alpha-enolase in plasminogen activation on the cell surface. We produced and characterized a monoclonal antibody (MAb) 11G1 against purified alpha-enolase, which abrogated about 90% of cell-dependent plasminogen activation by either uPA or tPA on leukocytoid cell lines of different lineages: B-lymphocytic, T-lymphocytic, granulocytic, and monocytic cells. In addition, MAb 11G1 also blocked enhancement of plasmin formation by peripheral blood neutrophils and monocytes. In contrast, MAb 11G1 did not affect plasmin generation in the presence of fibrin, indicating that this antibody did not interact with fibrinolytic components in the absence of cells. These data suggest that, although leukocytic cells display several molecules that bind plasminogen, alpha-enolase is responsible for the majority of the promotion of plasminogen activation on the surfaces of leukocytic cells.

Adenocarcinoma↗
PubMed2000

Helicobacter pylori interactions with plasminogen.

Helicobacter pylori is the causative agent of chronic gastritis, peptic ulcer, and gastric malignancies. A number of virulence factors have been described including several adhesins, a cytotoxin, neutrophil-activating protein, and expression of binding of extracellular matrix proteins, like collagen type IV, laminin, and vitronectin. H. pylori strains commonly express binding of soluble plasminogen. Coccoid forms also express binding. Plasminogen binding was optimal at pH 7.0. The binding is mediated by two cell surface proteins of 42 and 57 kDa. Scatchard plot analysis showed a straight line with a K(d) of 7 x 10(-7) M. Lysine and E-aminocaproic acid inhibited binding. The binding domain on the plasminogen molecule is the fifth kringle, miniplasminogen. Plasminogen is converted to plasmin by tissue plasminogen activator. During H. pylori infection the activity of tissue plasminogen activator is decreased and that of urokinase increased. This is reversed after eradication therapy. The plasminogen binding and conversion to plasmin is the only proteolytic activity of H. pylori, and may enhance tissue penetration and be involved in carcinogenesis.

Extracellular Matrix↗
PubMed1985

Studies on the influence of reactants and buffer environment on clot lysis induced by human plasminogen activators.

Clot lysis induced by tissue plasminogen activator and urokinase has been studied and the influences of pH, ionic environment and reactant concentrations have been determined. Both pH and ionic strength strongly affect the rate of clot lysis and distinctly different dependency profiles are obtained for tissue plasminogen activator and urokinase. Variations in concentration of plasminogen also profoundly affect the rate of clot lysis, maxima being obtained at different plasminogen concentrations depending on the concentration of fibrinogen. For urokinase, these maxima occurred at about a tenfold higher concentration of plasminogen than for the tissue plasminogen activator. The lysis times are directly dependent on the concentration of fibrinogen. Variation in thrombin concentration did not significantly affect the lysis times. Suitable conditions for the assays of tissue plasminogen activator and urokinase are suggested.

Fibrinogen↗
PubMed2006

Melanotransferrin stimulates t-PA-dependent activation of plasminogen in endothelial cells leading to cell detachment.

Tissue plasminogen activator (t-PA) is an extracellular serine protease that converts the proenzyme plasminogen into the broad-spectrum substrate serine protease, plasmin. Plasmin, one of the most potent pro-angiogenic factors, is a key element in fibrinolysis, cell migration, tissue remodeling and tumor invasion. In the present investigation, we assessed the impact of the truncated form of soluble melanotransferrin (sMTf) on plasminogen activation by t-PA and subsequent endothelial cell detachment. Co-treatment of human endothelial microvessel cells with plasminogen, t-PA and sMTf significantly increased plasmin formation and activity in the culture medium. Plasmin generated in the presence of sMTf also led to a 30% reduction in fibronectin detection within cell lysates and to a 9-fold increase within the corresponding cell medium. Moreover, the presence of sMTf increases EC detachment by 6-fold compared to cells treated only with plasminogen and t-PA. Although the addition of alpha(2)-antiplasmin completely prevented plasmin formation and EC detachment, epigallocatechin gallate, GM6001 and a specific antibody directed against MMP-2 prevented cellular detachment without interfering with plasminogen activation. Overall, these data suggest that the anti-angiogenic properties of sMTf may result from local overstimulation of plasminogen activation by t-PA, thus leading to subsequent degradation of the Fn matrix and EC detachment.

Antigens, Neoplasm↗
PubMed2006

Effect of ultrasound on enzymatic activity of selected plasminogen activators.

