Kuipers B, van der Poll T, Levi M, van Deventer S J, ten Cate H, Imai Y, Hack C E, ten Cate J W
Center of Hemostasis, Thrombosis, Atherosclerosis and Inflammation Research, University of Amsterdam, The Netherlands.
J Immunol. 1994 Mar 1;152(5):2438-46.
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.
血小板活化因子（PAF）被推测在脓毒症发病机制中起作用。此外，体外研究揭示了PAF与细胞因子网络之间的紧密相互作用，并且PAF被认为是中性粒细胞功能的重要刺激物。为了评估PAF在体内内毒素血症中细胞因子诱导和中性粒细胞脱颗粒过程中的中间作用，对12只健康成年黑猩猩静脉注射大剂量大肠杆菌内毒素（4 ng/kg）；4只动物仅接受内毒素，而其他黑猩猩则输注特异性强效PAF拮抗剂TCV-309（大剂量100μg/kg，随后以100μg/kg/h（n = 4）或500μg/kg/h（n = 4）持续输注5小时）。在两个剂量下，TCV-309均显著抑制内毒素诱导的细胞因子水平升高。单独注射内毒素后TNF峰值浓度为366±96 pg/ml，而在内毒素与低剂量或高剂量TCV-309联合给药后分别为105±47 pg/ml和115±56 pg/ml（p < 0.05）。TCV-309还降低了可溶性TNFR的出现。I型可溶性TNFR的最大水平从2.53±0.27 ng/ml（仅内毒素）降至1.69±0.36 ng/ml（高剂量TCV-309；p < 0.05）；II型可溶性TNFR的峰值从8.62±1.19 ng/ml降至5.76±0.92 ng/ml（p < 0.05）。此外，TCV-309减弱了内毒素诱导的IL-6释放（单独内毒素后为160±82 pg/ml，低剂量TCV-309组为63±30 pg/ml（p < 0.05），高剂量组为65±29 pg/ml（p = 0.07））以及IL-8释放（分别为279±168，与71±15和46±17 pg/ml；两者p < 0.05）。TCV-309倾向于降低内毒素引起的血清IL-1R拮抗剂水平升高。相反，TCV-309不影响内毒素引起的中性粒细胞增多，也不抑制内毒素诱导的中性粒细胞脱颗粒，这通过血浆中弹性蛋白酶-α1-抗胰蛋白酶复合物水平监测。我们得出结论，PAF在体内内毒素血症中细胞因子网络的刺激和可溶性TNFR的脱落中直接或间接发挥作用。PAF似乎不是内毒素诱导的中性粒细胞增多或中性粒细胞脱颗粒的重要中间因素。
