Modulation of intracellular signal pathway for preventing liver damage after extended hepatectomy

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Ischemia-reperfusion (I/R) injury of the liver is one of major problems after extended hepatectomy or liver transplantation. To perform operation much safer, some strategies to prevent I/R injury has been required.Nrf2 is a transcription factor that protects cell and tissues from oxidative stress by activating protective antioxidant and detoxifying enzymes. It is likely that preoperative activation of Nrf2 in liver-consisting cells results in prevention of I/R injury of the liver. In this protocol, we evaluated whether Nrf2 activation confer the tolerance for I/R injury of the liver.Oltipraz, 15-deoxy-Δ 12, 14-prostagrandine J2 (PGJ2), and diallyl sulfide (DAS) were used to confirm whether these drugs activate Nrf2 in liver-consisting cells. Liver epithelial cells and liver stellate cells were isolated from rat and mouse liver and cultured. Immunofluorescent assay revealed that Nrf-2 translocated into the nucleus immediately after stimulating by these drugs in both types of cells. The expression of HO-1 was also induced by PGJ2 in a dose dependent manner.It has been reported that activation of stellate cells has detrimental effect during hepatic I/R. To evaluate the effect of PGJ2 on stellate cell activation, the mRNA expression of alpha smooth muscle actin and type I collagen was examined by real time PCR. PGJ2 significantly inhibited the expression of both genes, suggesting that PGJ2 effectively suppressed the activation of stellate cells.Finally, the effect of PGJ2 on I/R injury was examined. C57/B16 mouse was used. We applied 70% ischemia model (60 min). PGJ2 was administrated intravenously via tail vein 3 hours before ischemia.The increasing of AST/ALT level 3 and 6 hours after reperfusion was significantly suppressed by PGJ2. In addition, TUNEL assay revealed that apoptosis after I/R was also suppressed.These data suggested that Nrf2 activation by PGJ2 may bring the beneficial effect in the field of liver surgery.