scholarly journals Differential regulation of tissue factor and plasminogen activator inhibitor by human mononuclear cells

Blood ◽  
1989 ◽  
Vol 74 (5) ◽  
pp. 1644-1650 ◽  
Author(s):  
BS Schwartz ◽  
JD Bradshaw
Keyword(s):  
Tissue Factor ◽  
Plasminogen Activator ◽  
Mononuclear Cells ◽  
Tritiated Thymidine ◽  
Plasminogen Activator Inhibitor ◽  
Thymidine Uptake ◽  
Fibrin Deposition ◽  
Peripheral Blood Mononuclear ◽  
Immune Mediated ◽  
Activator Inhibitor

Abstract Fibrin is a hallmark of immune-mediated tissue lesions. The presence of fibrin in such lesions implies both the formation of fibrin via coagulation and the accompanying restriction of fibrinolysis, allowing fibrin to persist. Previous work has shown that human monocytes exposed to an inflammatory stimulus such as lipopolysaccharide (LPS) produce both tissue factor (TF) and plasminogen activator inhibitor--type 2 (PAI-2). These two proteins favor fibrin deposition, and evidence implies that cellular production of these two molecules may be linked. Another proinflammatory process pertinent to immune-mediated tissue damage and fibrin deposition is the response to alloantigen. Peripheral- blood mononuclear cells (PBM), consisting of lymphocytes and monocytes together, responded to alloantigen stimulation with differential expression of TF and PAI-2. PBM exposed to alloantigen developed high levels of TF activity, with no concomitant increase in PAI-2 activity or antigen. Alloantigen-stimulated PBM did not accumulate intracellular PAI-2, nor did they degrade PAI-2 added to cultures. This lack of PAI-2 production was not due to inadequate stimulation, as tritiated thymidine uptake and TF production demonstrated recognition of, and a vigorous reaction to, alloantigen. The divergent TF and PAI-2 responses of PBM exposed to alloantigen was maintained over 5 days and was reflected by mRNA profiles. These results imply that under specific physiologically relevant conditions, the procoagulant and antifibrinolytic effectors of inflammatory mononuclear cells can be independently regulated. This would imply more flexibility to monocyte mechanisms that favor fibrin deposition than previously thought.

scholarly journals Differential regulation of tissue factor and plasminogen activator inhibitor by human mononuclear cells

Blood ◽  
1989 ◽  
Vol 74 (5) ◽  
pp. 1644-1650
Author(s):  
BS Schwartz ◽  
JD Bradshaw
Keyword(s):  
Tissue Factor ◽  
Plasminogen Activator ◽  
Mononuclear Cells ◽  
Tritiated Thymidine ◽  
Plasminogen Activator Inhibitor ◽  
Thymidine Uptake ◽  
Fibrin Deposition ◽  
Peripheral Blood Mononuclear ◽  
Immune Mediated ◽  
Activator Inhibitor

Fibrin is a hallmark of immune-mediated tissue lesions. The presence of fibrin in such lesions implies both the formation of fibrin via coagulation and the accompanying restriction of fibrinolysis, allowing fibrin to persist. Previous work has shown that human monocytes exposed to an inflammatory stimulus such as lipopolysaccharide (LPS) produce both tissue factor (TF) and plasminogen activator inhibitor--type 2 (PAI-2). These two proteins favor fibrin deposition, and evidence implies that cellular production of these two molecules may be linked. Another proinflammatory process pertinent to immune-mediated tissue damage and fibrin deposition is the response to alloantigen. Peripheral- blood mononuclear cells (PBM), consisting of lymphocytes and monocytes together, responded to alloantigen stimulation with differential expression of TF and PAI-2. PBM exposed to alloantigen developed high levels of TF activity, with no concomitant increase in PAI-2 activity or antigen. Alloantigen-stimulated PBM did not accumulate intracellular PAI-2, nor did they degrade PAI-2 added to cultures. This lack of PAI-2 production was not due to inadequate stimulation, as tritiated thymidine uptake and TF production demonstrated recognition of, and a vigorous reaction to, alloantigen. The divergent TF and PAI-2 responses of PBM exposed to alloantigen was maintained over 5 days and was reflected by mRNA profiles. These results imply that under specific physiologically relevant conditions, the procoagulant and antifibrinolytic effectors of inflammatory mononuclear cells can be independently regulated. This would imply more flexibility to monocyte mechanisms that favor fibrin deposition than previously thought.

scholarly journals Endotoxin-induced production of plasminogen activator inhibitor by human monocytes is autonomous and can be inhibited by lipid X

