Objective: Clinical and experimental studies suggest that impairment of the mucosal barrier system increases gut-derived endotoxin in the portal blood, which causes liver injury. The aim of this study was to elucidate the mechanism of liver injury caused by gut defence failure. Design: Wistar rats were administered either enteral lipopolysaccharide (LPS) or LPS via the portal vein. Methods: Blood samples were collected via the inferior vena cava at necropsy. Serum aspartate transaminase (AST) and alanine transaminase (ALT) were analysed by standard enzymatic procedures and cytokines [tumour necrosis factor-α, interleukin (IL)-1β, interferon-γ, IL-6 and hepatocyte growth factor (HGF)] were measured by enzyme-linked immunosorbent assay. Livers were removed and snap-frozen in liquid nitrogen. CD14, CD68, Toll-like receptor (TLR) 2, TLR4 and Fas ligand (FasL) were analysed immunohistochemically. Expression of TLR2, TLR4 and CD14 mRNA was determined by reverse transcriptase-polymerase chain reaction. Results: In enterally-treated rats, AST and ALT were not increased and cytokine levels were under the limits of detection in the absence of a rise in HGF. Enteral administration of LPS increased HGF dose-dependently. Injection of LPS in the portal vein resulted in significant increases in AST, ALT, tumour necrosis factor-α, IL-1β, interferon-γ and IL-6 levels, but no change in HGF levels. Immunohistochemical analysis revealed that intraportal LPS administration increased CD14, TLR4, CD68 and FasL. Reverse transcriptase-polymerase chain reaction analysis demonstrated that TLR4 mRNA expression was upregulated 0.5 h after intraportal LPS administration. Conclusions: Our data suggest that Kupffer cell activation mediated by intraportal LPS via TLR4 is involved in liver injury, possibly through both tumour necrosis factor-α/IL-1β and FasL, and that lack of HGF activity in the impaired gut could not counteract liver injury.
|Number of pages||9|
|Journal||European Journal of Gastroenterology and Hepatology|
|Publication status||Published - Oct 2004|
- Fas ligand
- Gut defence
- Toll-like receptor
ASJC Scopus subject areas