Abstract
The plasminogen activator inhibitor-1 (PAI-1)-dependent fibrinolytic inhibition occurring in endotoxemia contributes to disseminated intravascular coagulation (DIC). Previous findings suggest that tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) are responsible for the increase in the level of PAI-1. These observations usually arose from mild endotoxemia models. We analyzed the effect of FR167653, an inhibitor of the TNF-alpha/IL-1beta production, on the PAI-1 levels in rabbits given endotoxin at a dose sufficient to induce DIC: the steep plasma PAI-1 increase was not attenuated by FR167653, in spite of achieving efficient inhibition of the TNF-alpha production. No IL-1beta was detected during endotoxemia. These results suggest that PAI-1 increase might be independent of TNF-alpha and IL-1beta. If these findings applied to humans, therapeutic intervention directing these cytokines would not be useful for the treatment of fibrinolysis in patients with severe sepsis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Disseminated Intravascular Coagulation / chemically induced
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Disseminated Intravascular Coagulation / etiology
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Disseminated Intravascular Coagulation / prevention & control
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Endotoxemia / blood
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Endotoxemia / complications
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Endotoxemia / drug therapy
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Endotoxins / administration & dosage
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Endotoxins / pharmacology*
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Fibrin / drug effects
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Fibrin / metabolism
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Interleukin-1 / blood
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Interleukin-1 / physiology*
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Kidney / blood supply
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Kidney / pathology
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Lipopolysaccharides / administration & dosage
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Lipopolysaccharides / pharmacology
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Lung / blood supply
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Lung / pathology
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Male
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Plasminogen Activator Inhibitor 1 / blood*
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Plasminogen Activator Inhibitor 1 / physiology
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Pyrazoles / administration & dosage
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Pyrazoles / pharmacology
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Pyridines / administration & dosage
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Pyridines / pharmacology
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Rabbits
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / physiology*
Substances
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Endotoxins
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FR 167653
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Interleukin-1
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Lipopolysaccharides
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Plasminogen Activator Inhibitor 1
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Pyrazoles
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Pyridines
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Tumor Necrosis Factor-alpha
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Fibrin