Kupffer cells are a major source of increased platelet activating factor in the CCl4-induced cirrhotic rat liver.
OBJECTIVE
Endothelin-1 (ET-1) stimulates the synthesis of platelet-activating factor (PAF) by Kupffer cells in vitro. Hepatic concentrations of both ET-1 (a potent vasoconstrictor) and PAF (a mediator of hepatic vasoconstriction and the cirrhotic hyperdynamic state) increase in cirrhosis. The aim of this study was to determine if the responsiveness of Kupffer cells to produce PAF upon ET-1 challenge is modified by cirrhosis.


METHODS
Kupffer cells, isolated from the livers of control and CCl(4)-induced cirrhotic rats, were placed in serum-free medium after overnight culture. PAF and ET-1 receptors, ET-1-induced PAF synthesis, and PAF- and ET-1-induced prostaglandin E(2) (PGE(2)) synthesis were determined 24 h later.


RESULTS
Both basal and ET-1-stimulated PAF synthesis was increased in cirrhotic Kupffer cells as indicated by increased cell-associated and released PAF. Cirrhotic Kupffer cells also had elevated densities of functional receptors for both PAF and ET-1 (exclusively ET(B)), as measured by ligand binding, mRNA expression of the respective receptors, and ligand-stimulated PGE(2) synthesis.


CONCLUSIONS
Cirrhosis sensitizes Kupffer cells to both ET-1 and PAF by elevating their respective receptor levels. Since both mediators individually cause portal hypertension, an increase in ET-1-stimulated PAF synthesis in Kupffer cells will exacerbate the hepatic and extrahepatic complications of cirrhosis.
Yang
Yongping
Y
Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, E-1542 BST, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
Harvey
Stephen A K
SA
Gandhi
Chandrashekhar R
CR
D000818:Animals; D002251:Carbon Tetrachloride; D002478:Cells, Cultured; D015232:Dinoprostone / Q000096:biosynthesis; D019332:Endothelin-1 / Q000494:pharmacology; D015870:Gene Expression; D007728:Kupffer Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D010972:Platelet Activating Factor / Q000378:metabolism* / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
D019332:Endothelin-1; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D044023:Receptor, Endothelin B; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D002251:Carbon Tetrachloride; D015232:Dinoprostone