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 revealed tight interactions between PAF and the cytokine network, and PAF is 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 chimpanzees were i.v. injected with a bolus dose of Escherichia coli endotoxin (4 ng/kg); four animals received endotoxin alone, whereas the other chimpanzees were infused with the specific and potent PAF antagonist TCV-309 (bolus of 100 micrograms/kg, followed by either 100 micrograms/kg/h (n = 4) or 500 micrograms/kg/h (n = 4) for 5 h). At both doses TCV-309 significantly inhibited the endotoxin-induced rise in cytokine levels. Peak TNF concentrations after injection of endotoxin alone were 366 +/- 96 pg/ml, vs 105 +/- 47 and 115 +/- 56 pg/ml after administration of endotoxin together with the lower or higher dose of TCV-309, respectively (p < 0.05). TCV-309 also reduced the appearance of soluble TNFRs. Maximal 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, TCV-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 group (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-1R antagonist levels. In contrast, TCV-309 did not affect the neutrophilic leukocytosis elicited by endotoxin, nor did it inhibit endotoxin-induced neutrophil degranulation, as monitored by the plasma levels of elastase-alpha 1-antitrypsin complexes. We conclude that PAF plays a role, either directly or indirectly, in the stimulation of the cytokine network and in the shedding of soluble TNFR in endotoxemia. PAF does not seem to be an important intermediate factor in endotoxin-induced neutrophilia or neutrophil degranulation.
Kuipers
B
B
Center of Hemostasis, Thrombosis, Atherosclerosis and Inflammation Research, University of Amsterdam, The Netherlands.
van der Poll
T
T
Levi
M
M
van Deventer
S J
SJ
ten Cate
H
H
Imai
Y
Y
Hack
C E
CE
ten Cate
J W
JW
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis* / Q000097:blood; D004195:Disease Models, Animal; D004731:Endotoxins / Q000633:toxicity; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D007546:Isoquinolines / Q000494:pharmacology*; D007958:Leukocyte Count; D019272:Leukocyte Elastase; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D002679:Pan troglodytes; D010196:Pancreatic Elastase / Q000378:metabolism; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D011726:Pyridinium Compounds / Q000494:pharmacology*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D012795:Sialoglycoproteins / Q000097:blood; D044005:Tetrahydroisoquinolines; D014115:Toxemia / Q000097:blood / Q000209:etiology / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000378:metabolism
D016207:Cytokines; D004731:Endotoxins; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6; D016209:Interleukin-8; D007546:Isoquinolines; D010972:Platelet Activating Factor; D011726:Pyridinium Compounds; D018124:Receptors, Tumor Necrosis Factor; D012795:Sialoglycoproteins; D044005:Tetrahydroisoquinolines; D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin; C037741:alpha 1-antitrypsin-leukocyte elastase complex; C044101:endotoxin, Escherichia coli; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; C067430:TCV 309