INTRODUCTION: Ultrasound has been shown to accelerate enzymatic fibrinolysis with adjunctive plasminogen activators. Additionally, ultrasound is known for interaction with biological substances on molecular level in sonodynamic therapy and sonochemistry. Therefore, we investigated the possibility of ultrasound affecting the biological activity of plasminogen activators used in thrombolysis treatment. MATERIALS AND METHODS: Four currently marketed plasminogen activators were evaluated: urokinase, streptokinase, alteplase, and reteplase. The tests were conducted in reconstituted, undiluted plasminogen activator. Each test contained a control and a test sample. The test sample was incubated in a water bath at temperatures of approximately 34 degrees C and exposed to ultrasound for 1h. The control was incubated in the same water bath as the test sample for the same duration but was not exposed to ultrasound. The ultrasound frequency and intensity used for this experiment were 1 MHz and 2.5-3.1W/cm2, respectively. For quantitative measurement of biological activity of the test and control samples of each plasminogen activator either specific chromogenic substrates or the fibrin clot liquefaction time was used. RESULTS: Student t-test was applied to compare treated vs. control group for each plasminogen activator. The p-value for urokinase, streptokinase, alteplase, and reteplase are 0.43, 0.76, 0.70, and 0.30, respectively. CONCLUSION: Ultrasound with a frequency of 1 MHz and intensities of 2.5-3.1W/cm2 had no statistically significant impact on biological activity of selected plasminogen activators.

Combined Modality Therapy↗
PubMed2000

Interaction of Leishmania mexicana promastigotes with the plasminogen-plasmin system.

The binding of human plasminogen and plasmin to the promastigote form of Leishmania mexicana was investigated. L. mexicana was capable to bind both molecules, the binding being inhibited by epsilon-aminocaproic acid. Scatchard plot analysis revealed a dissociation constant (Kd) value of 2.4+/-0.8 microM and 0.9+/-0.1 x 10(4) binding sites per cell for plasminogen and a Kd value of 1.2+/-0.4 microM and 1.6+/-0.2 x 10(5) binding sites per cell for plasmin. C-terminal lysine residues are involved in plasminogen binding to cells, since carboxypeptidase B treatment reduced this binding by 34%. Ligand blotting analysis showed a group of proteins, with molecular masses between 105 and 115 kDa, capable to interact with plasminogen. Zymogram analysis showed that the protease activity acquired by L. mexicana, due to the interaction with either plasminogen or plasmin, comprises an important fraction of the total protease activity at pH 7.7. Plasminogen activation by tissue-type plasminogen activator (t-PA) was enhanced by the presence of L. mexicana promastigotes. These results raise the question whether the interaction of L. mexicana with components of the fibrinolytic system is involved in the virulence of the parasite.

Animals↗
PubMed2004

The antiangiogenic agent Neovastat (AE-941) stimulates tissue plasminogen activator activity.

The plasminogen activator/plasmin system represents a key component of the proteolytic machinery underlying angiogenesis. In this work, we investigated the effect of Neovastat (AE-941), a naturally occurring multifunctional antiangiogenic agent that is currently in Phase III clinical trials, on tissue and urokinase plasminogen activator activities. We found that in vitro, Neovastat at 100 microg/ml markedly stimulates t-PA-mediated plasmin generation, while it slightly inhibits the generation of plasmin mediated by uPA. The stimulatory effect of Neovastat on t-PA activity was markedly increased by a heat treatment, resulting in a 15-fold increase in the rate of activation of plasminogen. Neovastat did not directly stimulate the activity of t-PA or plasmin towards exogenous substrates, suggesting that its effect requires the presence of plasminogen. Accordingly, kinetic analysis showed that Neovastat increases both the k(cat) of t-PA as well as its affinity for plasminogen by 10-fold. The stimulation of t-PA activity by Neovastat was also correlated with a direct interaction of Neovastat with plasminogen as monitored by the surface plasmon resonance technology. Overall, these results identify Neovastat as a potent stimulator of t-PA-dependent activation of plasminogen, further emphasizing its pleiotropic mechanism of action on several molecular events involved in angiogenesis.

Angiogenesis Inhibitors↗
PubMed2000

Tumour cell thrombospondin-1 regulates tumour cell adhesion and invasion through the urokinase plasminogen activator receptor.

We have previously shown that platelet-produced thrombospondin-1 up-regulates the urokinase plasminogen activator and its receptor and promotes tumour cell invasion. Although tumour cells produce thrombospondin-1 in vivo, they produce only minimal amounts of thrombospondin-1 in vitro. To determine the effect of tumour cell-produced thrombospondin-1 in the regulation of the plasminogen/plasmin system and tumour cell invasion, we studied THBS-1-transfected MDA-MB-435 breast cancer cells that overexpress thrombospondin-1. The role of urokinase plasminogen receptor in thrombospondin-1-mediated adhesion and invasion was studied by antisense inhibition, enzymatic cleavage and antibody neutralization. Tumour cell adhesion to collagen and laminin was evaluated. Tumour cell invasion was studied in a modified Boyden chamber collagen invasion assay. Tumour cell thrombospondin-1 induced a 2-7 fold increase in urokinase plasminogen activator receptor and cell-associated urokinase plasminogen activator expression and a 50-65% increase in cell-associated urokinase plasminogen activator and plasmin activities. Furthermore, tumour cell thrombospondin-1 promoted tumour cell invasion and decreased tumour cell adhesion through up-regulation of urokinase plasminogen activator receptor-controlled urokinase plasminogen activator and plasmin activities. We conclude that tumour cell-produced thrombospondin-1 may play a critical role in the regulation of tumour cell adhesion and tumour cell invasion.

