Development of measurement for hepatic isc hemia-repetfusion in jiry accoidirg to are gulation of activin-follistin system

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Background)Ischemia-reperfusion injury to the liver are of clinical importance in humans after hemorrhagic and cardiogenic shock, liver surgery, or liver transplantation. It was reported that blockade of the action of activin with administration of follistatin accelerates recovery from ischemia renal injury by accelerating regeneration after ischemia. In this study we evaluated the role of activin-follistatin on hepatic ischemia reperfusion injury and develop the new measurement for hepatic ischemia reperfusion injury.Method and Results)1) Effects of preactivation by portal vein ligation on liver regeneration (assessment according to activin)This study evaluated the effect of regenerating livers preactivated by PVL following massive hepatectomy. The mRNA expression levels of activin A and ActR II A were significantly higher in regenerating liver group than in normal liver group at late pahse. The regenerating liver preactivated by PVL is restricted late-phase liver regeneration after m … More assive hepatectomy.2) Beneficial Effects of follistatin in hepatic ischemia reperfusion injury Total hepatic ischemia for 30 min was performed followed by reperfusion. Follistatin (1mg/ body) was administered at the time of reperfusion. Four of 5 animals died in control group within 3days after reperfusion, whereas 80% of animals survived in follistatin group (P<0.05). AST was significantly lower at 3 hr after reperfusion in follistatin group (P<0.05). LDH was also lower at 6 hr after reperfusion in follistatin group (P<0.05). Follistatin inhibited the mRNA expression of bA subunit of activin. Moreover the expression of IL-6, which is inflammatory cytokine, was suppressed at 6 hr after reperfusion (P<0.05).3)Beneficial Effects of fluvastatin on Hepatic Ischemia-Reperfusion InjuryRats were divided into 3 groups: fluvastatin group; oral administration of fluvastatin (20mg/kg/day)for 2 days before the operation, control group, sham group. Fluvastatin and control groups were given total hepatic warm ischemia for 30 min. After reperfusion, an expression of mRNA level of endotherial NO synthase (eNOS) and NOX4 was determined by reverse transcriptase (RT)-PCR, tumor necrosis factor- a (TNF-α)and interleukine-1 β(IL-1β) mRNA by real-time RT-PCR. In the fluvastatin group, the expression of eNOS mRNA was significantly higher, and NOX4 mRNA was significantly lower (p<0.05). Furthermore, the expression of inflammatory cytokines mRNA were suppressed in the fluvastatin group. In particular, TNF- α was significantly lower in the fluvastatin group (P<0.05).4) Beneficial Effects of fluvastatin on Liver Microcirculation and Regeneration The liver regeneration rate in fluvastatin group was significantly higher at 72 hours after hepatectomy (p<0.05). Sinusoidal area in fluvastatin group was maintained histologicaly. Furthermore, the expression of-SMA protein in the liver was inhibited in fluvastatin group at 48 hours after hepatectomy.Summary) We were not able to elucidate the regulation of liver regneration using activin, because we had difficulty with the purification of activin. In this study, we clarified the regulatory mechanism of hepatic ischemia-reperfusion injury and effect of several modulators including follistatin for hepatic ischemia-reperfusion injury using molecular biological method. Less