The lower intestinal tract-specific induction of heme oxygenase-1 by glutamine protects against endotoxemic intestinal injury.
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.
Uehara
Kenji
K
Department of Anesthesiology and Resuscitology, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama City 700-8558, Japan.
Takahashi
Toru
T
Fujii
Hiromi
H
Shimizu
Hiroko
H
Omori
Emiko
E
Matsumi
Masaki
M
Yokoyama
Masataka
M
Morita
Kiyoshi
K
Akagi
Reiko
R
Sassa
Shigeru
S
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
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