Blood ◽  
1989 ◽  
Vol 73 (8) ◽  
pp. 2188-2195 ◽  
Author(s):  
BS Schwartz ◽  
MC Monroe ◽  
JD Bradshaw
Keyword(s):  
Tissue Factor ◽  
Plasminogen Activator ◽  
Lipid A ◽  
Mononuclear Cells ◽  
Plasminogen Activator Inhibitor ◽  
Dependent Manner ◽  
Peripheral Blood Mononuclear ◽  
Inhibitor Type ◽  
Activator Inhibitor Type ◽  
Activator Inhibitor

Abstract Peripheral blood mononuclear cells (PBMs) produce both tissue factor and plasminogen activator inhibitor type 2 (PAI-2) in response to gram- negative bacterial lipopolysaccharide (LPS). The cellular roles in the tissue factor response have been previously elucidated, and we now report those roles in PAI-2 production. Monocytes are the only cells among LPS-stimulated PBMs that produce PAI-2 as assessed by measurement of PAI-2 activity and antigen. Concomitant immunohistochemistry demonstrated that monocytes contain PAI-2, with a greater number staining positively and more intensely after exposure to LPS. LPS- stimulated monocytes produced increased amounts of PAI-2 with or without addition of lymphocytes. Lymphocytes prestimulated with LPS and then washed did not induce PAI-2 production in monocytes to which they were added. Lipid X, a precursor in the biosynthetic pathway of lipid A and LPS, was able to inhibit LPS induction of monocyte PAI-2 in a dose- dependent manner. This inhibition was not due to cellular toxicity, the phospholipidlike nature of lipid X, interference with the PAI-2 assay, or monocyte production of a substance interfering with PAI-2. Lipid X was an effective inhibitor of PAI-2 production even when added up to 30 minutes after LPS.

Increased Mononuclear Cell Tissue Factor and Type-2 Plasminogen Activator Inhibitor and Reduced Plasma Fibrinolytic Capacity in Children with Lymphoma

1994 ◽  
Vol 72 (01) ◽  
pp. 054-057 ◽  
Author(s):  
N Semeraro ◽  
P Montemurro ◽  
P Giordano ◽  
N Santoro ◽  
D De Mattia ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Plasminogen Activator ◽  
Blood Clotting ◽  
Mononuclear Cells ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Fibrin Deposition ◽  
Activator Inhibitor ◽  
Pai 1 ◽  
D Dimer

SummaryBlood clotting activation and fibrin deposition are common findings in lymphoma patients. We evaluated the capacity of peripheral blood mononuclear cells to produce procoagulant activity (PCA) and plasminogen activator inhibitor (PAI) in 12 children with newly diagnosed lymphoma (8 non-Hodgkin’s, 4 Hodgkin’s) and in 12 matched healthy donors. In the same subjects we also measured plasma antigen levels of tissue-type PA (t-PA), urokinase-type PA (u-PA), PAI-1, PAI-2, and D-dimer. PCA generated by mononuclear cells after incubation for 20 h at 37° C was significantly higher in patients than in controls (p = 0.027). In all samples it was identified as tissue factor by functional criteria (dependence on factor VII). Moreover, culture medium obtained from patients’ mononuclear cells after incubation for 20 h at 37° C contained significantly higher amounts of PAI activity and PAI-2 antigen than control samples (p <0.001). Plasma PAI-1 and t-PA antigens were significantly augmented in patients (p <0.005), the mean increase of PAI-I being about 5 times higher than that of t-PA. Plasma levels of D-dimer wete markedly increased in the patients’ group (p <0.001), whereas u-PA and PAI-2 antigens did not differ from controls. It is suggested that monocytes from lymphoma patients are endowed with functional abnormalities leading to the simultaneous expression of tissue factor and antifibrinolytic activity. These abnormalities, coupled with a reduced plasma fibrinolytic potential, could play an important pathogenetic role in blood clotting activation and fibrin deposition associated with lymphoma.

scholarly journals Endotoxin-induced production of plasminogen activator inhibitor by human monocytes is autonomous and can be inhibited by lipid X

Blood ◽  
1989 ◽  
Vol 73 (8) ◽  
pp. 2188-2195
Author(s):  
BS Schwartz ◽  
MC Monroe ◽  
JD Bradshaw
Keyword(s):  
Tissue Factor ◽  
Plasminogen Activator ◽  
Lipid A ◽  
Mononuclear Cells ◽  
Plasminogen Activator Inhibitor ◽  
Dependent Manner ◽  
Peripheral Blood Mononuclear ◽  
Inhibitor Type ◽  
Activator Inhibitor Type ◽  
Activator Inhibitor

