The Significance of Ischemic Tolerance in Severe Liver Ischemia / Reperfusion Injury
2003 Volume 19 Issue 1 Pages 31-42
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2003 Volume 19 Issue 1 Pages 31-42
Although HSP 70 has been reported to play a major role in establishing the ischemic tolerance, the precise mechanism of this phenomenon has not been quitely understood. The purposes of the present study are to evaluate the cytoprotective effect of ischemic preconditioning, and administration of geranylgeranylacetone (GGA), which is expected to induce HSP 70, and to elucidate the cytoprotective mechanism of HSP 70 from the standpoint of the functional relationship between HSP 70 and transcription factor NF-κB.
Materials and methods. Male Wistar rats were subjected to 45 minutes of hepatic ischemia followed reperfusion. The animals were divided into 3 groups. Group I were subjected to 45-minute liver ischemia/reperfusion (I/R). Group P were subjected to 30-minute I/R as a preconditioning prior to 45-minute I/R. Group G were given to oral geranylgeranylacetone (GGA) at a dose of 200 mg/kg body weight for 7 days prior to 45-minute I/R. Examined were survival rate, liver function (ALT and hyaluronic acid), hepatic tissue blood flow (laser Doppler), histological findings (TEM, SEM), expression of HSP 70 and NF-κB (Western blot analysis), NF-κB DNA binding activity (electrophoretic mobility shift assay), and NO-2 +NO-3 concentration in isolated hepatocyte culture (Griess method). Results. Hepatic blood flow, serum ALT levels, serum HA levels, and histological findings showed a significant improvement in groups P and G, whereas ischemia/reperfusion injury was very severe in group I. HSP 70 induction was significantly increased in groups P and G. And the expression and activation of NF-κB were inhibited in groups P and G. The NO production was suppressed in groups P and G. Conclusion. Ischemic preconditioning and the oral administration of GGA induced the ischemic tolerance by inducing HSP 70. The mechanism was not only 1) that Hsp 70 suppressed NF-κB and regulated the overproduction of NO attributable to iNOS but 2) that it was involved in the maintaining the function of eNOS within 6 hours after reflow as well.
