Therapeutic approach to regulate innate immune response by Toll-like receptor 4 antagonist E5564 in rats with D-galactosamine-induced acute severe liver injury.

Abstract

BACKGROUND AND AIMS:

Toll-like receptor 4 (TLR4) is a transmembrane protein, existing mainly in macrophages, such as Kupffer cells of the liver. It plays an important role in recognizing and mediating macrophage activation and pro-inflammatory cytokine release. Activation of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-alpha is pivotal in the progression of liver injury. Gut-derived endotoxin has been considered to play an important role in the development and progression of a D-galactosamine (GalN)-induced acute severe liver injury (ALI) model. E5564, a synthetic analog of the lipid A component of endotoxin, inhibits endotoxin-stimulated inflammation and is under study for patients with sepsis. In this study, we seek to explore the effect of TLR4 antagonist E5564 on GalN-induced ALI in rats.

METHODS:

ALI was induced in male Wistar rats by the i.p. injection of 1 g/kg bodyweight of GalN and immediately after GalN injection they were treated with an i.v. injection of 3 mg/kg bodyweight of E5564. At 24 h after GalN injection with or without E5564, serum levels of total bilirubin (T.Bil), alanine aminotransferase (ALT) and TNF-alpha were analyzed. Expression levels of TNF-alpha, TLR4 and CD14 mRNA in the whole liver of rats was detected by reverse transcription polymerase chain reaction analysis.

RESULTS:

The i.v. injection of E5564 reduced the elevation of serum T.Bil, ALT and TNF-alpha levels in rats treated with GalN. The expression level of TNF-alpha mRNA in the whole liver, which was increased at 24 h after GalN injection, was also reduced by i.v. injection of E5564.

CONCLUSION:

TLR4 antagonist E5564 reduced GalN-induced ALI in rats. It may contribute to the treatment of acute liver failure through blocking endotoxin-induced TNF-alpha overproduction of macrophages.

• Authors: Toshiyuki Kitazawa, Tatsuhiro Tsujimoto, Hideto Kawaratani, Hiroshi Fukui
• Journal: Journal of gastroenterology and hepatology (J Gastroenterol Hepatol) Vol. 24 Issue 6 Pg. 1089-94 (Jun 2009) ISSN: 1440-1746 [Electronic] Australia
• PMID: 19226379 (Publication Type: Journal Article)

Chemical References

• E5564
• Lipid A
• Toll-Like Receptor 4
• Tumor Necrosis Factor-alpha
• RNA
• Galactosamine
• Aspartate Aminotransferases
• Alanine Transaminase
• Bilirubin

Topics

• Alanine Transaminase (metabolism)
• Animals
• Aspartate Aminotransferases (metabolism)
• Bilirubin (metabolism)
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Galactosamine
• Lipid A (analogs & derivatives, pharmacology)
• Liver Failure, Acute (chemically induced, drug therapy)
• Male
• RNA (metabolism)
• Rats
• Rats, Wistar
• Reverse Transcriptase Polymerase Chain Reaction
• Toll-Like Receptor 4 (antagonists & inhibitors)
• Tumor Necrosis Factor-alpha (metabolism)