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Contribution of interleukin-1 to activation of coagulation and
fibrinolysis, neutrophil degranulation, and the release of secretory- type
phospholipase A2 in sepsis: studies in nonhuman primates after
interleukin-1 alpha administration and during lethal bacteremia
PM Jansen, MA Boermeester, E Fischer, IW de Jong, T van der Poll, LL Moldawer, CE Hack and SF Lowry
Central Laboratory of the Netherlands Red Cross Blood Transfusion Service,
Amsterdam.
Although studies with interleukin-1 receptor antagonist (IL-1ra) in animal
models have shown that IL-1 contributes to mortality in sepsis, the
mechanisms whereby IL-1 mediates lethal effects are not well established. A
possible mechanism is that IL-1 enhances the activation and release of
other inflammatory mediator systems such as coagulation, fibrinolysis,
neutrophils, and secretory-type phospholipase A2 (sPLA2). We investigated
this possibility by assessing the effect of intravenously injected
recombinant human IL-1 alpha (rhIL-1 alpha) on these plasma parameters in
baboons. In addition, we examined the course of these inflammatory
parameters in baboons after a challenge with a lethal dose of Escherichia
coli and while receiving a 24-hour constant infusion of IL-1ra or placebo.
Intravenous administration of IL-1 alpha (10 micrograms/kg) induced the
formation of thrombin, as evidenced by the appearance of
thrombin-antithrombin III (TAT) complexes into the circulation (peak
levels, 188 +/- 92 ng/mL at 2 hours), as well as the activation of
fibrinolysis, assessed by circulating plasmin-alpha 2- antiplasmin
complexes (PAP complexes; peak levels, 0.4% +/- 0.03% of fully activated
plasma at 1 hour), the release of tissue-type plasminogen activator (t-PA;
peak levels, 6 +/- 2 ng/mL at 2 hours), and its inhibitor, plasminogen
activator inhibitor (PAI; peak levels, 724 +/- 246 ng/mL at 4 hours). Il-1
alpha administration also induced the release of sPLA2 (maximal levels, 336
+/- 185 ng/mL at 8 hours), but not degranulation of neutrophils. In the
septic baboons, a significant reduction of the formation of thrombin (peak
TAT levels decreased from 582 +/- 78 ng/mL to 219 +/- 106 ng/mL; P <
.005), the release of t-PA (peak levels decreased from 37 +/- 11 ng/mL to
17 +/- 2 ng/mL; P < .001), and its inhibitor, PAI (peak levels decreased
from 2,639 +/- 974 ng/mL to 1,110 +/- 153 ng/mL; P <.001), was observed
in the group receiving IL-1ra compared to that receiving placebo. The
release of neutrophilic elastase was also significantly attenuated in
IL-1a-treated animals (peak levels, 1,024 +/- 393 and 655 +/- 104 ng/mL in
control and treatment groups, respectively; P < .05). The difference
between sPLA2 levels in both groups, although higher in the controls
(maximal levels, 3,140 +/- 1,435 ng/mL in control v 2,217 +/- 1,375 ng/mL
in IL-1ra-treated group), was not significant. Thus, IL-1 contributes to
activation of various other mediator systems in severe sepsis in nonhuman
primates. We propose that these effects may explain the lethal actions of
IL-1 in this sepsis model and suggest a similar role for IL-1 in severe
human sepsis.
Volume 86,
Issue 3,
pp. 1027-1034,
08/01/1995
Copyright © 1995 by The American Society of Hematology
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