Differential effects of anti-tumor necrosis factor monoclonal antibodies on systemic inflammatory responses in experimental endotoxemia in chimpanzees.
Tumor necrosis factor (TNF) is considered to be a pivotal mediator of endotoxin-induced lethality. To assess the intermediate role of TNF in specific systemic inflammatory responses known to contribute to tissue injury in endotoxemia, eight healthy adult chimpanzees were intravenously injected with Escherichia coli endotoxin (4 ng/kg). In four of these animals the administration of endotoxin was followed immediately by a bolus intravenous injection of an anti-TNF monoclonal antibody (15 mg/kg). Treatment with anti-TNF completely prevented the endotoxin-induced increase in serum TNF activity, and profoundly reduced the appearance of interleukin-6 and -8 (both P < .05). Neutrophilia and lymphopenia were not affected by anti-TNF, whereas neutrophil degranulation, as measured by the plasma concentrations of elastase-alpha 1-antitrypsin complexes, was only slightly reduced (peak levels after endotoxin alone 31.0 +/- 3.4 ng/mL, versus 25.5 +/- 3.4 ng/mL after endotoxin with anti-TNF; P < .05). Anti-TNF did not influence endotoxin-induced activation of the coagulation system, as reflected by unchanged increases in the plasma concentrations of the prothrombin fragment F1 + 2 and thrombin-antithrombin III complexes. In contrast, anti-TNF strongly attenuated the activation of the fibrinolytic system, ie, peak plasma levels of plasmin-alpha 2-antiplasmin were 33.8 +/- 11.1 nmol/L after endotoxin alone and 17.0 +/- 2.9 nmol/L after endotoxin with anti-TNF (P < .05). These results suggest that TNF is not the common mediator of systemic inflammatory changes in low-grade endotoxemia. Moreover, the finding that in this mild model anti-TNF specifically inhibited fibrinolysis suggests that treatment with anti-TNF potentially may enhance the tendency towards microvascular thrombosis in sepsis.
van der Poll
T
T
Center of Hemostasis, Thrombosis, Atherosclerosis, and Inflammation Research, University of Amsterdam, The Netherlands.
Levi
M
M
van Deventer
S J
SJ
ten Cate
H
H
Haagmans
B L
BL
Biemond
B J
BJ
Büller
H R
HR
Hack
C E
CE
ten Cate
J W
JW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001777:Blood Coagulation; D004731:Endotoxins / Q000097:blood*; D005342:Fibrinolysis; D007249:Inflammation / Q000628:therapy*; D016209:Interleukin-8 / Q000096:biosynthesis; D007958:Leukocyte Count; D019272:Leukocyte Elastase; D002679:Pan troglodytes; D010196:Pancreatic Elastase / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000276:immunology*; D000515:alpha 1-Antitrypsin / Q000032:analysis
D000911:Antibodies, Monoclonal; D004731:Endotoxins; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin; C037741:alpha 1-antitrypsin-leukocyte elastase complex; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase