Geranylgeranylacetone, a heat shock protein inducer, prevents primary graft nonfunction in rat liver transplantation.
BACKGROUND
Heat shock proteins (HSPs) are well known as cytoprotective proteins. Geranylgeranylacetone (GGA), a nontoxic anti-ulcer drug, was recently shown to have HSP-inducing capacity. In the present study, the activity of GGA was tested in a rat orthotopic liver transplantation (OLT) model to determine whether the compound has beneficial effects in warm ischemia-reperfusion injury.


METHODS
Either GGA or a control vehicle was orally administered to donor rats before graft harvest. Harvested livers were subjected to 45-min warm ischemia (37 degrees C) followed by OLT. HSP mRNA expressions and HSP syntheses in the graft livers were evaluated by reverse transcriptase polymerase chain reaction and Western blot analysis, respectively.


RESULTS
When the donors were treated with a vehicle, all recipients died of primary nonfunction within 2 days after OLT. In contrast, when the donors were treated with GGA (200 mg/kg per day) for 4 weeks, the 7-day survival rate of recipients was dramatically improved (90%). By giving a high dose of GGA (600 mg/kg per day) for 1 week, a similar improvement in recipient survival was seen (83.3%). GGA administration accumulated mRNA for both HSP72 and HSP90 in the livers even before warm ischemia and facilitated the syntheses of HSP72 and HSP90 after warm ischemia. In addition, GGA pretreatment also significantly reduced the serum levels of tumor necrosis factor-alpha (TNF-alpha) after reperfusion.


CONCLUSIONS
These findings indicate that both the enhanced induction of HSPs and the suppression of a cytotoxic mediator (TNF-alpha) might be involved in the beneficial effects of GGA on ischemia-reperfusion injury. Thus, oral administration of GGA would be a useful tool for preventing primary nonfunction in liver transplantation.
Fudaba
Y
Y
Second Department of Surgery, Hiroshima University, Faculty of Medicine, 1-2-3 Kasumi Minami-ku Hiroshima 734-8551, Japan.
Ohdan
H
H
Tashiro
H
H
Ito
H
H
Fukuda
Y
Y
Dohi
K
K
Asahara
T
T
D000818:Animals; D004224:Diterpenes / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology*; D050884:HSP72 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics*; D006498:Hepatectomy; D008099:Liver / Q000187:drug effects / Q000502:physiology; D016031:Liver Transplantation / Q000473:pathology / Q000502:physiology*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011914:Rats, Inbred BN; D014019:Tissue Donors; D020858:Tissue and Organ Harvesting / Q000379:methods; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004224:Diterpenes; D050884:HSP72 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C031049:geranylgeranylacetone