title: The lower intestinal tract-specific induction of heme oxygenase-1 by glutamine protects against endotoxemic intestinal injury.
abstract: OBJECTIVE
  The aim of the present study was to investigate whether glutamine pretreatment improves intestinal injury in rats with endotoxemia by its heme oxygenase-1 induction in the lower intestinal tract.
  
  
  METHODS
  Randomized, blinded, controlled animal study.
  
  
  METHODS
  University-based animal research facility.
  
  
  METHODS
  Sprague-Dawley male rats, weighing 220-250 g (n = 201).
  
  
  METHODS
  Rats were treated with glutamine (0.75 g/kg) dissolved in lactated Ringer's solution via the tail vein. Endotoxemia was induced in rats by intraperitoneal injection of lipopolysaccharide (10 mg/kg or 20 mg/kg for survival study). Lipopolysaccharide-treated animals were pretreated with glutamine or lactated Ringer's solution 9 hrs before lipopolysaccharide treatment. Some of the glutamine-pretreated animals further received tin mesoporphyrin (1 micromol/kg), a specific inhibitor of heme oxygenase activity, 1 hr before lipopolysaccharide treatment.
  
  
  RESULTS
  Glutamine treatment markedly induced heme oxygenase-1 messenger RNA and protein in the mucosal epithelial cells as well as in the lamina propria cells in the ileum and the colon, whereas its expression in the duodenum and the jejunum was not influenced by the treatment. Glutamine treatment before lipopolysaccharide administration significantly ameliorated lipopolysaccharide-induced mucosal injury, inflammation, and apoptotic cell death in the ileum and the colon, as judged by significant decreases in tumor necrosis factor-alpha gene expression, histologic damage scores, and expression of activated caspase-3 and by an increase in gene expression of Bcl-2. In addition, glutamine treatment markedly decreased lipopolysaccharide-induced mortality. In contrast, treatment with tin mesoporphyrin abolished the beneficial effect of glutamine pretreatment.
  
  
  CONCLUSIONS
  Glutamine pretreatment significantly ameliorated intestinal tissue injury of rats following lipopolysaccharide treatment. The same treatment also improved the survival of animals from endotoxemia. The protective effect of glutamine is mediated by its lower intestine-specific induction of heme oxygenase-1, since its inhibition by tin mesoporphyrin completely abolished the beneficial effect of glutamine.
authors.affiliation: Department of Anesthesiology and Resuscitology, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama City 700-8558, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Uehara
authors.forename: Toru
authors.initials: T
authors.lastname: Takahashi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Fujii
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shimizu
authors.forename: Emiko
authors.initials: E
authors.lastname: Omori
authors.forename: Masaki
authors.initials: M
authors.lastname: Matsumi
authors.forename: Masataka
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Morita
authors.forename: Reiko
authors.initials: R
authors.lastname: Akagi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Sassa
mesh_terms: D000818:Animals; D017209:Apoptosis; D003106:Colon / Q000378:metabolism / Q000473:pathology; D019446:Endotoxemia / Q000201:enzymology* / Q000473:pathology; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004926:Escherichia coli; D005973:Glutamine / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051547:Heme Oxygenase-1; D007082:Ileum / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000201:enzymology / Q000473:pathology; D007422:Intestines / Q000201:enzymology* / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D008665:Metalloporphyrins; D014409:Tumor Necrosis Factor-alpha; C055421:tin mesoporphyrin; D005973:Glutamine; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1