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Effect of a recombinant dimeric tumor necrosis factor receptor on
inflammatory responses to intravenous endotoxin in normal humans
T van der Poll, SM Coyle, M Levi, PM Jansen, M Dentener, K Barbosa, WA Buurman, CE Hack, JW ten Cate, JM Agosti and SF Lowry
Department of Surgery, UMDNJ-Robert Wood Johnson Medical School, New
Brunswick 08903, USA.
To determine the role of tumor necrosis factor (TNF) in lipopolysaccharide
(LPS)-induced inflammation, 12 healthy subjects received an intravenous
injection with LPS (2 ng/kg) preceded by infusion of either a recombinant
human dimeric TNF receptor type II-IgG fusion protein (TNFR:Fc; 6 mg/m2; n
= 6) or vehicle (n = 6) from -30 minutes to directly before LPS injection.
LPS elicited a transient increase in plasma TNF activity, peaking after 1.5
hours (219 +/- 42 pg/mL; P < .05). Infusion of TNFR:Fc completely
neutralized endogenous TNF activity. LPS administration was associated with
an early activation of fibrinolysis (plasma concentrations of tissue-type
plasminogen activator, plasminogen activator activity, and plasmin-
alpha2-antiplasmin complexes), followed by inhibition (plasma plasminogen
activator inhibitor type I), changes that were completely prevented by
TNFR:Fc. By contrast, TNFR:Fc did not influence LPS- induced activation of
coagulation (plasma levels of prothrombin fragment F1 + 2 and
thrombin-antithrombin III complexes). TNFR:Fc strongly inhibited
endothelial cell activation (plasma levels of soluble E-selectin), modestly
reduced neutrophil responses (neutrophilia and plasma concentrations of
elastase-alpha1-antitrypsin complexes and lactoferrin), but did not affect
the release of secretory phospholipase A2 or lipopolysaccharide-binding
protein (P > .05). Infusion of TNFR:Fc only (without LPS) in another 6
normal subjects did not induce any inflammatory response. These data
indicate that TNF is involved in only some inflammatory responses to
intravenous LPS in humans.
Volume 89,
Issue 10,
pp. 3727-3734,
05/15/1997
Copyright © 1997 by The American Society of Hematology
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