Blotting, Western↗
PubMed1985

Porcine granulosa cell production of plasminogen activator: disparity between the effects of hCG and pFSH.

Fibrinolytic activity in porcine follicular fluid and plasminogen activator production by porcine granulosa cells in response to gonadotropins is described. Fibrinolytic activity was determined using a solid phase assay in which 125I-fibrinogen was coupled to latex beads. Urokinase plus plasminogen served as the standard. Porcine follicular fluid contained protease inhibitors as evidenced by its ability to inhibit the activity of an urokinase-plasminogen standard. Removal of these inhibitors by acid precipitation revealed plasminogen-dependent and -independent fibrinolytic activity. Cultured granulosa cells produced plasminogen activator in amounts that increased over time. This pattern was most significant in cells stimulated by hCG. Cells incubated with hCG produced significantly more plasminogen activator when compared to those cells cultured in absence of gonadotropin. The enhancement was most marked during the second 48 hrs in culture (p = 0.032). FSH was found to have no stimulatory effect on plasminogen activator production by cultured porcine granulosa cells.

Animals↗
PubMed1994

Binding of tissue-type plasminogen activator (t-PA) to Neisseria meningitidis and Haemophilus influenzae.

Forty-nine bacterial strains representing five species known to interact with human plasminogen were tested for the ability to bind the two major human plasminogen activators, t-PA and urokinase. The bacterial species tested included Haemophilus influenzae, Neisseria meningitidis, Streptococcus pyogenes, Streptococcus equisimilis and human group G streptococci. All N. meningitidis and 11 of 14 H. influenzae strains displayed substantial binding of t-PA with values in the range of 20-46%. On the contrary, none of the streptococcal strains bound significant amounts of tPA. With urokinase no binding could be found for any of the bacterial species tested. Scatchard analysis with a selected H. influenzae strain (HI23354) demonstrated 10,000 receptors per bacterium for t-PA with a Kd value of about 20 nmol l-1. The corresponding values with a selected N. meningitidis strain (Mo 52) was 8500 receptors per bacterium and 70 nmol l-1. t-PA binding could be reduced about 40% by the addition of 10 mmol l-1 of the lysine analogue epsilon-aminocaproic acd (EACA) whereas no inhibitory effect could be demonstrated with arginine. Addition of 2 mumol l-1 of plasminogen which is enough to occupy all bacterial sites for plasminogen did not interfere with the t-PA binding, suggesting that the receptors for t-PA and plasminogen are distinct. Using very high plasminogen concentrations however, t-PA binding could be reduced by about 50% possibly due to an interaction between t-PA and plasminogen in the fluid phase. Our results demonstrate the occurrence of a previously unknown type of bacterial receptor that is capable of specifically binding t-PA.

Aminocaproic Acid↗
PubMed1995

Bacterial plasminogen receptors: in vitro evidence for a role in degradation of the mammalian extracellular matrix.

The potential of bacterium-bound plasmin to degrade mammalian extracellular matrix and to enhance bacterial penetration through basement membrane was assessed with the adherent strain SH401-1 of Salmonella enterica serovar Typhimurium. Typhimurium SH401-1 was able to bind plasminogen and to enhance the tissue-type plasminogen activator-mediated activation of the single-chain plasminogen to the two-chain plasmin. The end product, the enzymatically active, bacterium-bound plasmin activity, was also formed in a normal human plasma milieu in the presence of exogenous tissue-type plasminogen activator, indicating that plasmin was protected from the plasminogen activator inhibitors and plasmin inhibitors of plasma. Plasmin bound on Typhimurium cells degraded 125I-labeled laminin as well as 3H-labeled extracellular matrix prepared from the human endothelial cell line EA.hy926. The degradations were not seen with Typhimurium cells without plasminogen and were inhibited by the low-molecular-weight plasmin inhibitor aprotinin. Plasmin bound on Typhimurium cells also potentiated penetration of bacterial cells through the basement membrane preparation Matrigel reconstituted on membrane filters. The results give in vitro evidence for degradation of the mammalian extracellular matrix by bacterium-bound plasmin and for a pathogenetic role for bacterial plasminogen receptors.

Extracellular Matrix↗
PubMed2002

Plasminogen directs the pleiotropic effects of uPA in liver injury and repair.

