Generation in plasma of a fast-acting inhibitor of plasminogen activator in response to endotoxin stimulation.
Endotoxin producing bacteria cause disseminated intravascular coagulation (DIC); however, the mechanism of endotoxin action in man is still unclear. Impairment of the fibrinolytic system has been suggested as a contributing mechanism. A single injection of Escherichia coli lipopolysaccharide in rabbits resulted in a marked and prolonged increase of the levels of a fast-acting inhibitor of plasminogen activator (PA-inhibitor) in plasma (from 3.9 +/- 0.7 to 41 +/- 13.2 U/ml after 3 h). Gel filtration studies indicated that inhibition of human tissue-type plasminogen activator (t-PA) by rabbit plasma is accompanied by a change in the elution profile of the activator compatible with the formation of an enzyme-inhibitor complex with an apparent molecular weight of 100,000. Injection of human t-PA (1,500 IU/kg body wt) in endotoxin treated animals resulted in very fast inhibition of t-PA and formation of a similar complex. The half-life of circulating PA-inhibitor activity in rabbits was about 7 min as estimated by donor receiver plasma transfusion experiments. Stimulation of cultured human endothelial cells with endotoxin resulted in enhanced rate of accumulation of PA-inhibitor activity in the culture medium (two- to sevenfold increase). In five patients with septicemia, markedly increased levels of PA-inhibitor (14.3 +/- 15.5 U/ml) as compared with control subjects (1.3 +/- 0.7 U/ml) were observed in plasma. A very strong correlation (r = 0.98) was found between inhibition of t-PA and of urokinase in all conditions, suggesting that this fast-acting inhibitor reacts with both plasminogen activators. These data suggest that the appearance of this fast-acting PA-inhibitor is very sensitive to endotoxin stimulation. The marked increase in the level of PA-inhibitor in blood may contribute to the pathogenesis of DIC in septicemia.
D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D001798:Blood Proteins / Q000096:biosynthesis; D001803:Blood Transfusion; D003470:Culture Media; D004211:Disseminated Intravascular Coagulation / Q000209:etiology; D004727:Endothelium / Q000378:metabolism; D004731:Endotoxins / Q000494:pharmacology*; D006023:Glycoproteins / Q000096:biosynthesis / Q000097:blood*; D006207:Half-Life; D006801:Humans; D010960:Plasminogen Activators / Q000037:antagonists & inhibitors*; D015849:Plasminogen Inactivators; D011817:Rabbits; D018805:Sepsis / Q000097:blood; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors
D001798:Blood Proteins; D003470:Culture Media; D004731:Endotoxins; D006023:Glycoproteins; D015849:Plasminogen Inactivators; C031220:urokinase inhibitor; D001127:Arginine Vasopressin; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator