Multiple organ failure and macrophage function in severe liver injury: Toll-like receptor and endotoxin clearance

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Role of innate immunity in the progression of liver injury was investigated in various experimental models of rats.Firstly, Acute hepatic failure (AHF) was induced in rats by injection of D-galactosamine (GalN, 1g/kg b.w.). In this model, the expression of Toll-like receptor (TLR) 4 mRNA of Kupffer cells was increased compared with controls but those of splenic macrophages and alveolar macrophages did not change. The expressions of liver TNF-α mRNA and TLR4 mRNA were increased in parallel with the progression of liver injury.Secondly, AHF with multiple organ failure was induced in rats by the concomitant administration of GalN (500mg/kg b.w.) and endotoxin (LPS; E.coli 055:B55,50μg/kg b.w.). In this model, more than 90% animals died of AHF within 24 hrs after the injection of GalN and LPS. The expression of liver TNF-α mRNA and CD14 mRNA were increased in parallel with the progression of liver injury. However, TLR4 mRNA was down-regulated at first (at 1lhr and 3hr) and recovered later (at 24hr) in survivors. TLR4 antagonist E5564 revealed rescue effect on this lethal AHF model.Thirdly, the expressions of liver TNF-α mRNA, CD14 mRNA and TLR4 mRNA were gradually increased with the progression of inflammation and fibrosis in non-alcoholic steatohepatitis (NASH) of rat induced by choline-deficient 1-amino acid-defined (CDAA) diet. This suggests that gut-derived endotoxin may activate TLR4-TNF-α axis and induce liver injury in this NASH model.In conclusion, activated innate immunity through TLR4 may be important in the development and progression of AHF and NASH.