Plasminogen Activator Inhibitor 1: A New Prognostic Marker in Septic Shock

Pralong, G.; Calandra, Thierry; Glauser, M. P.; Schellekens, J. F. P.; Verhoef, J.; Bachmann, Fédor; Kruithof, Egbert K. O.

doi:10.1055/s-0038-1646614

Cited by 205 publications

(95 citation statements)

References 42 publications

(38 reference statements)

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“…demonstrate that hypoxia also induces PAI-1 expression in hypoxic tissues, which is similar to the clinical situation during sepsis, characterized by a prothrombotic tendency with markedly elevated levels of PAI-1 (40). Treatment of rats with endotoxin results in decreased tPA activity and increased PAI-1 expression in several tissues, including aorta, with tPA activity decreasing due to a shift in the balance between tPA and PAI-1 (41,42).…”

Section: Discussionmentioning

confidence: 70%

Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition.

Pinsky¹,

Liao²,

Lawson³

et al. 1998

J. Clin. Invest.

178

109

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Oxygen deprivation, as occurs during tissue ischemia, tips the natural anticoagulant/procoagulant balance of the endovascular wall to favor activation of coagulation. To investigate the effects of low ambient oxygen tension on the fibrinolytic system, mice were placed in a hypoxic environment with pO 2 Ͻ 40 Torr. Plasma levels of plasminogen activator inhibitor-1 (PAI-1) antigen, detected by ELISA, increased in a time-dependent fashion after hypoxic exposure (increased as early as 4 h, P Ͻ 0.05 vs. normoxic controls), and were accompanied by an increase in plasma PAI-1 activity by 4 h ( P Ͻ 0.05 vs. normoxic controls). Northern analysis of hypoxic murine lung demonstrated an increase in PAI-1 mRNA compared with normoxic controls; in contrast, transcripts for both tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) decreased under hypoxic conditions. Immunocolocalization studies identified macrophages as the predominant source of increased PAI-1 within hypoxic lung. Using a transformed murine macrophage line, striking induction of PAI-1 transcripts occurred under hypoxic conditions, due to both increased de novo transcription as well as increased mRNA stability. Consistent with an important role of the fibrinolytic system in hypoxia-induced fibrin accumulation, PAI-1 ϩ / ϩ mice exposed to hypoxia exhibited increased pulmonary fibrin deposition based upon a fibrin immunoblot, intravascular fibrin identified by immunostaining, and increased accumulation of 125 I-fibrinogen/fibrin in hypoxic tissue. In contrast, mice deficient for the PAI-1 gene (PAI-1 Ϫ / Ϫ ) similarly exposed to hypoxic conditions did not display increased fibrin accumulation compared with normoxic PAI-1 ϩ / ϩ controls. Furthermore, homozygous null uPA (uPA Ϫ / Ϫ ) and tPA (tPA Ϫ / Ϫ ) mice subjected to oxygen deprivation showed increased fibrin deposition compared with wildtype controls. These studies identify enhanced expression of PAI-1 as an important mechanism suppressing fibrinolysis under conditions of low oxygen tension, a response which may be further amplified by decreased expression of plasminogen activators. Taken together, these data provide insight into an important potential role of macrophages and the fibrinolytic system in ischemia-induced thrombosis.

show abstract

Section: Discussionmentioning

confidence: 70%

Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition.

Pinsky¹,

Liao²,

Lawson³

et al. 1998

J. Clin. Invest.

178

109

View full text Add to dashboard Cite

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“…Others have studied fibrinolytic responses to various forms of sepsis, seeking, among other things, to determine whether PAI-1 levels are of prognostic value [8,9]. This patient recorded the highest level of PAI-1 encountered in this laboratory.…”

Section: Discussionmentioning

confidence: 99%

Fibrinolytic changes in a patient with toxic shock syndrome; release of active u-PA

et al. 1998

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“…Elevated levels of plasma PAI-1 are observed in a variety of thrombotic conditions (15), including myocardial infarction (16), deep vein thrombosis (17), and disseminated intravascular coagulation (18). Increased PAI-1 gene expression also was demonstrated in several specific histopathologies [e.g., lung fibrosis (19), glomerulonephritis (20,21), and atherosclerosis (22,23)].…”

mentioning

confidence: 99%

Plasminogen activator inhibitor-1 is a major stress-regulated gene: Implications for stress-induced thrombosis in aged individuals

Yamamoto

Takeshita

Shimokawa

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

142

127

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Plasminogen activator inhibitor-1 (PAI-1) is one of the primary inhibitors of the fibrinolytic system and has been implicated in a variety of thrombotic disorders. In this report, stress-induced changes in murine PAI-1 gene expression were investigated to study the role of this inhibitor in the development of stress-induced hypercoagulability. Restraint stress led to a dramatic induction of plasma PAI-1 antigen and of tissue PAI-1 mRNA with maximum induction in adipose tissues. In situ hybridization analysis of the stressed mice revealed that strong signals for PAI-1 mRNA were localized to hepatocytes, renal tubular epithelial cells, adrenomedullar chromaffin cells, neural cells in the paraaortic sympathetic ganglion, vascular smooth muscle cells, and adipocytes, but not to endothelial cells. These observations indicate that the stress induces the PAI-1 gene expression in a tissue-specific and cell type-specific manner. The induction of PAI-1 mRNA by restraint stress was greater than that observed for heat shock protein, a typical stress protein, suggesting that PAI-1 is one of the most highly induced stress proteins. Importantly, the magnitude of induction of PAI-1 mRNA by stress increased markedly with age, and this increase in PAI-1 correlated with tissue thrombosis in the older stressed mice. Moreover, much less tissue thrombosis was induced by restraint stress in young and aged PAI-1-deficient mice compared with agematched wild-type mice. These results suggest that the large induction of PAI-1 by stress increases the risk for thrombosis in the older populations, and that the adipose tissue may be involved.

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Plasminogen Activator Inhibitor 1: A New Prognostic Marker in Septic Shock

Cited by 205 publications

References 42 publications

Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition.

Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition.

Fibrinolytic changes in a patient with toxic shock syndrome; release of active u-PA

Plasminogen activator inhibitor-1 is a major stress-regulated gene: Implications for stress-induced thrombosis in aged individuals

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