PENTOXIFYLLINE ATTENUATES NEUTROPHIL ACTIVATION IN EXPERIMENTAL ENDOTOXEMIA IN CHIMPANZEES

Costimulation of neutrophils and cytokines may play an important role in organ injury in sepsis. Pentoxifylline inhibits various neutrophil functions in vitro, and attenuates endotoxin-induced production of TNF in both in vitro and in vivo models. To assess the effect of pentoxif ylline on neutrophil activation in endotoxemia, nine adult chimpanzees (Pan troglodytes) were i.v. injected with saline (n = 2), Escherichia coli endotoxin (4 ng/kg; n = 4), or E. coli endotoxin (4 ng/kg) in co mbination with pentoxifylline (500 mg/3 h, starting 30 min before the endotoxin injection; n = 3). Serial blood samples were obtained for me asurements of leukocyte counts and the granulocytic proteinases elasta se complexed with alpha1-antitrypsin and lactoferrin, and cytokines du ring the next 5 h. No changes were observed in the saline-treated chim panzees. Endotoxin induced a marked leukocytosis and neutrophilia, whi ch were slightly reduced by pentoxifylline. In contrast, pentoxifyllin e almost completely prevented endotoxin-induced neutrophil degranulati on: peak elastase-alpha1-antitrypsin was 164 +/- 21 ng/ml (mean +/- SE ) after endotoxin alone, vs 71 +/- 7 ng/ml after endotoxin with pentox ifylline (t = 3 h; p < 0.05); peak lactoferrin was 329 +/- 15 and 182 +/- 5 ng/ml, respectively (t = 5 h; p < 0.05). Pentoxifylline also inh ibited the endotoxin-induced release of TNF (271 +/- 26 vs 55 +/- 23 p g/ml at t = 1.5 h; p < 0.05) and IL-6 (225 +/- 42 vs 73 +/- 25 pg/ml a t t = 2 h; p < 0.05). IL-8 release was not significantly inhibited by pentoxifylline. In none of the animals activation of the C system coul d be detected. We conclude that pentoxifylline attenuates neutrophil a ctivation in endotoxemia in chimpanzees, probably in part by inhibitin g the release of TNF.