Effect of a recombinant dimeric tumor necrosis factor receptor on inflammatory responses to intravenous endotoxin in normal humans.
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.
van der Poll
T
T
Department of Surgery, UMDNJ-Robert Wood Johnson Medical School, New Brunswick 08903, USA.
Coyle
S M
SM
Levi
M
M
Jansen
P M
PM
Dentener
M
M
Barbosa
K
K
Buurman
W A
WA
Hack
C E
CE
ten Cate
J W
JW
Agosti
J M
JM
Lowry
S F
SF
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects; D001779:Blood Coagulation Factors / Q000032:analysis; D016207:Cytokines / Q000097:blood; D019040:E-Selectin / Q000097:blood; D019446:Endotoxemia / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D004731:Endotoxins / Q000008:administration & dosage / Q000009:adverse effects; D000068800:Etanercept; D005342:Fibrinolysis / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000209:etiology / Q000517:prevention & control; D007275:Injections, Intravenous; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D009504:Neutrophils; D010741:Phospholipases A / Q000097:blood; D054467:Phospholipases A2; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001779:Blood Coagulation Factors; D016207:Cytokines; D019040:E-Selectin; D004731:Endotoxins; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C044101:endotoxin, Escherichia coli; D010741:Phospholipases A; D054467:Phospholipases A2; D000068800:Etanercept