Disturbed Oxygen Metabolism Induced by Perturbation of Microcirculation.

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There is an increasing body of evidence that the disturbance of microcirculation in hepatic lobules is involved in the pathogenesis of a wide variety of lever damage. Among them are alcohol-and drug-induced damage and liver injury caused by ischemia-reperfusion process, which occurs in case of major liver surgery including liver transplantation. To investigate the mechanisms of these liver damages and of liver regeneration process, we applied the medical-engineering technology and molecular biological techniques. For analyzing the hepatic microcirculation, we developed an in vivo super-magnified video microscopy system which allows us to monitor sinusoidal blood cell flow velocity and regional cellular oxygenation. Ethanol causes severe microcirculatory disturbances in midzone of hepatic lobule which could account for later tissue damage. CC1_4 and galactosamine also induced a microcirculatory change of the hepatic lobules which preceeded the liver damage. Microciroulatory disorder also plays an important role in liver transplantation. during regeneration of the liver following drug-induced liver damage. Expression of the protooncogenes and their products is specifically enhanced in parallel with increased DNA replication. Zonal heterogeneity of c-Ha-ras gane expression was evident, and a higher number of gene products was detected in the pericentral (PC) region than in periportal (PP) region after CC1_4-treatment, which caused a severe structural damage and microcirculatory disorder in PC region. Protein kinase C, an important protein in signal transduction, also shows heterogeneous activation (more in PC than in PP) during liver regeneration, which might trigger cellular functions and proliferation and mediate the biological action of hepatotrophic factors. In conclusion, the microcirculatory disorder has a role in pathogenesis and repair process of alcohol-and drug-induced liver damage and following liver transplantation.