Participation of platelet-activating factor in the lipopolysaccharide-induced liver injury in partially hepatectomized rats.
Platelet-activating factor (PAF) has been shown to be an important mediator in the pathogenesis of lipopolysaccharide (LPS)-induced liver injury in regenerating rat livers. Both LPS and PAF activate nuclear factor-kappa B (NF-kappaB), a key transcription factor for tumor necrosis factor-alpha (TNF-alpha) and cytokine-induced neutrophil chemoattractant (CINC). The aim of this study is to investigate how PAF participates in the LPS-induced and NF-kappaB-mediated regulation of TNF-alpha and CINC in regenerating rat livers. LPS (1.5 mg/kg) was intravenously administered into 70% hepatectomized rats and sham-operated rats 48 hours postoperatively. LPS administration caused a high mortality rate, scattered necrosis in the liver with infiltration of CINC-positive neutrophils, and a continuous CINC messenger RNA up-regulation and activation of NF-kappaB in the liver only in hepatectomized rats. These phenomena were all effectively prevented by pretreatment and posttreatment with a PAF receptor antagonist, TCV-309. Hepatectomized rats showed NF-kappaB staining in hepatocytes, Kupffer cells, and neutrophils around necrosis 4 hours after the LPS injection, representing the activation of this factor in these cells. Based on these results, we propose that PAF contributes to continuous CINC up-regulation and NF-kappaB activation via accumulation and activation of neutrophils, and thereby is involved in LPS-induced liver injury in regenerating rat livers.
Sakaguchi
T
T
Department of Surgery II, Hamamatsu University School of Medicine, Hamamatsu, Japan. takasa@hama-med.ac.jp
Nakamura
S
S
Suzuki
S
S
Oda
T
T
Ichiyama
A
A
Baba
S
S
Okamoto
T
T
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000097:blood / Q000235:genetics / Q000378:metabolism; D004586:Electrophoresis; D006133:Growth Substances / Q000097:blood / Q000235:genetics / Q000378:metabolism; D006498:Hepatectomy / Q000379:methods; D007158:Immunologic Techniques; D036341:Intercellular Signaling Peptides and Proteins; D007728:Kupffer Cells / Q000473:pathology; D008070:Lipopolysaccharides; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000503:physiopathology*; D008115:Liver Regeneration; D008297:Male; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology; D010972:Platelet Activating Factor / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics
D019743:Chemokines, CXC; D002630:Chemotactic Factors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; C039351:platelet activating factor receptor; D000410:Alanine Transaminase