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The role of tumor necrosis factor alpha (TNFo0 in endotoxin-induced shock was investigated in pigs receiving 5/~g kg -~ of Escherichia coli endotoxin (LPS)during 60 rain of continuous infusion intothe superior mesenteric artery. I_PS concentration in aortic plasma, as determined by a chromogenic Limtdus amoebocyte lysate (LAL) test, reached a peak of approximately 1000 ng I -t during LPS infusion, and declined rapidly after discontinuation of the infusion. Serum TNF levels were determined by a bioassay using the L929 murine transformed fibroblast line. Eight of the 17 animals infused with LPS died within 30 min after beginning LPS administration, while the other 9 pigs survived beyond the experimental observation period of 3 h, although they were in a state of shock. No difference in LPS concentration was found between the surivors and the non-survivors. However, the serum TNF levels in non-survivors were significantly higher than in sur~,ivors when measured at 30 min after beginning LPS administration. In survivors, the peak increase in serum TNF levels was measured at 60 rain after the beginning of LPS injection and returned rapidly to the baseline values. Although the role of TNF inducing rapid death seems to be dominant, the hemodynamic, hematology and blood chemistry disturbances seen during shock continued in survivors long after the return of TNF to baseline levels. These findings indicate that besides TNF other mediators are also invol~ed in the LPS infusioninduced shock.

The role of platelet-activating factor (PAF) in circulatory shock of intestinal origin was investigated in anesthetized dogs by measuring PAF levels in the superior mesenteric vein during reperfusion after 2-h occlusion of the superior mesenteric artery; by monitoring the effects of BN 52021, a specific PAF receptor antagonist; and by studying the circulatory effects of exogenous PAF injected into the superior mesenteric vein. PAF was measured by a platelet-aggregation assay. Identity of PAF-like bioactivity was ascertained by thin-layer chromatography, high-pressure liquid chromatography, and alkaline treatment. Removal of the superior mesenteric artery occlusion caused an immediate dramatic decrease in mean arterial blood pressure with concomitant increase in mean portal venous pressure and hematocrit values. PAF concentration in the superior mesenteric vein increased from 0.2 +/- 0.1 to 2.8 +/- 0.4 ng/ml (n = 4, P less than 0.05) within the first 5 min of reperfusion. Administration of exogenous PAF (0.1 microgram/kg) injected into the superior mesenteric vein produced similar hemodynamical effects. Pretreatment of the animals with BN 52021 (4 mg/kg), a specific PAF receptor antagonist, prevented the circulatory collapse. The present results suggest that PAF release during intestinal ischemia may play an important role in the development of circulatory collapse caused by mesenteric artery occlusion.

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.

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