Involvement of platelet-activating factor in hepatic apoptosis and necrosis in chronic ethanol-fed rats given endotoxin.
OBJECTIVE
Platelet-activating factor (PAF)-a potent activator of neutrophils-plays an important role in the pathogenesis of endotoxin-induced tissue injury. However, the role of PAF in hepatic damage during alcoholic hepatitis remains unclear. The aims of the present study were to test whether PAF contributes to hepatic injury in an animal model of alcoholic hepatitis and to investigate the involvement of the Fas-receptor/Fas-ligand system in this process.


METHODS
Male Sprague-Dawley rats were pair-fed with Lieber-DeCarli ethanol liquid diet or isocaloric control diet for 6 weeks. Liver injury was induced by the intravenous (i.v.) injection of lipopolysaccharide (LPS) (1 mg/kg). Rats were pretreated with a specific PAF receptor antagonist (TCV-309; 100 mg/kg i.v.) or vehicle 1 h before LPS treatment.


RESULTS
Chronic ethanol administration remarkably sensitized the rats to the effects of LPS, with resultant severe hepatocellular injury, accompanied by significant increases in serum levels of alanine aminotransferase (ALT), tumour necrosis factor (TNF)-alpha and interleukin (IL)-8 (CINC/gro). Histological examination of the damaged livers showed hepatocyte apoptosis and necrosis with extensive infiltration by neutrophils, whereas immunohistochemical studies revealed enhanced Fas-receptor expression on hepatocytes and hepatic accumulation of neutrophils expressing Fas-ligand. Pretreatment with the PAF receptor antagonist protected against hepatic injury, suppressing hepatocyte apoptosis and necrosis, infiltration of neutrophils, expression of Fas-receptor and Fas-ligand, and serum TNF-alpha levels.


CONCLUSIONS
Our study suggests that PAF is an important mediator of hepatic injury in the ethanol/endotoxin model of alcoholic hepatitis.
Murohisa
Gou
G
Second Department of Internal Medicine, Hamamatsu University School of Medicine, 3600 Handa-cho, Hamamatsu, Shizuoka 431-3192, Japan.
Kobayashi
Yoshimasa
Y
Kawasaki
Tsunehisa
T
Nakamura
Satoshi
S
Nakamura
Hirotoshi
H
D000818:Animals; D017209:Apoptosis; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004926:Escherichia coli / Q000276:immunology; D000431:Ethanol / Q000494:pharmacology; D053222:Fas Ligand Protein; D006519:Hepatitis, Alcoholic / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D007546:Isoquinolines / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D009336:Necrosis; D010972:Platelet Activating Factor / Q000502:physiology*; D011726:Pyridinium Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044005:Tetrahydroisoquinolines; D019014:fas Receptor / Q000378:metabolism
D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D007546:Isoquinolines; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D010972:Platelet Activating Factor; D011726:Pyridinium Compounds; D044005:Tetrahydroisoquinolines; D019014:fas Receptor; D000431:Ethanol; C067430:TCV 309