PLATELET-ACTIVATING-FACTOR ANTAGONIST TCV-309 ATTENUATES THE INDUCTION OF THE CYTOKINE NETWORK IN EXPERIMENTAL ENDOTOXEMIA IN CHIMPANZEES

Platelet-activating factor (PAF) has been postulated to play a role in the pathogenesis of sepsis. Additionally, in vitro studies have revea led tight interactions between PAF and the cytokine network, and PAF i s considered to be an important stimulator of neutrophil functions. To assess the intermediate role of PAF in the induction of cytokines and neutrophil degranulation in endotoxemia in vivo, 12 healthy adult chi mpanzees were i.v. injected with a bolus dose of Escherichia coil endo toxin (4 ng/kg); four animals received endotoxin alone, whereas the ot her chimpanzees were infused with the specific and potent PAF antagoni st TCV-309 (bolus of 100 mu g/kg, followed by either 100 mu g/kg/h (n = 4) or 500 mu g/kg/h (n = 4) for 5 h). At both doses TCV-309 signific antly inhibited the endotoxin-induced rise in cytokine levels. Peak TN F concentrations after injection of endotoxin alone were 366 +/- 96 pg /ml, vs 105 +/- 47 and 115 +/- 56 pg/ml after administration of endoto xin together with the lower or higher dose of TCV-309, respectively (p < 0.05). TCV-309 also reduced the appearance of soluble TNFRs. Maxima l levels of the type I soluble TNFR were diminished from 2.53 +/- 0.27 ng/ml (endotoxin alone) to 1.69 +/- 0.36 ng/ml (high dose TCV-309; p < 0.05); peak values of the type II soluble TNFR were diminished from 8.62 +/- 1.19 ng/ml to 5.76 +/- 0.92 ng/ml (p < 0.05). Furthermore, TC V-309 attenuated the endotoxin-induced release of IL-6 (160 +/- 82 pg/ ml after endotoxin alone, vs 63 +/- 30 pg/ml in the low dose TCV-309 g roup (p < 0.05) and 65 +/- 29 pg/ml in the high dose group (p = 0.07) as well as that of IL-8 (279 +/- 168, vs 71 +/- 15 and 46 +/- 17 pg/ml , respectively; both p < 0.05). TCV-309 tended to reduce the endotoxin -provoked rise in serum IL-l R antagonist levels. In contrast, TCV-309 did not affect the neutrophilic leukocytosis elicited by endotoxin, n or did it inhibit endotoxin-induced neutrophil degranulation, as monit ored by the plasma levels of elastase-alpha 1-antitrypsin complexes. W e conclude that PAF plays a role, either directly or indirectly, in th e stimulation of the cytokine network and in the shedding of soluble T NFR in endotoxemia. PAF does not seem to be an important intermediate factor in endotoxin-induced neutrophilia or neutrophil degranulation.