Restriction of gut-derived endotoxin impairs DNA synthesis for liver regeneration.
The influence of restricting gut-derived endotoxin availability on liver regeneration after partial hepatectomy was evaluated. Partial hepatectomy was performed by 67% liver resection of ether-anesthetized rats. Liver regeneration was quantified after partial hepatectomy by [3H]thymidine incorporation into hepatic DNA; endotoxemia due to absorption of endogenous endotoxin from the gut into the portal circulation was determined by qualitative lysate assay of perchloric acid-extracted plasma samples, and plasma levels of the hepatotrophic factors insulin and glucagon were measured by radioimmunoassay. Treatments to restrict gut-derived endotoxin included chronic gavage with neomycin and cefazolin for gut sterilization, chronic gavage with cholestyramine to bind endotoxin within the gut, subcutaneous administration of polymyxin B to neutralize the lipid A portion of circulating endotoxin, intraperitoneal induction of endotoxin tolerance by progressively higher doses of endotoxin, and experimentation with isolator-reared defined flora Fisher rats that were Gram-negative bacteria deficient and therefore endotoxin deficient. All treatments to restrict endogenous endotoxin impaired DNA synthesis in regenerating livers particularly 21 h posthepatectomy when replication was increasing most rapidly in normal rats. We hypothesize that impairment of DNA synthesis after partial hepatectomy in endotoxin-restricted animals was due to the observed lack of normal systemic endotoxemic as well as hyperinsulinemic and hyperglucagonemic responses to 67% liver resection.
D000818:Animals; D002437:Cefazolin / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis*; D004731:Endotoxins / Q000494:pharmacology*; D005934:Glucagon / Q000097:blood; D006498:Hepatectomy; D007328:Insulin / Q000097:blood; D008115:Liver Regeneration; D008297:Male; D009355:Neomycin / Q000494:pharmacology; D011112:Polymyxin B / Q000494:pharmacology; D011168:Portal System; D051381:Rats; D011919:Rats, Inbred Strains; D012477:Salmonella enteritidis
D004731:Endotoxins; D007328:Insulin; D004247:DNA; D005934:Glucagon; D009355:Neomycin; D002437:Cefazolin; D011112:Polymyxin B