Role of platelet-activating factor in hepatic responses after bile duct ligation in rats.
Role of platelet-activating factor (PAF) as a potential mediator of hepatic pathophysiology was investigated using a rat model of obstructive jaundice. Over a 1-wk course of bile duct ligation, a sixfold increase in tissue levels of PAF (1.57 +/- 0.43 ng/g vs. control 0.24 +/- 0.08 ng/g) occurred in the liver, whereas no change was observed in PAF levels in plasma. Concomitantly, endotoxin was detected in portal blood drawn from jaundiced rats, and antagonism of the putative effect of endotoxin by neomycin plus polymyxin B reduced local PAF concentrations in livers from jaundiced animals. Induction of neutropenia failed to alter the elevated hepatic PAF concentrations. Moreover, a large quantity of PAF was released spontaneously from Kupffer cells isolated from livers derived from jaundiced rats but not from endothelial cells or hepatocytes from the same animals. An in vitro study using cultured Kupffer cells from normal rats indicated that Kupffer cells secreted a significant amount of PAF in response to lipopolysaccharide challenge; pretreatment of cells with polymyxin B prevented this stimulated PAF release. Treatment of animals with either of two PAF receptor antagonists (BN 52021 and WEB 2170) partially prevented the increase in tissue levels of eicosanoids and O2-derived free radicals and partially alleviated liver injury as judged by the appearance of glutamate-pyruvate transaminase in the plasma of jaundiced rats. The present study indicates 1) that endogenous PAF may be an important signaling mediator for the hepatic inflammatory alterations associated with short-term bile duct ligation and 2) that the interaction of Kupffer cells with portal endotoxin is the mechanism by which PAF is produced locally.
Zhou
W
W
Department of Biochemistry, University of Texas Health Science Center, San Antonio.
Chao
W
W
Levine
B A
BA
Olson
M S
MS
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001652:Bile Ducts; D002779:Cholestasis / Q000097:blood / Q000473:pathology / Q000503:physiopathology*; D004224:Diterpenes; D004731:Endotoxins / Q000097:blood; D046934:Ginkgolides; D007728:Kupffer Cells / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology; D008026:Ligation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014230:Triazoles / Q000494:pharmacology
D001381:Azepines; D004224:Diterpenes; D004731:Endotoxins; D046934:Ginkgolides; D007783:Lactones; D008070:Lipopolysaccharides; D010972:Platelet Activating Factor; D014230:Triazoles; C063964:bepafant; C045856:ginkgolide B