Failure of the gut barrier system enhances liver injury in rats: protection of hepatocytes by gut-derived hepatocyte growth factor.

Abstract

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-alpha, interleukin (IL)-1beta, interferon-gamma, 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-alpha, IL-1beta, interferon-gamma 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.

CONCLUSION:

s Our data suggest that Kupffer cell activation mediated by intraportal LPS via TLR4 is involved in liver injury, possibly through both tumour necrosis factor-alpha/IL-1beta and FasL, and that lack of HGF activity in the impaired gut could not counteract liver injury.

• Authors: Yasuhiro Choda, Yoshinori Morimoto, Hideaki Miyaso, Susumu Shinoura, Shinya Saito, Takahito Yagi, Hiromi Iwagaki, Noriaki Tanaka
• Journal: European journal of gastroenterology & hepatology (Eur J Gastroenterol Hepatol) Vol. 16 Issue 10 Pg. 1017-25 (Oct 2004) ISSN: 0954-691X [Print] England
• PMID: 15371926 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-1
• Interleukin-6
• Lipopolysaccharides
• Tumor Necrosis Factor-alpha
• Hepatocyte Growth Factor
• Interferon-gamma
• Aspartate Aminotransferases
• Alanine Transaminase

Topics

• Alanine Transaminase (blood)
• Animals
• Aspartate Aminotransferases (blood)
• Epithelial Cells (metabolism, microbiology)
• Escherichia coli Infections (metabolism)
• Hepatocyte Growth Factor (biosynthesis, blood)
• Hepatocytes (enzymology, microbiology)
• Interferon-gamma (blood)
• Interleukin-1 (blood)
• Interleukin-6 (blood)
• Intestinal Mucosa (metabolism, microbiology)
• Lipopolysaccharides
• Male
• Rats
• Rats, Wistar
• Tumor Necrosis Factor-alpha (analysis)