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Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599-7365
It is well known that females show a greater
susceptibility to alcohol-induced liver injury than males.
Additionally, females who consume alcohol regularly and have been obese
for 10 years or more are at greater risk for both hepatitis and
cirrhosis. Female rats on an enteral alcohol protocol exhibit injury
more quickly than males, with widespread fatty changes over a larger portion of the liver lobule. Levels of plasma endotoxin, intercellular adhesion molecule-1, free radical adducts, infiltrating neutrophils, and nuclear factor-
B are increased about twofold more in livers from
female than male rats after enteral alcohol treatment. Estrogen treatment in vivo increases the sensitivity of Kupffer
cells to endotoxin. Evidence has been presented that Kupffer cells are pivotal in the development of alcohol-induced liver injury. Destruction of Kupffer cells with gadolinium chloride
(GdCl3) or reduction of
bacterial endotoxin by sterilization of the gut with antibiotics blocks
early inflammation due to alcohol. Similar results have been obtained
with anti-tumor necrosis factor-
antibody. These findings led to the
hypothesis that alcohol-induced liver injury involves increases in
circulating endotoxin, leading to activation of Kupffer cells, which
causes a hypoxia-reoxygenation injury. This idea has been tested using
pimonidazole, a nitroimidazole marker, to quantitate hypoxia in
downstream pericentral regions of the liver lobule. After chronic
enteral alcohol, pimonidazole binding increases twofold. Enteral
alcohol also increases free radicals detected with electron spin
resonance. Importantly, hepatic hypoxia and radical production detected
in bile are decreased by destruction of Kupffer cells with
GdCl3. These data are consistent with the hypothesis that Kupffer cells participate in important gender
differences in liver injury caused by alcohol.
endotoxin; hepatic injury; hypoxia-reoxygenation; gender
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