Plasminogen Activator Inhibitor 1: Physiological and Pathophysiological Roles

Binder, Bernd R.; Christ, Günter; Грубер, Флориан; Grubic, Nelly; Hufnagl, Peter; Krebs, Michael; Mihaly, Judit; Prager, Gerald W.

doi:10.1152/nips.01369.2001

Cited by 178 publications

(219 citation statements)

References 18 publications

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“…11 PAI-1 is an important downregulator of plasmin activation and is expressed in animals and in cells after exposure to numerous agents, including cytokines and LPS. [22][23][24] In animal models of endotoxemia, antibodymediated inhibition or genetic knockout of PAI-1 significantly attenuated fibrin deposition in tissues, suggesting that PAI-1 activity is important for this effect of LPS exposure. [25][26][27] Interestingly, hepatic expression of the gene encoding PAI-1 is enhanced in LPS/RAN-treated rats, 10 and this expression is mirrored by an augmented concentration of PAI-1 protein in serum (Fig.…”

Section: Discussionmentioning

confidence: 99%

Role of Hepatic Fibrin in Idiosyncrasy–Like Liver Injury From Lipopolysaccharide–Ranitidine Coexposure in Rats

et al. 2004

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Coadministration of nonhepatotoxic doses of the histamine 2-receptor antagonist ranitidine (RAN) and bacterial lipopolysaccharide (LPS) results in hepatocellular injury in rats, the onset of which occurs in 3 to 6 hours. This reaction resembles RAN idiosyncratic hepatotoxicity in humans. Early fibrin deposition occurs in livers of rats cotreated with LPS/RAN. Accordingly, we tested the hypothesis that the hemostatic system contributes to liver injury in LPS/RAN-treated rats. Rats were given either LPS (44.4 ؋ 10 6 EU/kg) or its vehicle, then RAN (30 mg/kg) or its vehicle 2 hours later. They were killed 2, 3, 6, 12, or 24 hours after RAN treatment, and liver injury was estimated from serum alanine aminotransferase activity. A modest elevation in serum hyaluronic acid, which was most pronounced in LPS/RANcotreated rats, suggested altered sinusoidal endothelial cell function. A decrease in plasma fibrinogen and increases in thrombin-antithrombin dimers and in serum concentration of plasminogen activator inhibitor-1 occurred before the onset of liver injury. Hepatic fibrin deposition was observed in livers from LPS/RAN-cotreated rats 3 and 6 hours after RAN. Liver injury was abolished by the anticoagulant heparin and was significantly attenuated by the fibrinolytic agent streptokinase. Hypoxia, one potential consequence of sinusoidal fibrin deposition, was observed in livers of LPS/RAN-treated rats. In conclusion, the results suggest that the hemostatic system is activated after LPS/RAN cotreatment and that fibrin deposition in liver is important for the genesis of hepatic parenchymal cell injury in this model. B acterial lipopolysaccharide (endotoxin, LPS) is an outer cell wall component of gram-negative bacteria and a potent inflammagen. Exposure to large doses of LPS can cause extensive damage to the liver and other organs in humans and rodents. 1 Exposure of liver to smaller amounts of LPS is commonplace and occurs through multiple means, including LPS translocation from the intestinal lumen into the portal venous blood. 2 Inflammatory responses triggered by small doses of LPS typically are noninjurious, but several studies have shown they can markedly enhance the hepatotoxicity of a variety of chemicals. 2 Moreover, idiosyncratic hepatotoxicity during drug therapy may arise from coexposure to inflammagens such as LPS. 3 Idiosyncratic liver injury occurs during treatment with numerous drugs, typically in a small fraction of people taking the drug. These responses are seemingly unrelated to dose, and the time of onset relative to beginning of drug therapy is often highly variable. One drug that causes idiosyncratic hepatotoxicity is the histamine 2 receptorantagonist, ranitidine (RAN). RAN is used therapeutically for treatment of duodenal ulcers, gastric hypersecretory diseases, and gastroesophageal reflux disease, and it is estimated to cause liver injury in less than 0.1% of people taking the drug. 4 Mechanisms of RAN idiosyncrasy are not understood, but liver injury might develop in part from a coexisting infl...