The urokinase-type plasminogen activator (uPA) plays a central role in liver repair. Nevertheless, the hepatic overexpression of uPA results in panlobular injury and neonatal mortality. Here, we define the molecular mechanisms of liver injury and explore whether uPA can regulate liver repair independently of plasminogen. To address the hypothesis that the liver injury in transgenic mice results from the intracellular activation of plasminogen by transgene-derived uPA (uPAT), we generated mice that overexpress uPAT and lack functional plasminogen (uPAT-Plg(-)). In these mice, loss of plasminogen abolished the hepatocyte-specific injury and prevented the formation of regenerative nodules displayed by uPAT littermates. Despite the increased expression of hepatic uPA, livers of uPAT-Plg(-) mice were unable to clear necrotic cells and restore normal lobular organization after an acute injury. Notably, high levels of circulating uPA in uPAT-Plg(-) mice did not prevent the long-term extrahepatic abnormalities previously associated with plasminogen deficiency. These data demonstrate that plasminogen directs the hepatocyte injury induced by uPAT and mediates the reparative properties of uPA in the liver.

Animals↗
PubMed1995

Insulin-induced release of plasminogen activator from human blood platelets.

Incubation of washed platelets in Tyrode buffer, pH 7.5, with insulin (200 microU/ml) and CaCl2 (1.2 mM) at 37 degrees C for 3 h resulted in a threefold increase of plasminogen activator activity in the supernatant over the basal level as determined by both the amidolytic assay and the proteolysis of alpha-casein through the formation of plasmin from plasminogen. This plasminogen activator showed no plasmin-like activity and was inhibited by anti-tissue plasminogen activator antibody as well as by type 1 plasminogen activator inhibitor. The substrate specificity and the inhibition of the enzymic activity by various inhibitors indicated that the platelet plasminogen activator (pPA) was related to tissue-type plasminogen activator of relative molecular weight 56,000. Fibrinolytic activity of pPA and its insulin-dependent release were demonstrated by the shortening of euglobulin lysis time and by the clot lysis time of platelet-rich plasma from normal and type I diabetes mellitus patients. Treatment of platelet membranes with insulin also increased the release of pPA. Increased levels of adenosine 3',5'-cyclic monophosphate (cAMP) in platelets by incubation with various agents completely inhibited the insulin-induced release of the activator. On the other hand, inhibition of platelet aggregation by aspirin had no effect on the release of pPA, indicating that the effect of cAMP was not due to the inhibition of platelet aggregation by the nucleotide.

Alprostadil↗
PubMed2006

Plasminogen activator system and vascular disease.

Vascular diseases, such as atherosclerosis, thromboembolic disorders and stroke, in addition to surgical procedures such as restenosis, all share the plasminogen activator system as a central component in the pathogenesis of vascular injury. Since the development of plasminogen deficient mice our knowledge of the effects of this proteolytic system in cardiovascular disease has vastly increased. The plasminogen activator system plays a key role in vascular homeostasis and constitutes a critical response mechanism to cardiovascular injury. The central components of the PA system are the proteolytic activators, urokinase-plasminogen activator (u-PA) and tissue-type plasminogen activator (t-PA), plasminogen (plg) and its degradation product, plasmin, together with the major inhibitors of this system, plasminogen activator inhibitor-1 and -2 (PAI-1, PAI-2). An extensive network of additional proteases, inhibitors, receptors and modulators directly associate and are influenced by the PA system, the largest group being the Matrix Metalloproteinases (MMPs) and their respective inhibitors the Tissue inhibitors of MMPs (TIMPS).

Animals↗
PubMed1991

Influence of intrinsic and extrinsic plasminogen upon the lysis of thrombi in vitro.

When the rate of lysis of artificial thrombi (prepared from plasma or whole blood) was expressed according to the concentration of tissue type plasminogen activator (t-PA) or single chain urokinase type plasminogen activator (sc-uPA) then bell-shaped dose response curves were obtained, low rates being observed at concentrations of activator greater than 500 units/ml. Bell-shaped dose response curves were not observed for rate of lysis of artificial thrombi over the concentrations of streptokinase tested (SK) or for the lysis of plasma gel clots by any of the activators tested. Further investigation indicated that the preponderant mechanism for dissolution of thrombi at 500 units/ml of t-PA was by activation of the plasminogen within the thrombus (intrinsic) since the plasminogen present in the plasma perfusing the thrombus (extrinsic) rapidly became depleted. On the other hand, at 50 units/ml t-PA the lysis was observed to be due preponderantly to the action of plasmin arising from extrinsic rather than intrinsic plasminogen. If "plasminogen enriched" thrombi were prepared in the presence of Lys plasminogen (Lys-Plg) faster rates of lysis occurred and bell-shaped biometric curves were not observed.

Fibrin↗