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Visualization and Analysis of Blood Flow and Oxygen Consumption in Hepatic Microcirculation: Application to an Acute Hepatitis Model
Published on: August 5, 2012
Topographic dissociation between mitochondrial dysfunction and cell death during low-flow hypoxia in perfused rat
M Suematsu1, H Suzuki, H Ishii
1Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Background:
Although it has been postulated that mitochondrial dysfunction and oxygen radicals may play a role in the mechanisms of hypoxic liver injury, little is known about the intralobular topographic relationship between a disorder in oxygen metabolism and cell death during hypoxia.
Experimental Design:
Intralobular heterogeneity of mitochondrial dysfunction and its topographic relationship to cell death during 25% low-flow hypoxia was visually demonstrated in perfused rat hepatic microcirculatory units by dual-color digital microfluorography using rhodamine 123, a fluorochrome sensitive to the mitochondrial membrane potential, and propidium iodide, which labels the nuclei of nonviable cells with a concomitant enhancement of fluorescence.
Results:
In the normoperfused liver from fasted rats, no significant depletion of the mitochondrial membrane potential values was observed in any portion of lobules during 100 minutes. In the liver treated with the 40-minute hypoxia, the mitochondrial membrane potential values within the entire lobule were significantly decreased. After a longer period of hypoxia, the pericentral fluorescence decreased to background levels, and the intralobular gradient showed a steep decline midway between the periportal and pericentral regions. Cell death was at first prominent in the midzone at 40 minutes, and then extended towards the pericentral regions, forming centrilobular necrosis at 100 minutes. Although allopurinol diminished the early midzonal cell death and retarded the development of centrilobular necrosis, it did not attenuate depression of the mitochondrial membrane potential.
Conclusions:
It is conceivable that mitochondrial dysfunction per se may not be related to the intralobular distribution of cell death during hypoxia. On the other hand, mitochondrial dysfunction in the centrilobular regions seems to be an important event leading to early midzonal oxidative tissue damage in that this change may involve ATP breakdown and the subsequent enhancement of xanthine oxidase-mediated oxidative cell injury in the midzonal regions, which are incompletely oxygenated.
