Effects of OPC-6535 on lipopolysaccharide-induced acute liver injury in the rat: involvement of superoxide and tumor necrosis factor-alpha from hepatic macrophages.
BACKGROUND
The objective of this study was to investigate the effects of OPC-6535 on Propionibacterium acnes-primed and lipopolysaccharide-induced liver injury in the rat.


METHODS
P. acnes was administered intravenously to the rat at 16 mg/kg 7 days before the experiments. In liver perfusion experiments, lipopolysaccharide was mixed in perfusion buffer at 2.5 microg/mL. The chemiluminescence method and histochemical reduction of nitro blue tetrazolium were used for detecting superoxide. Release of cytokines into the perfusate was examined. In in vivo experiments, lipopolysaccharide was administered intravenously to the rat at 200 microg/kg. Concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and cytokines were determined in the plasma, and myeloperoxidase activity was measured in the liver tissue. OPC-6535 was given intravenously at 1 mg/kg 30 minutes before lipopolysaccharide challenge, and was then, in perfusion experiments, added to the buffer at 10 micromol/L.


RESULTS
In perfusion experiments, P. acnes and lipopolysaccharide caused dramatic production of superoxide, tumor necrosis factor-alpha (TNF-alpha) and growth-related oncogene/cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1). Superoxide was mainly from hepatic macrophages. Treatment with OPC-6535 suppressed superoxide and TNF-alpha but did not affect GRO/CINC-1. In in vivo experiments, P. acnes and lipopolysaccharide increased the level of TNF-alpha, GRO/CINC-1, AST and ALT in the plasma, and myeloperoxidase activity in the liver. OPC-6535 reduced TNF-alpha, AST, and ALT, but did not affect GRO/CINC-1 or myeloperoxidase.


CONCLUSIONS
Attenuation of liver injury by OPC-6535 is believed to be due to its inhibitory effects on superoxide and TNF-alpha production by hepatic macrophages in P. acnes- and lipopolysaccharide-treated rats.
Hasegawa
Tadashi
T
1st Department of Surgery, Gunma University School of Medicine, 3-39-22 Showamachi, Maebashi, Gunma 371-8511 Japan.
Sakurai
Kazushi
K
Kambayashi
Yasuhiro
Y
Saniabadi
Abby R
AR
Nagamoto
Hisashi
H
Tsukada
Katsuhiko
K
Takahashi
Atsushi
A
Kuwano
Hiroyuki
H
Nakano
Minoru
M
D000818:Animals; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D008163:Luminescent Measurements; D008264:Macrophages / Q000502:physiology*; D008297:Male; D009580:Nitroblue Tetrazolium / Q000378:metabolism; D010477:Perfusion; D009195:Peroxidase / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C513297:Cxcl1 protein, rat; D007093:Imidazoles; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D011719:Pyrazines; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; C063412:2-methyl-6-(4-methoxyphenyl)-3,7-dihydroimidazo(1,2-alpha)pyrazin-3-one; D009580:Nitroblue Tetrazolium; D009195:Peroxidase; C108965:tetomilast