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

• Published in: British journal of pharmacology 1991-11, Vol.104 (3), p.691-699
• Main Authors: Mózes, Tibor, Zijlstra, Freek J., Heiligers, Jan P.C., Tak, Corné J.A.M., Ben‐Efraim, Shlomo, Bonta, Iván L., Saxena, Pramod R.
• Format: Article
• Language: English
• Subjects: Anesthesia; Animals; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Blood Chemical Analysis; Blood Glucose - metabolism; eicosanoids; Eicosanoids - metabolism; Endotoxin; Escherichia coli; Female; Hemodynamics - drug effects; Hemodynamics - physiology; indomethacin; Indomethacin - pharmacology; Lipopolysaccharides - toxicity; Medical sciences; PAF; Pharmacology. Drug treatments; Platelet Activating Factor - metabolism; Regional Blood Flow - drug effects; shock; Shock, Septic - metabolism; Shock, Septic - physiopathology; Swine; Tumor Necrosis Factor-alpha - metabolism; tumour necrosis factor (TNF)
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1991.tb12490.x

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 μg kg−1 E. coli lipopolysaccharide (LPS) over 60 min 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 F1α (6‐keto PGF1α) 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 (2 mg kg−1, i.v. bolus 60 min before the start of LPS infusion, followed by a continuous infusion of 3 mg kg−1 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 (2 mg 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.