Glutamine Synthetase: A Key Enzyme for Intestinal Epithelial Differentiation?

Weiss, Michael D.; DeMarco, Vincent G.; Strauss, Daniel; Samuelson, D. A.; Lane, Meredith E.; Neu, Josef

doi:10.1177/0148607199023003140

Cited by 36 publications

(20 citation statements)

References 18 publications

(5 reference statements)

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“…Intestinal explants from mouse embryos have been demonstrated to respond to Gln by increasing formation of villi, initiating absorptive cell differentiation, and increasing DNA synthesis and the number of epithelial cells (5). Our previous studies in cell cultures have demonstrated that Gln deprivation inhibits differentiation (52). Here, we see no dependency of these differentiation markers on protein, Gln, or Glu intake.…”

Section: Discussioncontrasting

confidence: 48%

Glutamine decreases lipopolysaccharide-induced intestinal inflammation in infant rats

Li¹,

Liboni²,

Fang³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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Using a gastrostomy-fed (GF) rat infant "pup-in-a-cup" model, the effects of protein deprivation and supplemental glutamine (Gln) and glutamate (Glu) were examined to test the hypothesis that Gln decreases the proinflammatory response induced by LPS in the developing infant rat small intestine. Four groups of 6- to 7-day-old pups were fed a rat milk substitute (RMS), one providing 100% and three providing 25% of normal protein intake for another 6 days. Two of the 25% protein-fed groups received supplemental Gln or Glu. GF and LPS treatment blunted body growth and intestinal villus height and increased intestinal cytokine-induced neutrophil chemoattractant (CINC) mRNA in the protein-deprived, non-Gln-treated group compared with mother-fed pups (P < 0.05). Gln blunted intestinal CINC mRNA (P < 0.05), but Glu did not. Intestinal CINC peptide in the LPS-treated pups provided 100 and 25% protein was elevated approximately 13-fold compared with the mother-reared pups (P < 0.001). Gln and Glu decreased intestinal CINC peptide by 73 and 80%, respectively. GF, LPS-treated pups also had a higher level of plasma CINC peptide (P < 0.05). Gln but not Glu decreased plasma CINC peptide (P < 0.05). An approximate sixfold elevation of intestinal MPO activity in the GF, LPS-treated rats was decreased by Gln and Glu by 92% (P < 0.001) and 54% (P < 0.05), respectively. Intestinal and plasma TNF-alpha were increased in GF, LPS-treated pups (P < 0.01), and Gln and Glu both blunted this increase (P < 0.05) in the intestine but not in the plasma. The results indicate that Gln decreases the LPS-induced inflammatory response in infant rat intestine under different conditions of protein intake.

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Section: Discussioncontrasting

confidence: 48%

Glutamine decreases lipopolysaccharide-induced intestinal inflammation in infant rats

Li¹,

Liboni²,

Fang³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The glutamine synthetase activity of rat intestinal crypt epithelial cells cultured in 4 mM glutamine increased by 203 and 500%, respectively (p ! 0.05), with an associated increase in cell proliferation when exposed to dexamethasone at 0.39 Ìl/l (10 -9 M ) and 39.25 Ìg/l (10 -7 M), respectively [45,46]. These concentrations of dexamethasone are 10-to 100-fold lower than the serum levels (262-397 Ìg/l) in low-gestation infants receiving 0.5 mg/kg/day as estimated from the mean volume of distribution of dexamethasone of 1.26-1.91 liters per kilogram in those born at !27 weeks of gestation and ^3.5 weeks old [47,48].…”

Section: Adrenal Immaturity Postnatal Dexamethasone Necrotizing Entmentioning

confidence: 99%

Hormonal Factors in the Morbidities Associated with Extreme Prematurity and the Potential Benefits of Hormonal Supplement

Yeung

Smyth²

2002

Neonatology

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Cortisol and thyroid hormones are known to modulate the maturation of various fetal organ systems, enzymes, and biochemical pathways. The cortisol furnished by the structural and biochemical immature fetal adrenal gland renders the extremely premature infants relatively cortisol deficient in comparison with the term newborns. The premature infants also have elevated fetal androgens, the production of which persists until ≈42 weeks of postconceptional age. The androgens produced by the fetal adrenal cortex and the müllerian inhibiting substance produced by the fetal testis have antiglucocorticoid and inhibitory effects on human fetal lung growth and maturation in vitro. Hypothalamic-pituitary-thyroid axis and thyroid function are also immature in extreme prematurity. In addition, there is reduced tissue thyroid hormone responsiveness. Superimposed on this is the reduced thyroid function seen in non-thyroidal illness in which elevated cytokine levels have been implicated. Repeated courses of antenatal steroids and high-dose postnatal dexamethasone appear to be deleterious to lung and brain development. This may be through inhibition of cell replication and catabolism as well as decreased thyroid-stimulating hormone secretion and reduced peripheral conversion of T₄ to T₃. Furthermore, dexamethasone has been found to enhance neurosteroid production in the immature brain, potentially altering brain development. Considered together, the relative cortisol deficiency/androgen excess and reduced thyroid function as well as prolonged high-dose postnatal dexamethasone therapy in these infants may be important factors in their high degree of morbidity. We propose to restrict antenatal steroids to a single course and hypothesize that the overall outcome of low-gestation infants would be improved with (1) hydrocortisone (i.v./p.o.) supplement at a fixed dose of 0.5 mg/kg birth weight every 12 h in infants <30 weeks of gestation from birth till 32 weeks of postconceptional age and (2) T₃ (i.v./p.o.) supplement at a fixed dose of 0.4 µg/kg birth weight every 12 h in those <27 weeks of gestation from birth till 32 weeks of postconceptional age.

