Chronic systemic endotoxin exposure: an animal model in experimental hepatic encephalopathy.
Plasma levels of gut-derived endotoxins (lipopolysaccharides, LPS) are often elevated in cirrhotics and are thought to contribute to hepatic encephalopathy. Circulating LPS activates macrophages to produce tumor necrosis factor alpha (TNF-alpha) and other potentially cytotoxic proinflammatory mediators. A pathogenic role for endotoxins is supported by studies showing that treatment with Lacto-bacillusor antibiotics, both of which reduce LPS-producing intestinal Gram-negative bacteria, alleviates experimental liver damage. To mimic the "leaky gut" syndrome with endotoxin translocation into the circulation in cirrhotics, a new animal model was developed. Rats were chronically exposed to ethanol and for the four last weeks also infused with endotoxin into the jugular vein from subcutaneously implanted osmotic minipumps. Animals receiving endotoxin had elevated hepatic expression of both pro- and anti-inflammatory cytokines, but compared to ethanol treatment alone hepatic steatosis and inflammatory changes were only marginally increased. This demonstrates marked endotoxin tolerance, probably as a consequence of a counteracting anti-inflammatory cytokine response. The role of gut-derived endotoxin in hepatic encephalopathy has recently received considerable attention. To further delineate the role and actions of endotoxin and its extrahepatic effects, studies applying both acute challenge and chronic infusion seem warranted. The chronic endotoxin model, mimicking the "leaky gut," may best be combined with more robust ways to impair liver function, such as carbon tetrachloride treatment, bile duct ligation, or galactosamine administration.
Lindros
Kai O
KO
National Public Health Institute, Alcohol Research Center, Helsinki, Finland. kai.lindros@ktl.fi
Järveläinen
Harri A
HA
D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity; D002908:Chronic Disease; D004195:Disease Models, Animal; D004731:Endotoxins / Q000008:administration & dosage / Q000633:toxicity*; D006501:Hepatic Encephalopathy / Q000523:psychology*; D007262:Infusions, Intravenous; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity; D051381:Rats
D001427:Bacterial Toxins; D004731:Endotoxins; D008070:Lipopolysaccharides; C027952:salmonella toxin