Exacerbation of alcoholic liver injury by enteral endotoxin in rats

Increased gut permeability (leaky gut) and endotoxin-mediated Kupffer cell activation are proposed as the mechanisms of alcoholic liver injury. Althou gh ethanol feeding is shown to sensitize the liver for injury induced by pa rental administration of lipopolysaccharide (LPS), how enteral LPS loading affects alcoholic liver injury is yet to be tested. The present study provi des direct evidence for enhanced entrance to portal circulation of LPS ente rally administered to the intragastric ethanol infusion model. Portal and s ystemic blood endotoxin levels increased to 43.0 +/- 4.1 and 6.2 +/- 4.3 pg /mL at 2 hours following enteral LPS administration (5 mg/kg) in alcohol-fe d animals, while no such increases were observed in pair-fed controls. Howe ver, endotoxin levels in systemic blood of alcohol-fed rats were reduced to 0 to 1.5 pg/mL 16 hours after LPS administration. Weekly enteral administr ation of LPS to the model for 9 weeks exacerbated an increase in plasma ala nine transaminase (ALT) levels (227 +/- 75 vs. 140 +/- 70; P <.01), mononuc lear infiltration (25 +/- 22 vs. 6.4 +/- 4.4/10 mm(2); P=.02), sinusoidal c ongestion, and spotty necrosis, and induced diffuse coagulative necrosis an d centrilobular fibrosis in some animals. Reverse-transcription polymerase chain reaction (RT-PCR) analysis confirmed the LPS effect at the tissue lev el by demonstrating accentuated induction of tumor necrosis factor <alpha> (TNF-alpha) and Cox-2 mRNA, In conclusion, enteral LPS administration poten tiates alcoholic liver necrosis, inflammation, and fibrosis despite efficie nt endotoxin clearance by the liver and mild systemic endotoxemia that occu rs episodically following enteral LPS challenge.