YAMAOKA Yoshio Kyoto University Medicine, Professor, 医学研究科, 教授 (90089102)
YAMAMOTO Yuzo Akita University, Medicine, Professor, 医学部, 教授 (70281730)
HATANO Etsurou Kyoto University Medicine, Assistant Professor, 医学研究科, 助手 (80359801)
TERAJIMA Hiroaki Kyoto University Medicine, Lecturer, 医学研究科, 講師 (40314215)
|Budget Amount *help
¥13,600,000 (Direct Cost: ¥13,600,000)
Fiscal Year 2003: ¥6,500,000 (Direct Cost: ¥6,500,000)
Fiscal Year 2002: ¥7,100,000 (Direct Cost: ¥7,100,000)
First, we established the cirrhotic rat model by orally administrating thioacetamide for 8 weeks. In this model, caveolin-1, already shown to antagonize eNOS in the liver, was overexpressed. In this research, we decided to examine the effect of HMG-CoA reducase inhibitors on hepatic ischemia/reperfusion injury because they have been reported to modulate the function of caveolin-1. In our experiments, we used pravastatin.
We examined the effect of pravastatin on hepatic I/R injury in normal rat liver, but pre-treatment of pravastatin did not suppress the injury compared with the control. We also examined the effect in the cirrhotic rat liver. In the cirrhotic liver, serum transaminase levels after hepatic I/R were much lower than in normal liver. The I/R injury in the pravastatin-treated group tended to be suppressed compare with the control, but it was not significant. The results suggested that the mechanism of hepatic I/R injury in cirrhotic liver might be different from in normal liv
So, to elucidate the difference of mechanism of hepatic I/R injury between normal liver and cirrhotic liver, the difference of the gene expression between them was examined with, DNA array technique using mRNA extracted from normal rat liver and cirrhotic rat liver. The result showed that several genes related with cell cycle and stress proteins were up-regulated. Although the precise examination of those genes is needed, modulating those genes would be alternative targets for suppressing I/R injury in cirrhotic liver.
Because pravastatin did not show the suppressive effect on I/R injury, we tried other ways for manupulation of sinusoidal cells using Y-27632, a ROCK/Rho kinase inhibitor, and pyrrolidine dithinocarbamate (PDTC), which induced heme oxygenase-1 in the liver. The former improved hepatic micro-circulation and suppressed hepatic I/R injury in normal rat liver and endotoxic liver injury, and the latter showed dilatative effect of hepatic sinusoids and suppressed I/R injury in normal liver. Those results suggest that modulating sinusoidal cells be a novel possible approach to minimize hepatic I/R injury, even in cirrhotic liver.
We believe the results above altogether will be the basis for developing novel approach to suppress the disturbance of sinusoidal circulation and I/R injury in cirrhotic liver. Less