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 lipopolysaccha ride (LPS)-induced inflammation, 12 healthy subjects received an intra venous injection with LPS (2 ng/kg) preceded by infusion of either a r ecombinant human dimeric TNF receptor type II-IgG fusion protein (TNFR :Fc; 6 mg/m(2); 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). Infusi on of TNFR:Fc completely neutralized endogenous TNF activity. LPS admi nistration was associated with an early activation of fibrinolysis (pl asma concentrations of tissue-type plasminogen activator, plasminogen activator activity, and plasmin-alpha(2) antiplasmin complexes), follo wed by inhibition (plasma plasminogen activator inhibitor type I), cha nges that were completely prevented by TNFR:Fc. By contrast, TNFR:Fc d id 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 leve ls of soluble E-selectin), modestly reduced neutrophil responses (neut rophilia and plasma concentrations of elastase-alpha(1)-antitrypsin co mplexes and lactoferrin), but did not affect the release of secretory phospholipase A(2) or lipopolysaccharide-binding protein (P > .05). In fusion 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 hum ans. (C) 1997 by The American Society of Hematology.