The activity of tissue factor pathway inhibitor in experimental models of superantigen-induced shock and polymicrobial intra-abdominal sepsis.
OBJECTIVE
To study recombinant human tissue factor pathway inhibitor (rhTFPI) in a superantigen-induced shock model and in a cecal ligation and puncture (CLP) model of peritonitis in mice.


METHODS
Prospective, randomized, experimental study.


METHODS
An experimental animal research laboratory.


METHODS
Eighty BALB/c mice for the superantigen model, and 56 BALB/c mice for the CLP model.


METHODS
In the superantigen-induced shock model, animals received rhTFPI (350 mg/kg) subcutaneously every 12 hrs (n = 30) or saline control (n = 30) for 60 hrs after staphylococcal enterotoxin B (SEB; 10 microg iv) and a sublethal dose of E. coli 0111:B4 lipopolysaccharide (LPS; 75 microg ip). Control groups received SEB alone (n = 10) and LPS alone (n = 10). In the CLP model, rhTFPI or saline was given every 8 hrs for 48 hrs by using a 21-gauge needle (n = 9) or 23-gauge needle (n = 14) for CLP. A sham surgery control group (n = 10) was also included.


RESULTS
There was 0% mortality in the SEB and LPS control groups. The mortality rate was 64% in the saline control group that received both SEB and LPS (19 of 30), whereas the rhTFPI- treated animals had a mortality rate of 20% (6 of 30; p < .01). The rhTFPI-treated group had significantly lower interleukin-6 levels (61.8 +/- 41 pg/mL vs. 285 +/- 63 pg/mL; p < .05) than the control group but no differences in tumor necrosis factor-alpha or interferon-gamma levels. In the CLP experiment, rhTFPI-treated animals did not have any survival advantage over the control group after the large-bore (21-gauge) needle puncture. The rhTFPI group had significantly improved 7-day mortality rate after CLP with the small-bore needle (23-gauge; 21.4% [rhTFPI] vs. 71.4% [control], p < .01). Plasma LPS, interleukin-6, interferon-gamma, and tumor necrosis factor-alpha levels were unchanged by rhTFPI treatment, but significantly reduced LPS (p = .006) and IFNgamma (p = .001) levels were found in the peritoneal fluid.


CONCLUSIONS
Tissue factor pathway inhibitor significantly improves the mortality rate in models of superantigen-induced shock and polymicrobial intra-abdominal infection, supporting its potential use in clinical trials for septic shock.
Opal
S M
SM
Brown University School of Medicine, Providence, RI, USA. steven_opal@brown.edu
Palardy
J E
JE
Parejo
N A
NA
Creasey
A A
AA
D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D016207:Cytokines / Q000097:blood; D004731:Endotoxins / Q000097:blood; D065427:Factor Xa Inhibitors; D008074:Lipoproteins / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D010538:Peritonitis / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D011897:Random Allocation; D011994:Recombinant Proteins / Q000627:therapeutic use; D012772:Shock, Septic / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D013210:Staphylococcus; D018709:Statistics, Nonparametric; D018089:Superantigens; D015996:Survival Rate
D000925:Anticoagulants; D016207:Cytokines; D004731:Endotoxins; D065427:Factor Xa Inhibitors; D008074:Lipoproteins; D011994:Recombinant Proteins; D018089:Superantigens; C051928:lipoprotein-associated coagulation inhibitor