Sequential release of tumour necrosis factor, platelet activating factor and eicosanoids during endotoxin shock in anaesthetized pigs; protective effects of indomethacin

Abstract

1 The effects of indomethacin were investigated on haemodynamics, haematological and blood glucose values, and the release of tumour necrosis factor (TNF), platelet activating factor (PAF) and eicosanoids in anaesthetized pigs receiving 5 pgkg-' E. coli lipopolysaccharide (LPS) over 60min into the superior mesenteric artery. The animals were observed for an additional period of 2 h after the termination of LPS infusion.2 Eight of the 17 animals infused with LPS and not treated with indomethacin died within 30 min after the beginning of LPS infusion (non-survivors), while the other 9 survived the experimental period of 3 h though in a state of shock (survivors).3 No alterations were observed in plasma concentrations of PAF and eicosanoids (thromboxane B2 (TXB2), 6-keto prostaglandin F1l (6-keto PGF1a) and leukotriene B4 (LTB4)) in non-survivors. However, a marked increase was detected in TNF release. A significant, though transient, increase in concentrations of PAF, TNF and eicosanoids occurred in the survivors. The peak in the concentrations of PAF and TXB2 preceded the maximum in TNF values in survivors. 4 Another group of 7 LPS-infused pigs was treated with indomethacin (2mgkg-1, i.v. bolus 60min before the start of LPS infusion, followed by a continuous infusion of 3mgkg-h-1). This treatment prevented death and shock despite the high concentrations of circulating TNF and PAF. Concentrations of cyclo-oxygenase enzyme products were reduced, whereas LTB4 release was not affected. The effect of indomethacin on haemodynamic changes occurred earlier than on cyclo-oxygenase products. 5 In another group of 6 pigs indomethacin (2mg kg-1, i.v.) was given 20-25 min after the start of LPS infusion at which time mean arterial blood pressure (MABP) had decreased below 40 mmHg indicating imminent death. This indomethacin treatment immediately reversed the hypotension, restored the organ perfusion, delayed the haemoconcentration and thrombocytopenia and prevented death. However, TNF and PAF concentrations remained elevated. Concentrations of cyclo-oxygenase products studied were reduced by the end of the observation period, whereas LTB4 production was unaffected. 6 The decrease in MABP induced by exogenous PAF was temporarily prevented by indomethacin. 7 These data indicate that the beneficial effect of indomethacin in LPS-induced septic shock is related to cyclo-oxygenase inhibition as well as to a direct vasoconstrictor property of the drug.

Receptors, Mediators, and Mechanisms Involved in Bacterial Sepsis and Septic Shock

“…The lipid mediators-eicosanoids and PAF-released by the macrophages and liver sinusoidal endothelial cells have important functions as well (197,230,254,279). Besides the vasoactive functions of these agents (368,369), PGE 1 and PGE 2 inhibit the transcription of TNF-␣ mRNA in macrophages, resulting in a long-term inhibition of TNF-␣ release (175,317,389,458). The last group of products released in response to LPS are the reactive oxygen species.…”

Increase in Plasma Platelet-Activating Factor Levels in Enterally Fed Preterm Infants

“…Endotoxin was detectable in the plasma of only 1 neonate with a detectable PAF level. In an animal model of endotoxin shock, plasma PAF levels were elevated only within 30 min after an intravenous endotoxin infusion was begun [13]; therefore, the elevated PAF levels we found are unlikely to have been due to prior transient endotoxinemia.…”

Endothelins

“…In endotoxic shock, increased circulating endothelin plasma levels were reported in humans (Pittet et al 1991;Weitzberg et al 1991) and other species (Battistini et al 1993;Nakamura et al 1991), probably because of endotoxin stimulation (Gugiura et al 1989) and hypoxia (Shirakami et al 1991). Since it has been reported that the cardiovascular response to endotoxinaemia is partly mediated by eicosanoids (Mozes et al 1991), and that endothelin induces the release of thromboxane A2 and prostacyclin (de Nucci et al 1988), some authors suggest a role for endothelin in endotoxic shock (Battistini et al 1993).…”