Peripheral blood mononuclear cells (PBMs) produce both tissue factor and plasminogen activator inhibitor type 2 (PAI-2) in response to gram- negative bacterial lipopolysaccharide (LPS). The cellular roles in the tissue factor response have been previously elucidated, and we now report those roles in PAI-2 production. Monocytes are the only cells among LPS-stimulated PBMs that produce PAI-2 as assessed by measurement of PAI-2 activity and antigen. Concomitant immunohistochemistry demonstrated that monocytes contain PAI-2, with a greater number staining positively and more intensely after exposure to LPS. LPS- stimulated monocytes produced increased amounts of PAI-2 with or without addition of lymphocytes. Lymphocytes prestimulated with LPS and then washed did not induce PAI-2 production in monocytes to which they were added. Lipid X, a precursor in the biosynthetic pathway of lipid A and LPS, was able to inhibit LPS induction of monocyte PAI-2 in a dose- dependent manner. This inhibition was not due to cellular toxicity, the phospholipidlike nature of lipid X, interference with the PAI-2 assay, or monocyte production of a substance interfering with PAI-2. Lipid X was an effective inhibitor of PAI-2 production even when added up to 30 minutes after LPS.

Helicobacter pyloriNeutrophil‐Activating Protein Stimulates Tissue Factor and Plasminogen Activator Inhibitor–2 Production by Human Blood Mononuclear Cells

2001 ◽  
Vol 183 (7) ◽  
pp. 1055-1062 ◽  
Author(s):  
Pasqualina Montemurro ◽  
Giovanna Barbuti ◽  
William G. Dundon ◽  
Giuseppe Del Giudice ◽  
Rino Rappuoli ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Plasminogen Activator ◽  
Human Blood ◽  
Mononuclear Cells ◽  
Plasminogen Activator Inhibitor ◽  
Blood Mononuclear Cells ◽  
Activator Inhibitor

scholarly journals Increased release of plasminogen activator inhibitor type 2 accompanies the human mononuclear cell tissue factor response to lipopolysaccharide

Blood ◽  
1988 ◽  
Vol 71 (3) ◽  
pp. 734-741 ◽  
Author(s):  
BS Schwartz ◽  
MC Monroe ◽  
EG Levin
Keyword(s):  
Tissue Factor ◽  
Plasminogen Activator ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Sodium Dodecyl ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Peripheral Blood Mononuclear ◽  
Inhibitor Type

Abstract Human peripheral blood mononuclear cells (PBM) respond to lipopolysaccharide (LPS) with increased release of a plasminogen activator (PA) inhibitor. This response is dose dependent and parallels the LPS-induced expression of PBM tissue factor activity. The PA inhibitors of control and LPS-stimulated PBMs appear identical as both are identified by antibodies to PA inhibitor type 2 of human placenta, but not by antibodies to type 1 inhibitor of bovine aortic endothelial cells. The PA inhibitor is specific for urokinase type PA as determined by the 125I-fibrin plate assay, and direct cleavage of 125I- plasminogen; it does not effectively inhibit tissue-type PA. The inhibitor forms an active site-dependent complex with 125I-urokinase, which then demonstrates an increase in mol wt from 33 kd to 68 kd on reduced sodium dodecyl sulfate (SDS) polyacrylamide gels. PBMs neither secrete nor express active PA. Hence, the exposure of PBMs to LPS results in conditions highly favorable to fibrin deposition and persistence: increased procoagulant and antifibrinolytic activities, accompanied by no measurable PA. Such modulation of these effectors may be important in the pathogenesis of fibrin characteristically found in tissue lesions of endotoxin-initiated processes.

scholarly journals Increased release of plasminogen activator inhibitor type 2 accompanies the human mononuclear cell tissue factor response to lipopolysaccharide

Blood ◽  
1988 ◽  
Vol 71 (3) ◽  
pp. 734-741
Author(s):  
BS Schwartz ◽  
MC Monroe ◽  
EG Levin
Keyword(s):  
Tissue Factor ◽  
Plasminogen Activator ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Sodium Dodecyl ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Peripheral Blood Mononuclear ◽  
Inhibitor Type

Human peripheral blood mononuclear cells (PBM) respond to lipopolysaccharide (LPS) with increased release of a plasminogen activator (PA) inhibitor. This response is dose dependent and parallels the LPS-induced expression of PBM tissue factor activity. The PA inhibitors of control and LPS-stimulated PBMs appear identical as both are identified by antibodies to PA inhibitor type 2 of human placenta, but not by antibodies to type 1 inhibitor of bovine aortic endothelial cells. The PA inhibitor is specific for urokinase type PA as determined by the 125I-fibrin plate assay, and direct cleavage of 125I- plasminogen; it does not effectively inhibit tissue-type PA. The inhibitor forms an active site-dependent complex with 125I-urokinase, which then demonstrates an increase in mol wt from 33 kd to 68 kd on reduced sodium dodecyl sulfate (SDS) polyacrylamide gels. PBMs neither secrete nor express active PA. Hence, the exposure of PBMs to LPS results in conditions highly favorable to fibrin deposition and persistence: increased procoagulant and antifibrinolytic activities, accompanied by no measurable PA. Such modulation of these effectors may be important in the pathogenesis of fibrin characteristically found in tissue lesions of endotoxin-initiated processes.

