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Chronic ethanol sensitizes the liver to endotoxin via effects on endothelial nitric oxide synthase regulation.
- Source :
-
Shock (Augusta, Ga.) [Shock] 2005 Nov; Vol. 24 (5), pp. 447-54. - Publication Year :
- 2005
-
Abstract
- In vivo studies have shown that chronic alcohol consumption sensitizes the liver to endotoxemic shock, leading to liver microcirculation disruption. In the present study, we investigated the molecular mechanisms involved, focusing on endothelial nitric oxide synthase (eNOS) activity and regulation, which represents one of the major vasodilatory pathways. Male Sprague-Dawley rats were fed an alcohol liquid diet or a control isocaloric diet for 5 weeks. Priming effects of ethanol were studied in a model with or without a 24-h LPS treatment (1 mg/kg body weight). At the end of the diet, liver tissue was harvested for western blot, reverse transcriptase-PCR, histological analysis, and immunostaining and blood for serum alanine aminotransferase analysis. Chronic ethanol and LPS alone induced a mild hepatitis and infiltration, respectively. Combined, LPS and chronic ethanol feeding showed a synergistic effect on the liver, leading to extensive steatohepatitis with extensive focal necrosis associated with significantly higher levels of serum ALT. Chronic ethanol and LPS significantly inhibited eNOS activity, but exerted their effects through different mechanisms. Caveolin-1, an eNOS inhibitory protein, was upregulated after LPS and chronic alcohol consumption. Additionally, chronic alcohol consumption down-regulated endothelin B receptor, eNOS protein levels, and eNOS phosphorylation. In conclusion, chronic ethanol consumption and LPS share a similar pathophysiology and both lead to the impairment of eNOS activity, but through distinct molecular mechanisms. The presence of focal necrosis in a mild stress model could provide a good animal study to investigate the advanced stages of alcoholic liver diseases.
- Subjects :
- Alanine Transaminase blood
Alcohol Drinking
Animals
Blotting, Western
Body Weight
Down-Regulation
Drug Synergism
Endothelin-1 metabolism
Ethanol pharmacology
Hepatitis
Immunohistochemistry
Lipopolysaccharides metabolism
Liver pathology
Male
Necrosis
Nitric Oxide Synthase metabolism
Nitric Oxide Synthase Type II metabolism
Phosphorylation
RNA metabolism
RNA, Messenger metabolism
Rats
Rats, Sprague-Dawley
Receptor, Endothelin B metabolism
Reverse Transcriptase Polymerase Chain Reaction
Endotoxins metabolism
Ethanol administration & dosage
Gene Expression Regulation, Enzymologic
Liver drug effects
Nitric Oxide Synthase Type III metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1073-2322
- Volume :
- 24
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Shock (Augusta, Ga.)
- Publication Type :
- Academic Journal
- Accession number :
- 16247331
- Full Text :
- https://doi.org/10.1097/01.shk.0000180616.13941.7d