Effect of a recombinant dimeric tumor necrosis factor receptor on inflammatory responses to intravenous endotoxin in normal humans

Blood. 1997 May 15;89(10):3727-34.

Abstract

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.

MeSH terms

  • Adult
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Blood Coagulation / drug effects
  • Blood Coagulation Factors / analysis
  • Cytokines / blood
  • E-Selectin / blood
  • Endotoxemia / blood
  • Endotoxemia / complications
  • Endotoxemia / drug therapy*
  • Endotoxemia / physiopathology
  • Endotoxins / administration & dosage
  • Endotoxins / adverse effects
  • Etanercept
  • Fibrinolysis / drug effects
  • Humans
  • Immunoglobulin G / genetics
  • Immunoglobulin G / metabolism*
  • Inflammation / etiology
  • Inflammation / prevention & control
  • Injections, Intravenous
  • Leukocyte Count / drug effects
  • Male
  • Neutrophils
  • Phospholipases A / blood
  • Phospholipases A2
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / physiology*

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Blood Coagulation Factors
  • Cytokines
  • E-Selectin
  • Endotoxins
  • Immunoglobulin G
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • endotoxin, Escherichia coli
  • Phospholipases A
  • Phospholipases A2
  • Etanercept