Thrombin modulates synthesis of plasminogen activator inhibitor type 2 by human peripheral blood monocytes

Ritchie, Heather; Jamieson, Alec; Booth, Nuala A.

doi:10.1182/blood.v86.9.3428.bloodjournal8693428

Cited by 35 publications

(53 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this study of severe sepsis patients, u-PA antigen levels rose and PAI-2 appeared in the plasma while levels of these agents in mononuclear cell fractions fell; indeed, u-PA and PAI-2 were sometimes no longer detectable in the mononuclear fraction in the sepsis patients. It appears likely from these results that leucocytes contribute significantly to plasma levels of these agents in sepsis, by releasing them in response to an undefined trigger such as endotoxin or thrombin (Ritchie et al, 1995). It seems unlikely that simple cell death is the cause of such release as, despite the fact that levels of PAI-1 in PMN and MC fractions did not fall, and indeed sometimes rose, in sepsis, leucocytes did not release their content of this agent.…”

Section: Discussionmentioning

confidence: 81%

Plasminogen activator inhibitor 2 and urokinase‐type plasminogen activator in plasma and leucocytes in patients with severe sepsis

Robbie

Dummer²,

Booth

et al. 2000

Br J Haematol

View full text Add to dashboard Cite

Summary. Proteins influencing plasminogen activation to plasmin, namely plasminogen activators tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) and their principal inhibitors, plasminogen activator inhibitor 1 (PAI-1) and PAI-2, were measured in the plasma, the polymorph and mononuclear cell fractions taken from patients with major sepsis who were entering a general intensive care unit. The purpose of this study was to elucidate the factors favouring the persistence of fibrin in the microvasculature and thus contributing to multiple organ failure. Levels of u-PA antigen in plasma rose in sepsis and u-PA activity, not detectable in normal plasma, appeared. Levels of u-PA antigen in the cell fractions fell concomitantly. t-PA antigen in plasma and in the mononuclear cell fraction rose in sepsis, but t-PA activity was not detectable. Plasma PAI-1 antigen levels were strikingly raised in sepsis, presumably accounting for the complete neutralization of t-PA activity. PAI-2 antigen, not normally detected in plasma, appeared in the plasma of some patients, whereas it disappeared from the cellular fractions. Appearance of PAI-2 in plasma was associated with non-survival of the patient. The observations indicate that all the agents involved in plasminogen activation are released into the plasma in major sepsis. The levels of PAI-1 reached were quantitatively sufficient to suppress all activity of the released t-PA, but the inhibitors did not prevent expression of u-PA activity in the circulation. Circulating active u-PA and PAI-2 in the plasma of patients with severe sepsis may represent material originating from leucocytes. Leucocyte release of these agents within fibrin deposits may influence the persistence of fibrin and thus the development of multiple organ failure.

show abstract

Section: Discussionmentioning

confidence: 81%

Plasminogen activator inhibitor 2 and urokinase‐type plasminogen activator in plasma and leucocytes in patients with severe sepsis

Robbie

Dummer²,

Booth

et al. 2000

Br J Haematol

View full text Add to dashboard Cite

show abstract

“…Because PAI‐2 is a major macrophage protein , we speculated that PAI‐2 deficiency would alter macrophage function, which in turn could contribute to the enhanced venous thrombus resolution associated with PAI‐2 −/− mice. Published studies implicate PAI‐2 as a promoter of macrophage differentiation and a modulator of cytokine genes that are important for sculpting the nature of immune responses .…”

Section: Resultsmentioning

confidence: 99%

Enhanced venous thrombus resolution in plasminogen activator inhibitor type‐2 deficient mice

