The endotoxin-induced plasminogen activator inhibitor-1 increase in rabbits is not tumor necrosis factor-alpha dependent and can occur in the absence of interleukin-1beta.
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.
D000818:Animals; D004211:Disseminated Intravascular Coagulation / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control; D019446:Endotoxemia / Q000097:blood / Q000150:complications / Q000188:drug therapy; D004731:Endotoxins / Q000008:administration & dosage / Q000494:pharmacology*; D005337:Fibrin / Q000187:drug effects / Q000378:metabolism; D007375:Interleukin-1 / Q000097:blood / Q000502:physiology*; D007668:Kidney / Q000098:blood supply / Q000473:pathology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D008168:Lung / Q000098:blood supply / Q000473:pathology; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood* / Q000502:physiology; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D011817:Rabbits; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*
D004731:Endotoxins; C104334:FR 167653; D007375:Interleukin-1; D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D011720:Pyrazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D005337:Fibrin