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Section: Discussionmentioning

confidence: 99%

Role of Hepatic Fibrin in Idiosyncrasy–Like Liver Injury From Lipopolysaccharide–Ranitidine Coexposure in Rats

et al. 2004

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“…Early modulation of TF activity is presently a therapeutic strategy in systemic inflammatory response syndrome patients [23]. On the other hand, PAI-1 plays an important role in the regulation of fibrinolysis and proteolysis by inhibiting tissue-type plasminogen activator and urokinase-type plasminogen activator [24]. Studies in animal models have indicated that increased PAI-1 activity enhances thrombosis, and antibodies against PAI-1 prevent the progression of thrombosis [25].…”

Section: Discussionmentioning

confidence: 99%

Carbon monoxide (CO)-releasing molecule-derived CO regulates tissue factor and plasminogen activator inhibitor type 1 in human endothelial cells

Maruyama

Morishita

Yuno

et al. 2012

Thrombosis Research

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“…Interaction of uPAR with uPA, PAI-1, low-density lipoprotein-receptor-related protein (LRP), vitronectin and integrins provides a novel mechanism for cell chemotaxis, adhesion and migration [10].…”

Section: Introductionmentioning

confidence: 99%

Chronic relapsing experimental allergic encephalomyelitis (CREAE) in plasminogen activator inhibitor‐1 knockout mice: the effect of fibrinolysis during neuroinflammation

East

Gverić

Baker

et al. 2007

Neuropathology Appl Neurobio

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During neuroinflammation in multiple sclerosis (MS) fibrinogen, not normally present in the brain or spinal cord, enters the central nervous system through a compromised blood-brain barrier. Fibrin deposited on axons is ineffectively removed by tissue plasminogen activator (tPA), a key contributory factor being the upregulation of plasminogen activator inhibitor-1 (PAI-1). Aims: This study investigated the role of PAI-1 during experimental neuroinflammatory disease. Methods: Chronic relapsing experimental allergic encephalomyelitis (CREAE), a model of MS, was induced with spinal cord homogenate in PAI-1 knockout (PAI-1 -/-) and wild type (WT) mice, backcrossed onto the Biozzi background. Results: Disease incidence and clinical severity were reduced in PAI-1 -/-mice, with animals developing clinical signs significantly later than WTs. Clinical relapses were absent in PAI-1 -/-mice and the subsequent reduction in neuroinflammation was coupled with a higher capacity for fibrinolysis in spinal cord samples from PAI-1 -/-mice, in association with increased tPA activity. Axonal damage was less apparent in PAI-1 -/-mice than in WTs, implicating fibrin in both inflammatory and degenerative events during CREAE. Conclusions: PAI-1 is a potential target for therapy in neuroinflammatory degenerative diseases, allowing effective fibrin removal and potentially reducing relapse rate and axonal damage.

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Plasminogen Activator Inhibitor 1: Physiological and Pathophysiological Roles

Cited by 178 publications

References 18 publications

Role of Hepatic Fibrin in Idiosyncrasy–Like Liver Injury From Lipopolysaccharide–Ranitidine Coexposure in Rats

Role of Hepatic Fibrin in Idiosyncrasy–Like Liver Injury From Lipopolysaccharide–Ranitidine Coexposure in Rats

Carbon monoxide (CO)-releasing molecule-derived CO regulates tissue factor and plasminogen activator inhibitor type 1 in human endothelial cells

Chronic relapsing experimental allergic encephalomyelitis (CREAE) in plasminogen activator inhibitor‐1 knockout mice: the effect of fibrinolysis during neuroinflammation

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