The selenoorganic compound ebselen suppresses liver injury induced by Propionibacterium acnes and lipopolysaccharide in rats.
Ebselen (2-phenyl-1,2-benzoisoselenazol-3[2H]-one) is a selenoorganic compound containing selenium that has various pharmacological effects, including anti-inflammatory and antioxidant activity. Kupffer cells, residual hepatic macrophages, play an important role in the development of liver injury by producing free radicals and cytokines. The aim of this study is to evaluate whether ebselen suppresses macrophage-associated liver injury in rats. In vivo, we examined the effects of ebselen on liver injury, induced by Propionibacterium acnes and lipopolysaccharide (P. acnes-LPS), in rats where hepatic macrophages are considered to be primarily involved in injury development. Ebselen administration reduced the incidence of death following hepatic failure by P. acnes-LPS (82% vs. 20%, p<0.05). Serum levels of alanine aminotransferase, at 5 h after LPS administration, were significantly lower in the ebselen-treated group than in the control group (202.4+/-100.3 IU/l vs. 558.4+/-146.4 IU/l, p<0.05). Histological evidence of injury, such as necrosis, hemorrhage, and degeneration, was also suppressed by ebselen. Further, to assess the mechanisms involved, we investigated the production of cytokines and superoxide anions produced by activated hepatic macrophages in vivo. Serum levels of TNF alpha, interleukin-18 (IL-18)/IFN gamma-inducing factor (IGIF), and interferon gamma (IFN gamma) at 1 h after LPS administration were significantly lower in the ebselen-treated group. Formazan depositions, which were generated by the perfusion of the liver with nitroblue tetrazolium, were also observed less frequently in the ebselen treated group, suggesting a suppression in the release of superoxide anion from activated hepatic macrophages. In addition, we examined the effects of ebselen on cytokine production and mRNA expression, in vitro, using rat primary Kupffer cell culture. Ebselen also inhibited TNF alpha production and mRNA expression in vitro. These data imply that ebselen suppresses liver injury by inhibiting the production and/or release of proinflammatory cytokines and superoxide from activated hepatic macrophages. These data also suggest that ebselen is potent in the prevention of hepatic injury, such as endotoxemia, where hepatic macrophage activation has been implicated.
Koyanagi
T
T
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Nakamuta
M
M
Enjoji
M
M
Iwamoto
H
H
Motomura
K
K
Sakai
H
H
Nawata
H
H
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D005562:Formazans / Q000378:metabolism; D016908:Gram-Positive Bacterial Infections / Q000378:metabolism / Q000473:pathology; D007202:Indicators and Reagents / Q000378:metabolism; D020382:Interleukin-18 / Q000097:blood; D054833:Isoindoles; D007728:Kupffer Cells / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000382:microbiology / Q000473:pathology*; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D016566:Organoselenium Compounds / Q000494:pharmacology*; D011425:Propionibacterium acnes / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000975:Antioxidants; D001393:Azoles; D005562:Formazans; D007202:Indicators and Reagents; D020382:Interleukin-18; D054833:Isoindoles; D008070:Lipopolysaccharides; D016566:Organoselenium Compounds; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; C042986:ebselen; D000410:Alanine Transaminase