Reduced early alcohol-induced liver injury in CD14-deficient mice.
Activation of Kupffer cells by gut-derived endotoxin is associated with alcohol-induced liver injury. Recently, it was shown that CD14-deficient mice are more resistant to endotoxin-induced shock than wild-type controls. Therefore, this study was designed to investigate the role of CD14 receptors in early alcohol-induced liver injury using CD14 knockout and wild-type BALB/c mice in a model of enteral ethanol delivery. Animals were given a high-fat liquid diet continuously with ethanol or isocaloric maltose-dextrin as control for 4 wk. The liver to body weight ratio in wild-type mice (5.8 +/- 0.3%) was increased significantly by ethanol (7.3 +/- 0.2%) but was not altered by ethanol in CD14-deficient mice. Ethanol elevated serum alanine aminotransferase levels nearly 3-fold in wild-type mice, but not in CD14-deficient mice. Wild-type and knockout mice given the control high-fat diet had normal liver histology, whereas ethanol caused severe liver injury (steatosis, inflammation, and necrosis; pathology score = 3.8 +/- 0.4). In contrast, CD14-deficient mice given ethanol showed minimal hepatic changes (score = 1.6 +/- 0.3, p < 0.05). Additionally, NF-kappa B, TGF-beta, and TNF-alpha were increased significantly in wild-type mice fed ethanol but not in the CD14 knockout. Thus, chronic ethanol feeding caused more severe liver injury in wild-type than CD14 knockouts, supporting the hypothesis that endotoxin acting via CD14 plays a major role in the development of early alcohol-induced liver injury.
Department of Pharmacology, Laboratory of Hepatobiology and Toxicology, University of North Carolina, Chapel Hill, NC 27599, USA.
M
M
Yin
B U
BU
Bradford
M D
MD
Wheeler
T
T
Uesugi
M
M
Froh
S M
SM
Goyert
R G
RG
Thurman
D000209:Acute-Phase Proteins; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D015415:Biomarkers; D001835:Body Weight / Q000235:genetics / Q000276:immunology; D002352:Carrier Proteins / Q000502:physiology; D016207:Cytokines / Q000502:physiology; D000431:Ethanol / Q000652:urine; D005260:Female; D006519:Hepatitis, Alcoholic / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D007113:Immunity, Innate / Q000235:genetics; D018950:Lipopolysaccharide Receptors / Q000235:genetics* / Q000502:physiology; D008070:Lipopolysaccharides / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009929:Organ Size / Q000235:genetics / Q000276:immunology; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D000410:Alanine Transaminase; D015415:Biomarkers; D002352:Carrier Proteins; D016207:Cytokines; D000431:Ethanol; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D000099231:Lipopolysaccharide-Binding Protein