Siefert

Chabasse

Mukhopadhyay

et al. 2014

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

Background The resolution of deep vein thrombosis (DVT) requires an inflammatory response and mobilization of proteases, such as urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs), to degrade the thrombus and remodel the injured vein wall. PAI-2 is a serine protease inhibitor (serpin) with unique immunosuppressive and cell survival properties that was originally identified as an inhibitor of uPA. Objective To investigate the role of PAI-2 in venous thrombus formation and resolution. Methods Venous thrombus resolution was compared in wild type C57BL/6, PAI-2 -/- and PAI-1 -/- mice using the stasis model of DVT. Formed thrombi were harvested, thrombus weights were recorded, and tissue was analyzed for uPA, and MMP activities, PAI-1 expression, and the nature of inflammatory cell infiltration. Results We found that absence of PAI-2 enhanced venous thrombus resolution, while thrombus formation was unaffected. Enhanced venous thrombus resolution in PAI-2 -/- mice was associated with increased uPA activity and reduced levels of PAI-1, with no significant effect on MMP-2 and -9 activities. PAI-1 deficiency resulted in an increase in thrombus resolution similar to PAI-2 deficiency, but additionally reduced venous thrombus formation and altered MMP activity. PAI-2 deficient thrombi had increased levels of the neutrophil chemoattractant, CXCL2, which was associated with early enhanced neutrophil recruitment. Conclusions These data identify PAI-2 as a novel regulator of venous thrombus resolution, which modulates several pathways involving both inflammatory and uPA activity mechanisms, distinct from PAI-1. Further examination of these pathways may lead to potential therapeutic prospects in accelerating thrombus resolution.

show abstract

“…Activation status of PMNs, assessed by the nitroblue tetrazolium test, was 2%. Monocytes, free of lymphocytes, were isolated as described previously and, where appropriate, stimulated with 1 U/ml thrombin for 24 h (Ritchie et al, 1995). Essentially purified neutrophils, free of eosinophils, were isolated using antibodies to CD-16 coupled to magnetic beads (Walsh et al, 1996).…”

Section: Methodsmentioning

confidence: 99%

Polymorphonuclear leucocytes mediate endogenous thrombus lysis via a u‐PA‐dependent mechanism

Moir

Booth

Bennett³

et al. 2001

Br J Haematol

View full text Add to dashboard Cite

Summary. Many human thrombi lyse spontaneously without the administration of lytic drugs and cause no clinical symptoms. The mechanisms by which this occurs are incompletely understood. We found that model thrombi prepared from whole human blood in a Chandler loop also exhibited significant spontaneous lysis. Lysis was inhibited by chemical protease inhibitors, consistent with proteolysis resulting primarily from serine proteases, with a small contribution from matrix metalloproteinases. Whole blood was fractionated into platelet-rich plasma and cell populations. Significant spontaneous lysis was observed in plateletrich thrombi enriched with polymorphonuclear leucocytes (PMNs), whereas mononuclear cells (MCs) and erythrocytes did not contribute to lysis. Incorporation of antibodies to urokinase (u-PA) and its receptor u-PAR neutralized a large proportion of the activity. Incubation of plasma with PMNs generated free u-PA activity, which was also detectable in model thrombi and in vivo human thrombi. Purified neutrophils, free of eosinophils, generated activity identical to PMNs. Smaller contributions to lysis by tissue-type plasminogen activator (t-PA), elastase and cathepsin G were also identified. These findings suggest a major role for circulating PMNs in endogenous thrombus lysis.

show abstract

Thrombin modulates synthesis of plasminogen activator inhibitor type 2 by human peripheral blood monocytes

Cited by 35 publications

References 36 publications

Plasminogen activator inhibitor 2 and urokinase‐type plasminogen activator in plasma and leucocytes in patients with severe sepsis

Plasminogen activator inhibitor 2 and urokinase‐type plasminogen activator in plasma and leucocytes in patients with severe sepsis

Enhanced venous thrombus resolution in plasminogen activator inhibitor type‐2 deficient mice

Polymorphonuclear leucocytes mediate endogenous thrombus lysis via a u‐PA‐dependent mechanism

Contact Info

Product

Resources

About