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-κB), a key transcription factor for tumor necrosis factor-α (TNF-α) and cytokine-induced neutrophil chemoattractant (CINC). The aim of this study is to investigate how PAF participates in the LPS-induced and NF-κB–mediated regulation of TNF-α 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-κB 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-κB 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-κB activationviaaccumulation and activation of neutrophils, and thereby is involved in LPS-induced liver injury in regenerating rat livers.