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Reduced early alcohol-induced liver injury in CD14-deficient mice
M Yin1, B U Bradford, M D Wheeler
1Department of Pharmacology, Laboratory of Hepatobiology and Toxicology, University of North Carolina, Chapel Hill, NC 27599, USA.
Abstract:
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.
Insights
CD14 receptors play a critical role in early alcohol-induced liver injury. Mice lacking CD14 showed significantly less liver damage and inflammation after chronic ethanol consumption, highlighting CD14
Area of Science:
- Hepatology
- Immunology
- Toxicology
Background:
- Gut-derived endotoxin activates Kupffer cells, contributing to alcohol-induced liver injury.
- CD14-deficient mice exhibit increased resistance to endotoxin-induced shock compared to wild-type controls.
Purpose of the Study:
- To investigate the role of CD14 receptors in the early stages of alcohol-induced liver injury.
- To compare liver injury in CD14 knockout mice versus wild-type mice following chronic ethanol administration.
Main Methods:
- Utilized a model of enteral ethanol delivery in CD14 knockout and wild-type BALB/c mice over 4 weeks.
- Assessed liver injury through liver-to-body weight ratio, serum alanine aminotransferase levels, liver histology, and inflammatory markers (NF-kappa B, TGF-beta, TNF-alpha).
Main Results:
- Ethanol significantly increased the liver-to-body weight ratio and serum alanine aminotransferase in wild-type mice, but not in CD14-deficient mice.
- Wild-type mice exhibited severe liver injury (steatosis, inflammation, necrosis) with ethanol, while CD14-deficient mice showed minimal hepatic changes.
- Ethanol-induced increases in NF-kappa B, TGF-beta, and TNF-alpha were observed in wild-type mice but not in CD14 knockouts.
Conclusions:
- CD14 deficiency confers significant protection against early alcohol-induced liver injury.
- Endotoxin acting via CD14 receptors is a major contributor to the development of alcohol-induced liver injury.