Inhibition of endotoxin-induced microvascular leakage by a platelet-activating factor antagonist and 5-lipoxygenase inhibitor.
The sepsis syndrome is associated with increased vascular permeability. Mediators may include platelet-activating factor (PAF) and leukotrienes. We conducted experiments in the hamster cheek pouch to determine the ability of a 5-lipoxygenase (5-LO) inhibitor and a PAF antagonist to attenuate the increase in microvascular permeability that results from tissue exposure to endotoxin. Endotoxin (Escherichia coli serotype 0127:B8) or saline was administered to the surface of the cheek pouch following systemic pretreatment with either the 5-LO inhibitor (Abbott-77523; 20 mg/kg, i.v.) or PAF antagonist (Abbott-84768: 1 mg/kg, i.v.). In control hamsters, endotoxin induced a large increase in fluorescein isothiocyanate-dextran leakage into the cheek pouch interstitium. This leakage was not associated with increased leukocyte rolling or adhesion to venular endothelium. In contrast, groups pretreated with the PAF antagonist or the 5-LO inhibitor showed little or no leakage in response to endotoxin. Therefore, PAF and leukotrienes are important mediators of endotoxin-induced increases in microvascular permeability to macromolecules.
Klabunde
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Department of Pharmacology, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Calvello
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D000704:Analysis of Variance; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D002448:Cell Adhesion / Q000187:drug effects; D002610:Cheek / Q000098:blood supply; D006224:Cricetinae; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D005663:Furans / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D008297:Male; D008782:Methylurea Compounds / Q000494:pharmacology*; D008833:Microcirculation / Q000187:drug effects; D008856:Microscopy, Fluorescence; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D012772:Shock, Septic / Q000503:physiopathology*; D013844:Thiazoles / Q000494:pharmacology*
C098560:Abbott 84768; D005663:Furans; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D008782:Methylurea Compounds; C098559:N-hydroxy-N-(2-methylfur-3-yl)methyl urea; D010972:Platelet Activating Factor; D011726:Pyridinium Compounds; D013844:Thiazoles