Mechanism of vulnerability to endotoxin of regenerating liver and its treatment

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Background. Platelet-activating factor (PAF) has been shown to be an important mediator in the pathogenesis of lipopolysaccharide (LPS)-induced liver ijury in regenerating rat livers. Both LPS and PPAF activate nuclear factor-kappa B (NF-kB), a key transcription factor for tumor necrosis factor-a (TNF-a) and cytokine-induced neutrophil attractant (CINC). The aim of this study is to investigate how PAF participates in the LPS-induced and NF-kB-mediated regulation of TNF-a and CINCin regenerating rat livers.Methods. LPS (1.5 mg/kg) was intravenously administered into 70 % hepatectomized rats and sham-operated rats 46 hours postoperatively.Results. 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-kB in the liver only in hepatectomized rats. These phenomena were all effectively prevented by pretreatment and posttreatment with a PAF receptor antagonist, TCV-309. Heptectomized rats showed NF-kB staining in hepatocytes, Kupffer cells, and neutrophils around necrosis 4 hours after the LPS injection, representing the activation of this factor in these cells.Conclusions. Based on these results, we propose that PAD contributes to continuous CINC up-regulation and NF-kB activation via accumulation and activation of neutrophils, and thereby is involved in LPS-induced liver injury in regenerating rat liver.