| Co-Investigator(Kenkyū-buntansha) |
ARIYOSHI Hideo Graduate School of Medicine, Osaka University, Assistant Professor, 医学系研究科, 助手 (60294055)
UMESHITA Kouji Osaka University Hospital, Osaka University, Assistant Professor, 医学系研究科, 助手 (60252649)
NAKAMORI Shoji Graduate School of Medicine, Osaka University, Assistant Professor, 医学系研究科, 助手 (70294080)
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| Research Abstract |
In this study, we demonstrated that calpain activation is an early event in the process of hepatocyte injury caused by ischemia-reperfusion in a rat partial warm hepatic ischemia model. The major findings are following.
1) Calpain was activated earlier than the delay of recovery of tissue ATP content, suggesting that calpain activation is an early and sensitive indicator of hepatic ischemic insult.
2) To determine the best method of 60 min hepatic vascular clamping, various clamping methods (6 cycles of10min ischemia with 5 min reperfusion, 4 cycles of 15 min ischemia with 5 min reperfusion, 3cycles of 20 min ischemia with 5 min reperfusion) were tried. From the data on tissue ATP content, energy charge, histologic changes, and calpain activation, it was concluded that 6 cycles of10min ischemia with 5 min reperfusion induced the least ischemic change.
3) During the above study, we also demonstrated by confocal laser microscopy that the local increase in intracellular calcium concentration
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by calcium influx was a prerequisite for calpain activation. In addition, it was demonstrated by immuno-electron microscopy that mitochondria was one of major activation site of calpain in hepatocytes.
4) The administration of methylpredonisolone significantly inhibited ischemia-reperfusio injury in accordance with the decresed expression of mRNA of inflamatory cytokines like IL-1, suggesting that steroid may be used in a multi-drug therapy for hepatic ischemia-reperfusion injury.
5) In clinical patients undergoing partial hepatectomy, we confirmed the feasibility of 6 cycles of ischemia with 5 min reperfusion. Prostaglandin E1 (PGE1) administration was also useful in prevention of calpain activation during hepativ vascular clamping, indicating that PGE1 may be another candidate for multi-drug therapy for hepatic ischemia-reperfusion injury.
6) In patients with chronic hepatitis, calpain was already activated ischemia-reperfusion induced calpain activation, but not hepatitis related calpain activation. Less
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