Plasminogen Activator Inhibitor-1 Inhibits Factor VIIa Bound to Tissue Factor

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1023-1023
Author(s):  
Prosenjit Sen ◽  
Andrey Komissarov ◽  
Usha R. Pendurthi ◽  
Steven Idell ◽  
L. Vijaya Mohan Rao
Keyword(s):  
Cell Surface ◽  
Tissue Factor ◽  
Plasminogen Activator ◽  
Factor Viia ◽  
Plasminogen Activator Inhibitor ◽  
Inhibitory Effect ◽  
Fibrin Deposition ◽  
Coagulant Activity ◽  
Activator Inhibitor ◽  
Pai 1

Abstract The tissue factor (TF) pathway of coagulation plays a primary role in hemostasis but the aberrant activation of TF-mediated coagulation leads to thrombus formation, the precipitating event in acute myocardial infarction, unstable angina and ischemic stroke. Tissue factor-mediated coagulation also contributes to the pathogenesis of acute lung injury by generating extravascular fibrin deposition in lung parenchyma. Pleural fibrin deposition is a common complication of pleural inflammation and occurs in a wide variety of pleural diseases. Thus, a proper regulation of TF activity is critical for maintenance of hemostatic balance. Tissue factor pathway inhibitor (TFPI) is the primary inhibitor for TF-mediated coagulation whereas antithrombin (AT) may function as an auxiliary second physiologic regulator. In pleural injury, concentrations of plasminogen activator inhibitor (PAI)-1, the predominant inhibitor of tissue-type and urokinase-type plasminogen activators, were increased about 1000-fold in exudative pleural fluids. In addition to inhibiting uPA and tPA, PAI-1 was also shown to inhibit thrombin and activated protein C. In the present study we investigated whether PAI-1 inhibits FVIIa activity. Free FVIIa or FVIIa complexed with relipidated TF (10 nM) was incubated with PAI-1 (1 μM) ± heparin (10 U/ml) or vitronectin (1 μM) for varying time periods and the extent of FVIIa inactivation was measured in a clotting assay. PAI-1 or PAI-1 + heparin exhibited no significant inhibitory effect on free factor VIIa coagulant activity. PAI-1, combined with equimolar concentration of vitronectin, inhibited free FVIIa activity, albeit very slowly (~15% inhibition in 2 h). However if FVIIa was complexed with relipidated TF, it was inhibited much more rapidly by PAI-1. The time required for 50% inactivation of FVIIa/TF by PAI-1 was about 85 min. Heparin increased the rate of PAI-1 inactivation of FVIIa/TF by about 2-fold whereas vitronectin enhanced PAI-1 inactivation of FVIIa/TF by 4 to 5-fold, inhibiting 50% of the FVIIa coagulant activity in less than 20 min. Heparin or vitronectin alone had no inhibitory effect on FVIIa/TF. To compare the efficiency of PAI-1 and PAI-1/vitronectin with AT/heparin to inhibit FVIIa/TF activity, we determined the loss of FVIIa coagulant activity in the presence of varying concentrations of PAI-1 ± vitronectin (1 μM) or AT ± heparin (10 U/ml). The IC50 values as follow; AT, &gt; 5 μM; PAI-1, 817 nM; AT/heparin, 25 nM; PAI-1/vitronectin, 125 nM. A 1:1 stochiometric complex between PAI-1 and FVIIa, with an apparent molecular weight of 100,000 was detected by SDS-PAGE. In additional studies, we investigated the ability of PAI-1 to inactivate FVIIa bound to TF on lung fibroblasts. PAI-1 inhibited FVIIa bound to cell surface TF, but to a lesser extent than FVIIa bound to relipidated TF. However, in the absence of heparin, PAI-1 and not AT is capable of inactivating FVIIa bound to TF. Interestingly, in contrast to the data observed with FVIIa bound to relipidated TF, heparin or vitronectin failed to accelerate PAI-1 inactivation of FVIIa bound to cell surface TF. At present, it is unclear why heparin and vitronectin failed to enhance the PAI-1 inhibitory effect on FVIIa bound to cell surface TF. Overall the data presented here in show that PAI-1 is capable of modulating FVIIa/TF activity. Further studies are needed evaluate whether PAI-1 inhibition of FVIIa/TF plays an important role in pathophysiology, particularly in lung inflammation.

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