Sex-Related Liver Injury Due to Alcohol Involves Activation of Kupffer Cells by Endotoxin
Females have a greater susceptibility to ethanol-induced liver injury than males. Females who drink ethanol regularly and have been overweight for 10 years or more are at greater risk for both hepatitis and cirrhosis than males, and females develop ethanol-induced liver injury more rapidly and with...
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| Main Author: | |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2000-01-01
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| Series: | Canadian Journal of Gastroenterology |
| Online Access: | http://dx.doi.org/10.1155/2000/735262 |
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| Summary: | Females have a greater susceptibility
to ethanol-induced liver injury than males. Females who
drink ethanol regularly and have been overweight for 10 years or
more are at greater risk for both hepatitis and cirrhosis than males,
and females develop ethanol-induced liver injury more rapidly and
with less ethanol than males. Female rats on an enteral ethanol protocol
exhibit injury more quickly than males and have widespread
fatty changes over a larger portion of the liver lobule. Moreover,
levels of plasma endotoxin, intracellular adhesion molecule-1, free
radical adducts, infiltrating neutrophils and nuclear factor kappa B
are doubled in female rat livers compared with male rat livers after enteral
ethanol treatment. Additionally, estrogen treatment in vivo increases
the sensitivity of hepatic macrophages or Kupffer cells to
endotoxin. Evidence has been presented that Kupffer cells are pivotal
in the development of ethanol-induced liver injury. Destroying Kupffer
cells with gadolinium chloride or decreasing bacterial endotoxin
by sterilizing the gut with antibiotics inhibits early inflammation due
to ethanol. Similar results have been obtained with anti-tumour necrosis
factor-alpha antibody. These data pointed to the hypothesis
that ethanol-induced liver injury involves elevations in circulating
endotoxin concentrations leading to activation of Kupffer cells,
which causes a hypoxia-reoxygenation injury. This theory has been
tested using pimonidazole, a 2-nitroimidazole marker, to quantify hypoxia
in downstream, pericentral regions of the hepatic lobule. After
chronic enteral ethanol treatment, pimonidazole binding doubles.
Enteral ethanol also increases free radicals detected with electron
spin resonance. Radical adducts, with coupling constants such as
alpha-hydroxyethyl radical, have been shown to arise from ethanol.
Importantly, hypoxia and radical production detected in bile are also
decreased by the destruction of Kupffer cells with gadolinium chloride.
These data support the hypothesis that Kupffer cells contribute
to the vital sex differences in liver injury caused by ethanol. |
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| ISSN: | 0835-7900 |