Overexpression of thioredoxin prevents acute hepatitis caused by thioacetamide or lipopolysaccharide in mice.
Thioredoxin (Trx) is a small redox-active protein with antioxidant and antiapoptotic effects. Trx transgenic (Tg) mice are more resistant to cerebral infarction and survive longer than wild-type (WT) C57BL/6 mice. The aim of the present study was to investigate the protective role of Trx in acute hepatitis models. The expression of endogenous Trx was decreased in thioacetamide (TAA)-induced acute hepatitis. TAA (100 microg/g) was injected intraperitoneally in WT and Tg mice. Survival rate after TAA injection was higher in Tg mice than in WT mice. The level of oxidative stress was significantly less in Tg mice than in WT mice, as shown by the protein carbonylation assay and lipid peroxidation assay. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-positive cells were less in Tg mice than in WT mice, which was consistent with DNA laddering assay. Caspase-3 and caspase-9 activities and cytochrome c release were significantly inhibited in Tg mice compared with those in WT mice. In addition, lipopolysaccharide (LPS) plus d-galactosamine (GalN), or anti-Fas antibody (Jo2) were injected. Survival rate after LPS plus GalN injection was much higher in Tg mice than in WT mice. In contrast, there was no difference in survival rate after Jo2 injection between WT and Tg mice. In conclusion, transgene of Trx attenuated TAA- or LPS-induced acute lethal hepatitis. In addition to an antioxidant effect, Trx has the potential to protect acute liver injury via an antiapoptotic effect, which mainly inhibits mitochondria-mediated apoptosis signaling.
Okuyama
Hiroaki
H
Department of Gastroenterological Surgery, Graduate School of Medicine, Kyoto University, Japan.
Nakamura
Hajime
H
Shimahara
Yasuyuki
Y
Araya
Shinichi
S
Kawada
Norifumi
N
Yamaoka
Yoshio
Y
Yodoi
Junji
J
D000208:Acute Disease; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis; D056486:Chemical and Drug Induced Liver Injury / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D015536:Down-Regulation; D005688:Galactosamine / Q000276:immunology; D006801:Humans; D008070:Lipopolysaccharides; D017093:Liver Failure / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015996:Survival Rate; D013853:Thioacetamide; D013879:Thioredoxins / Q000235:genetics* / Q000378:metabolism*; D019014:fas Receptor / Q000276:immunology
D000906:Antibodies; D008070:Lipopolysaccharides; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D013853:Thioacetamide; D013879:Thioredoxins; D005688:Galactosamine