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.

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.

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 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 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 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.

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