Protective effect of neutrophil elastase inhibitor (FR136706) in lethal acute liver failure induced by D-galactosamine and lipopolysaccharide in rats.
OBJECTIVE
It has been reported that liver dysfunction with ischemia-reperfusion is improved through selective inhibition of neutrophil elastase (NE) by NE inhibitor. This study was designed to investigate whether NE inhibitor has protective effect in lethal acute liver failure.


METHODS
Rats were treated with D-galactosamine plus lipopolysaccharide (GalN/LPS) to induce acute liver failure. NE inhibitor (FR136706) was administered intravenously before GalN/LPS injection.


RESULTS
NE inhibitor increased the survival rate to approximately 80% compared with less than 10% in GalN/LPS-treated rats. NE inhibitor prevented GalN/LPS-induced increase of enzymes and total bilirubin in serum, which are related to liver injury. Histopathological analysis revealed that NE inhibitor decreased the incidence of hepatic apoptosis and neutrophil infiltration in the liver. NE inhibitor inhibited the increased concentration of proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-6 and interferon-gamma), and chemokines (CINC-1 and MIP-2) in serum or liver caused by GalN/LPS, and enhanced anti-inflammatory cytokine, interleukin-10 concentration. NE inhibitor prevented the activation of the transcription factor, nuclear factor-kappa B, induced by GalN/LPS. NE inhibitor also reduced the induction of inducible nitric oxide synthase mRNA and its protein in GalN/LPS-treated liver, and resulted in a decrease in nitric oxide production.


CONCLUSIONS
These results indicate that NE inhibitor, FR136706, inhibits the induction of a variety of inflammatory mediators such as cytokines, chemokines, and nitric oxide, in part through the inhibition of nuclear factor-kappa B activation, resulting in the prevention of fulminant liver failure.
Uchida
Yoichiro
Y
Department of Surgery, Kansai Medical University, Osaka, Japan.
Kaibori
Masaki
M
Hijikawa
Takeshi
T
Ishizaki
Morihiko
M
Ozaki
Takashi
T
Tanaka
Hironori
H
Matsui
Kosuke
K
Tokuhara
Katsuji
K
Kwon
A-Hon
AH
Kamiyama
Yasuo
Y
Okumura
Tadayoshi
T
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005688:Galactosamine; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D053491:Proteinase Inhibitory Proteins, Secretory / Q000494:pharmacology* / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
D016207:Cytokines; C474655:FR136706; D008070:Lipopolysaccharides; D016328:NF-kappa B; D053491:Proteinase Inhibitory Proteins, Secretory; D011758:Pyrroles; D005688:Galactosamine; D007770:L-Lactate Dehydrogenase; D052247:Nitric Oxide Synthase Type II; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase