Relationship between PAF-acether and thromboxane A2 biosynthesis in endotoxin-induced intestinal damage in the rat.
PAF-receptor antagonists are known to inhibit gastrointestinal damage induced by endotoxin. In the present study, the interaction between the biosynthesis of PAF and thromboxane (TX) A2, as putative mediators of the acute intestinal damage induced by endotoxin, has been investigated in the anaesthetised rat. Bolus intravenous administration of lipopolysaccharide from E. coli (5-50 mg/kg) induced dose-related jejunal damage, assessed using both macroscopic and histological techniques. This damage was accompanied by significant increases in the jejunal formation of PAF determined by bioassay, and of TXB2, determined by radioimmunoassay. Pretreatment with the structurally-unrelated thromboxane synthase inhibitors, 1-benzyl imidazole (10-50 mg/kg) or OKY 1581 (25 mg/kg) substantially reduced both jejunal damage and TXB2 formation, but did not inhibit PAF formation. Likewise, pretreatment with indomethacin (5 mg/kg) or BW 755C (50 mg/kg) reduced jejunal damage and TXB2 formation but did not affect PAF formation. Pretreatment (2h) with dexamethasone (4 mg/kg) reduced jejunal damage and the formation of both TXB2 and PAF. Intravenous infusion of PAF (100 ng/kg/min for 10 min) induced jejunal damage and significantly increased the formation of TXB2, whereas non-specific jejunal damage induced by oral administration of ethanol did not augment PAF formation. The present findings that inhibition of jejunal thromboxane formation is associated with a substantial reduction in jejunal damage, with no corresponding inhibition in PAF formation, therefore suggests a complex interaction or sequential release of these tissue destructive mediators underlying the intestinal damage induced by endotoxin.
Boughton-Smith
N K
NK
Department of Pharmacology, Wellcome Research Laboratories, Beckenham, Kent, England, United Kingdom.
Hutcheson
I
I
Whittle
B J
BJ
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D004926:Escherichia coli; D000431:Ethanol / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007583:Jejunum / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008689:Methacrylates / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000096:biosynthesis* / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012772:Shock, Septic / Q000378:metabolism* / Q000473:pathology; D013928:Thromboxane A2 / Q000096:biosynthesis*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007093:Imidazoles; D008070:Lipopolysaccharides; D008689:Methacrylates; D010972:Platelet Activating Factor; D011720:Pyrazoles; D000431:Ethanol; C017062:1-benzylimidazole; D013928:Thromboxane A2; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; C031517:2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic acid; D011451:Prostaglandin-Endoperoxide Synthases; D013930:Thromboxane-A Synthase; D007213:Indomethacin