Project Details


The early signs of liver injury due to ethanol (e.g., fatty degeneration)
occur in the pericentral region of the liver lobule. The biochemical and
cellular mechanisms underlying this intralobular zonation of
ethanol-induced liver injury are largely unknown. To investigate this
problem, the applicant developed the micro-light guide and the mini-oxygen
electrode to measure the oxygen gradients across the periportal and
pericentral regions of the liver lobule. Research carried out with the
isolated, hemoglobin-free perfused rat liver produced evidence that the
treatment of the rat with ethanol increased the rate of oxygen uptake by
pericentral cells without affecting the respiratory activity of periportal
cells. In the present grant proposal, a new hypothesis concerning the
mechanism of ethanol-induced pericentral liver injury is formulated on the
basis of this observation, and critical experiments designed to test this
hypothesis are proposed. According to this hypothesis, ethanol selectively
uncouple mitochondria in the pericentral region by causing an influx of
Ca+2 and Na+ into the cytosol secondary to plasma membrane depolarization
resulting from ethanol-induced inhibition of glycolysis. Following the
measurements of the periportal and pericentral oxygen gradients, the
perfused liver will be rapidly frozen and thin-sectioned in a cryostat.
Quantitative histochemical techniques will be applied to the air-dried thin
sections of the liver to measure the intracellular phosphate potential,
(ATP)/(ADP)(Pi), the (NADH) (NAD+) ratio, and the lipid content of
hepatocytes in the periportal and pericentral regions of the liver lobule.
The micro-light guide and fluorescence microscopy will be employed to
measure the plasma membrane and mitochondrial inner membrane potentials
using voltage-sensitive dyes and lipid soluble organic ions. To
investigate the effects of chronic ethanol treatment on the immunological
properties of periportal and pericentral cells, methods will be developed
to raise monoclonal antibodies to these cells and their binding
characteristics will be studied in the perfused rat liver. The proposed
studies will contribute to our understanding of the possible roles of
metabolic and "immunological" zonations of the hepatic acinus in the basic
physiology and pathophysiology of the liver.
Effective start/end date9/1/828/31/87


  • National Institutes of Health


  • Medicine(all)

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