Tissue factor pathway inhibitor blocks cellular effects of endotoxin by binding to endotoxin and interfering with transfer to CD14.
Tissue factor pathway inhibitor (TFPI) is a Kunitz-type plasma protease inhibitor that inhibits factor Xa and the factor VIIa/tissue factor catalytic complex. It plays an important role in feedback inhibition of the coagulation cascade (Broze, Annu Rev Med 46:103, 1995). TFPI has also been used successfully to prevent lethality and attenuate coagulopathic responses in a baboon model of septic shock (Creasey et al, J Clin Invest 91:2850, 1993; and Carr et al, Circ Shock 44:126, 1995). However, the mechanism of reduced mortality in these animals could not be explained merely by the anticoagulant effect of TFPI, because TFPI-treated animals also had a significantly depressed interleukin-6 response. Moreover, inhibition of coagulopathic responses by other anticoagulants has failed to block the organ damage or lethal effect of endotoxic shock (Coalson et al, Circ Shock 5:423, 1978; Warr et al, Blood 75:1481, 1990; and Taylor et al, Blood 78:364, 1991). We show here that recombinant TFPI can bind to endotoxin in vitro. This binding prevents interaction of endotoxin with both lipopolysaccharide binding protein and CD14, thereby blocking cellular responses.
Park
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CT
Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY 10021, USA.
Creasey
A A
AA
Wright
S D
SD
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology*; D004731:Endotoxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004731:Endotoxins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008074:Lipoproteins; D011994:Recombinant Proteins; C051928:lipoprotein-associated coagulation inhibitor