Salvage effect of E5564, Toll-like receptor 4 antagonist on d-galactosamine and lipopolysaccharide-induced acute liver failure in rats.
OBJECTIVE
The transmembrane protein Toll-like receptor 4 (TLR4), which exists mainly in macrophages such as Kupffer cells of the liver, plays an important role in recognizing and mediating macrophage activation and pro-inflammatory cytokine release. Activation of the pro-inflammatory cytokine cascade, including tumor necrosis factor-alpha (TNF-alpha), has a pivotal role in the progression of severe liver injury. D-galactosamine (GalN) and lipopolysaccharide (LPS)-induced liver injury in rats is an experimental model of fulminant hepatic failure, where TNF-alpha plays a central role in the progression of liver injury. E5564, a synthetic analogue of the lipid A component of endotoxin, inhibits endotoxin-stimulated inflammation and is under study for patients with sepsis. In the present study, we sought to explore the salvage effect of TLR4 antagonist E5564 on GalN+LPS-induced acute liver failure (ALF) in rats.


METHODS
ALF was induced in male Wistar rats by the intraperitoneal injection of GalN (500 mg/kg) and LPS (50 microg/kg). Immediately after GalN+LPS injection, rats were treated with intravenous injection of E5564 (3 mg/kg). The cumulative survival rates of GalN+LPS-induced ALF rats were compared between those with and without E5564 treatment.


RESULTS
The intravenous injection of E5564 reduced the elevation of serum total bilirubin, aspartate aminotransferase, alanine aminotransferase and TNF-alpha levels in rats at 3 h after GalN+LPS injection, and improved the survival rate of GalN+LPS-induced ALF rats at 24 h (8% vs 43%).


CONCLUSIONS
TLR4 antagonist E5564 reduced GalN+LPS-induced acute liver injury in rats and improved the overall survival rate of GalN+LPS-induced ALF rats. It may contribute to the treatment of ALF through blocking endotoxin-induced TNF-alpha overproduction of macrophages.
Kitazawa
Toshiyuki
T
Third Department of Internal Medicine, Nara Medical University, Nara, Japan.
Tsujimoto
Tatsuhiro
T
Kawaratani
Hideto
H
Fukui
Hiroshi
H
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D015415:Biomarkers / Q000097:blood; D004195:Disease Models, Animal; D005688:Galactosamine; D007275:Injections, Intravenous; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D015415:Biomarkers; C404742:E5564; D008050:Lipid A; D008070:Lipopolysaccharides; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C482199:lipopolysaccharide, E coli O55-B5; D005688:Galactosamine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001663:Bilirubin