The beneficial effect of phosphocreatine accumulation in the creatine kinase transgenic mouse liver in endotoxin-induced hepatic cell death.
Purpose. The purpose of this study was to investigate the relationship between hepatic energy status and liver injury during sepsis, using transgenic mice which express creatine kinase in the liver catalyzing the phosphocreatine/creatine system. Methods. Creatine kinase transgenic mice were fed with normal rodent chow or chow containing 10% creatine for 5 days. Lipopolysaccharide (0.2 mg/kg) combined with d-galactosamine (600 mg/kg) was administered intraperitoneally. Results. Eighty percent of the creatine-fed transgenic mice had survived at 48 h post-d-galactosamine and lipopolysaccharide administration, compared with none of the normally fed transgenic mice. Hepatic phosphocreatine and ATP levels in the normally fed transgenic mice were significantly lower than those in the creatine-fed transgenic mice before and after lipopolysaccharide combined with d-galactosamine was administered. Massive hepatic hemorrhagic necrosis with apoptosis was seen in response to d-galactosamine and lipopolysaccharide in normally fed transgenic mice. These results are consistent with a significant increase in serum aminotransferase at 8 h. In contrast, there were faint necrotic changes in the liver with minimal cellular infiltration in creatine-fed transgenic mice. Conclusions. Maintenance of hepatic ATP levels protects from sepsis-induced liver injury and mortality.
Kanazawa
A
A
Department of Gastroenterological Surgery, Kyoto University Graduate School of Medicine, Japan.
Tanaka
A
A
Iwata
S
S
Satoh
S
S
Hatano
E
E
Shinohara
H
H
Kitai
T
T
Tsunekawa
S
S
Ikai
I
I
Yamamoto
M
M
Takahashi
R
R
Chance
B
B
Yamaoka
Y
Y
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D001921:Brain / Q000201:enzymology; D003402:Creatine Kinase / Q000235:genetics* / Q000378:metabolism*; D004734:Energy Metabolism; D005688:Galactosamine / Q000633:toxicity; D007527:Isoenzymes; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009336:Necrosis; D010725:Phosphocreatine / Q000378:metabolism*; D051381:Rats; D018805:Sepsis / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007527:Isoenzymes; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D010725:Phosphocreatine; D005688:Galactosamine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003402:Creatine Kinase