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“…Studies using IEC-6 cells have demonstrated that inhibition of GS with MS, an inhibitor of GS (14), causes a significant decrease in proliferation that requires supraphysiologic concentrations of exogenous glutamine for reversal (15). Inhibition of GS in Caco-2 cells grown in transwell cultures results in decreased transepithelial resistance, opening of intercellular junctions, and decreased microvilli seen on TEM (16).…”

mentioning

confidence: 99%

“…Evidence is accumulating that glutamine supplementation prevents mucosal breakdown and decreases intercellular hyperpermeability and subsequent translocation of bacteria (24 -31). Cell culture studies from our laboratory have demonstrated that inhibition of endogenous glutamine synthesis decreases proliferation (15) and intercellular junctional integrity (examined at the TEM level) (16). Further preliminary in vivo studies have demonstrated increased mortality and bacterial translocation with GS inhibition (32).…”

mentioning

confidence: 99%

Glutamine Supplementation and Deprivation: Effect on Artificially Reared Rat Small Intestinal Morphology

POTSIC

2002

Pediatric Research

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The mechanisms of how glutamine benefits critically ill patients have not been established. The purpose of this study was to determine the effects of dietary and endogenously produced glutamine on small intestinal morphology using light and transmission electron microscopy in artificially reared rat pups. It was hypothesized that deprivation of dietary glutamine leads to intestinal disease that is exacerbated by inhibition of glutamine synthetase by methionine sulfoximine (MS). Rat pups were placed into five different test groups: The first was a reference group that was reared by their mother. The other four groups were reared artificially and received a 10% Travasol amino acid solution at 5 g/kg per day, which does not contain glutamine, added to a mixture containing carbohydrates, lipids, and vitamins. This dose was chosen because it represents an approximation of the amount of glutamine these rats would be receiving in a normal rat diet (approximately 40 g/kg per day total protein, 10 to 15% of which is glutamine ϩ glutamate). The glutamine was manipulated by adding glutamine (Q) or MS or both. The four groups were as follows: MSϪQϪ, MSϪQϩ, MSϩQϪ, and MSϩQϩ. Light microscopy revealed the greatest blunting of villus height in the ileum of rats from the MSϩQϪ group when compared with the MSϪQϩ group (123 Ϯ 48.9 m versus 207 Ϯ 36 m, p Ͻ 0.05). The other two groups exhibited intermediate villus heights, but all were shorter than the villi from the mother-reared animals. The number of villi per unit length of bowel was also lowest in the animals that were treated with MS and not provided with dietary glutamine. Transmission electron microscopy demonstrated breakdown of the epithelial junctions in the glutamine-deprived and glutamine synthetase-inhibited intestines. Glutamine-deprived animals also displayed sloughing of microvilli, decreased actin cores, and degeneration of the terminal web. In summary, these studies support the hypothesis that glutamine is involved with maintenance of intestinal epithelial integrity. Previous studies have found that glutamine supplementation significantly decreases morbidity among critically ill patients. Adult bone marrow transplant recipients who received glutamine i.v. had significant decreases in length of hospital stay, hospital-acquired sepsis, and hospital costs (1, 2). Studies in VLBW infants found that glutamine supplementation resulted in decreased morbidity and hospital costs (3-5). Additionally, studies in rodents found that glutamine supplementation provides protection against sepsis and subsequent distal organ damage (6, 7). The mechanisms of how glutamine acts to promote these beneficial effects are not known. However, there is evidence that its effect on intestinal mucosal integrity may play a role. The addition of glutamine to TPN has been demonstrated to maintain the integrity of small intestinal mucosa, therefore, preventing the atrophy typically noted with TPN (8). In a previous study of multiple animal species, administration of glutaminase decreased plasma g...

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Glutamine Synthetase: A Key Enzyme for Intestinal Epithelial Differentiation?

Abstract: The experimental group was found to be less differentiated by all three markers of differentiation. Therefore, glutamine synthetase is important for Caco-2 cell differentiation.

Cited by 36 publications

References 18 publications

Glutamine decreases lipopolysaccharide-induced intestinal inflammation in infant rats

Glutamine decreases lipopolysaccharide-induced intestinal inflammation in infant rats

Hormonal Factors in the Morbidities Associated with Extreme Prematurity and the Potential Benefits of Hormonal Supplement

Glutamine Supplementation and Deprivation: Effect on Artificially Reared Rat Small Intestinal Morphology

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