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Inhibition of factor XII in septic baboons attenuates the activation of
complement and fibrinolytic systems and reduces the release of
interleukin-6 and neutrophil elastase
PM Jansen, RA Pixley, M Brouwer, IW de Jong, AC Chang, CE Hack, FB Taylor and RW Colman
Central Laboratory of the Netherlands Red Cross Blood Transfusion Service,
Amersterdam, The Netherlands.
In previous studies, we have shown that administration of monoclonal
antibody (MoAb) C6B7 against human factor XII to baboons challenged with a
lethal dose of Escherichia coli abrogates activation of the contact system
and modulates secondary hypotension. To evaluate the contribution of
activated contact proteases to the appearance of other inflammatory
mediators in this experimental model of sepsis, we studied the effect of
administration of MoAb C6B7 on activation of complement and fibrinolytic
cascades, stimulation of neutrophil degranulation, and release of the
proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and
interleukin-6 (IL-6). Activation of the complement system, as reflected by
circulating C3b/c and C4b/c levels, was significantly reduced in five
animals that had received MoAb C6B7 before a lethal dose of E coli as
compared with five control animals that had been given a lethal challenge
only. Inhibition of contact activation also modulated the fibrinolytic
response, since the release of tissue-type plasminogen activator (t-PA) and
the appearance of plasmin-alpha2-antiplasmin (PAP) complexes into the
circulation was significantly attenuated upon pretreatment with anti-factor
XII MoAb. In contrast, plasma levels of plasminogen activator inhibitor
(PAI) were modestly enhanced in the treatment group. Degranulation of
neutrophils, as assessed by circulating elastase-alpha1-protease inhibitor
complexes, and release of IL-6 but not of TNF-alpha was decreased in
anti-factor XII-treated animals. Observed differences in the inflammatory
response between treatment and control groups were not likely due to
different challenges, since the number of E coli that had been infused, as
well as circulating levels of endotoxin after the challenge, were similar
for both groups. These data suggest that activation of the contact system
modulates directly or indirectly various mediator systems involved in the
inflammatory response during severe sepsis in nonhuman primates.
Volume 87,
Issue 6,
pp. 2337-2344,
03/15/1996
Copyright © 1996 by The American Society of Hematology
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