Abstract |
Cellular responses to endotoxins are enhanced markedly by LPS-binding protein (LBP). Furthermore, it has been demonstrated that endotoxins and proinflammatory cytokines such as TNF-alpha participate in early alcohol-induced liver injury. Therefore, in this study, a long-term intragastric ethanol feeding model was used to test the hypothesis that LBP is involved in alcoholic hepatitis by comparing LBP knockout and wild-type mice. Two-month-old female mice were fed a high-fat liquid diet with either ethanol or isocaloric maltose- dextrin as control continuously for 4 wk. There was no difference in mean urine alcohol concentrations between the groups fed ethanol. Dietary alcohol significantly increased liver to body weight ratios and serum alanine aminotransferase levels in wild-type mice (189 +/- 31 U/L) over high-fat controls (24 +/- 7 U/L), effects which were blunted significantly in LBP knockout mice (60 +/- 17 U/L). Although no significant pathological changes were observed in high-fat controls, 4 wk of dietary ethanol caused steatosis, mild inflammation, and focal necrosis in wild-type animals as expected (pathology score, 5.9 +/- 0.5). These pathological changes were reduced significantly in LBP knockout mice fed ethanol (score, 2.6 +/- 0.5). Endotoxin levels in the portal vein were increased significantly after 4 wk in both groups fed ethanol. Moreover, ethanol increased TNF-alpha mRNA expression in wild-type, but not in LBP knockout mice. These data are consistent with the hypothesis that LBP plays an important role in early alcohol-induced liver injury by enhancing LPS-induced signal transduction, most likely in Kupffer cells.
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Authors | Takehiko Uesugi, Matthias Froh, Gavin E Arteel, Blair U Bradford, Michael D Wheeler, Erwin Gäbele, Fuyumi Isayama, Ronald G Thurman |
Journal | Journal of immunology (Baltimore, Md. : 1950)
(J Immunol)
Vol. 168
Issue 6
Pg. 2963-9
(Mar 15 2002)
ISSN: 0022-1767 [Print] United States |
PMID | 11884468
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Acute-Phase Proteins
- Carrier Proteins
- Cytokines
- Endotoxins
- Lipopolysaccharides
- Membrane Glycoproteins
- RNA, Messenger
- lipopolysaccharide-binding protein
- Ethanol
- Cytochrome P-450 CYP2E1
- Alanine Transaminase
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Topics |
- Acute-Phase Proteins
- Alanine Transaminase
(blood)
- Animals
- Carrier Proteins
(genetics, physiology)
- Cytochrome P-450 CYP2E1
(biosynthesis)
- Cytokines
(biosynthesis, genetics)
- Endotoxins
(blood)
- Ethanol
(toxicity, urine)
- Female
- Hepatitis, Alcoholic
(immunology, metabolism, pathology, physiopathology)
- Inflammation
(immunology)
- Intubation, Gastrointestinal
(methods)
- Lipopolysaccharides
(metabolism)
- Liver
(enzymology, immunology, metabolism, pathology)
- Membrane Glycoproteins
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Organ Size
(drug effects)
- RNA, Messenger
(biosynthesis)
- Weight Gain
(drug effects)
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