Kupffer cell inactivation alleviates ethanol-induced steatosis and CYP2E1 induction but not inflammatory responses in rat liver.
OBJECTIVE
Gadolinium chloride inactivates Kupffer cells and alleviates alcohol-induced liver lesions. We investigated the mechanism of gadolinium chloride protection after oral ethanol feeding.


METHODS
Rats were maintained ethanol-intoxicated for 6 weeks by feeding ethanol in a low-carbohydrate/high-fat liquid diet. Macrophages were inactivated by intravenous administrations of gadolinium chloride. At termination, liver samples and cell lysates obtained from the periportal and perivenous region were analyzed for histopathology, mRNA expression of endotoxin-associated parameters and cytokines and for enzymes involved in oxidative stress.


RESULTS
Ethanol treatment alone caused marked microvesicular/macrovacuolar steatosis and focal inflammation. Gadolinium significantly alleviated pathology, by reducing steatosis but not inflammation. Gadolinium treatment eliminated ED2 immunopositive Kupffer cells, which were larger and more frequent periportally. Ethanol significantly increased the mRNA expression of the endotoxin (LPS) receptor CD14 and the LPS binding protein LBP, but not that of the pro-inflammatory cytokines TNF-alpha and IL-1beta. The mRNA of CD14 was found to be expressed preferentially in the perivenous region, but gadolinium treatment had no significant effect on the expression or the distribution. However, gadolinium significantly moderated the ethanol induction of CYP2E1 and this effect correlated to the degree of steatosis. Ethanol increased glutathione transferase and reduced glutathione peroxidase activity, but these changes persisted after gadolinium treatment.


CONCLUSIONS
Our results suggest that gadolinium chloride reduces symptoms of ALD mainly by counteracting steatosis, and that CD14-positive Kupffer cell populations are not involved in gadolinium protection. The strong correlation between pathology and CYP2E1 induction might suggest a steatopathogenic role for this enzyme.
Järveläinen
H A
HA
Alcohol Research Center, National Public Health Institute, Helsinki, Finland.
Fang
C
C
Ingelman-Sundberg
M
M
Lukkari
T A
TA
Sippel
H
H
Lindros
K O
KO
D000209:Acute-Phase Proteins; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000503:physiopathology*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D000431:Ethanol; D005234:Fatty Liver / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D005682:Gadolinium / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D007728:Kupffer Cells / Q000502:physiology*; D018950:Lipopolysaccharide Receptors / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D000893:Anti-Inflammatory Agents; D002352:Carrier Proteins; D019392:Cytochrome P-450 CYP2E1; D000431:Ethanol; D005682:Gadolinium; D005979:Glutathione Peroxidase; D005982:Glutathione Transferase; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D000099231:Lipopolysaccharide-Binding Protein; C038958:gadolinium chloride