The role of the glutathione antioxidant system in gut barrier failure in a rodent model of experimental necrotizing enterocolitis

Kelly, Natasha; Friend, Kerri; Boyle, Patricia; Zhang, Xiao Ru; Wong, C.; Hackam, David J.; Zamora, Rubén; Ford, Henri R.; Upperman, Jeffrey S.

doi:10.1016/j.surg.2004.05.034

Cited by 70 publications

(60 citation statements)

References 14 publications

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“…The numerous risk factors for the pathogenesis of NEC have been well described; however, the exact cellular mechanisms involved in intestinal epithelial cell injury during NEC are still not clearly elucidated. Transient mesenteric ischemia-reperfusion injury resulting in the production of ROS has been implicated to contribute to NEC (3)(4)(5). Additionally, extensive apoptosis occurs in enterocytes in the apical villi of infants with NEC (23); however, the exact role of ROS on the intestinal epithelial cell fate during NEC as well as the cellular mechanisms that are involved in this process are largely unknown.…”

Section: Discussionmentioning

confidence: 99%

“…There are numerous presumed risk factors for NEC, which include perinatal stress, hypoxia, mesenteric ischemia-reperfusion, and hyperosmolar enteral feedings (2). In particular, a potential link between ROS produced by ischemia-reperfusion injury to the gut and the development of NEC has been suggested by several studies (3)(4)(5). However, the exact cellular signaling involved in oxidative stress-mediated intestinal epithelial cell apoptosis, which may occur during NEC, has not been clearly defined.…”

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confidence: 99%

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Signal Transduction Pathways Involved in Oxidative Stress-Induced Intestinal Epithelial Cell Apoptosis

et al. 2005

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confidence: 99%

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Signal Transduction Pathways Involved in Oxidative Stress-Induced Intestinal Epithelial Cell Apoptosis

et al. 2005

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“…This is of potential clinical interest because a decrease in the gut barrier function has been linked to the pathogenesis of intestinal (i.e. necrotizing enterocolitis) diseases (9) and extraintestinal, particularly allergic and autoimmune, disorders (10,11). The aim of this study was to further investigate in vitro the effect of bilirubin on intestinal epithelial permeability.…”

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confidence: 99%

Unconjugated Bilirubin Modulates the Intestinal Epithelial Barrier Function in a Human-Derived In Vitro Model

et al. 2006

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Unconjugated bilirubin promotes intestinal secretion without affecting nutrient digestion or absorption. In the current study, the effects of unconjugated bilirubin (UCB) on the barrier function of the intestinal epithelium were investigated. The apical side of human intestinal cell line Caco-2 monolayers was challenged with purified UCB. Transepithelial electrical resistance and paracellular fluxes of 10 kD Cascade blue conjugate dextran were measured. Cell monolayer viability was studied using LDH release and trypan blue exclusion tests. Redistribution of enterocyte tight junction occludin was studied by confocal microscopy. Bilirubin induced a dose-dependent decrease of transepithelial electrical resistance (TEER). This effect was maximal at 6 h and tended to be reversed at 48 h. Oxidated bilirubin was ineffective. Bilirubin significantly increased fluorescent dextran paracellular passage. Cell viability was not affected by UCB over the 5-200 nmol/L concentration range. H yperbilirubinemia is a common finding in both term and preterm neonates (1). Because bilirubin can cause severe damage to the central nervous system, most investigators have focused their research on its effects on neural cells (2). The interaction of bilirubin with other organs has also been explored, although to a lesser extent. In the intestine, for example, bilirubin is excreted with bile in the gut lumen mainly as mono or diglicuronides. However, the enzyme glycuronidase, of both endogenous and microbial origin, partially converts it to UCB (3). Previous reports have shown UCB concentrations in the intestinal lumen of hyperbilirubinemic newborns to be in the micromolar range (4,5). Investigators have also documented that UCB in the gut does not affect cell viability, nutrient absorption, or brush border enzyme activities, although it can induce watery diarrhea by direct stimulation of ion secretion (6,7). Jaehrig et al. (8) found that UCB transit in the intestinal lumen of the human newborn was associated with a decreased transmural potential difference. As the latter is an indirect measurement of the tightness of the intestinal barrier, they suggested that bilirubin could cause "some injury" to the intestinal fence by increasing its permeability. This is of potential clinical interest because a decrease in the gut barrier function has been linked to the pathogenesis of intestinal (i.e. necrotizing enterocolitis) diseases (9) and extraintestinal, particularly allergic and autoimmune, disorders (10,11). The aim of this study was to further investigate in vitro the effect of bilirubin on intestinal epithelial permeability. For this purpose, we have used monolayers of the well-established human transformed cell line Caco-2 that displays many biologic features of the primary intestinal epithelium (12,13). The study was approved by the Institutional Review Board of the "Facoltà di Medicina-Federico II." MATERIALS AND METHODSReagents. Cell culture chemicals were obtained from GIBCO-Life Technologies (Milan, Italy). 10 kD Cascade blu...

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“…We believe that the GSH antioxidant system is an important counterregulatory system in NEC [2]. The findings reported by Hall et al are interesting, but I have some concerns about the experimental design.…”

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confidence: 87%

“…Instead, our study was designed to answer the question whether whole body antioxidant defenses are compromised due to the systemic inflammatory response resulting from Bell stage II or III NEC. Because whole body cysteine and glutathione metabolism are impaired in sepsis [1] and altered by prematurity [2], we hypothesized that after intestinal necrosis/apoptosis/perforation, neonates with NEC would be unable to maintain whole body glutathione levels. If this hypothesis had proved to be correct, it would have provided a rationale for a therapeutic intervention study involving, for example, N-acetyl-cysteine.…”

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confidence: 99%

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Upperman

2005

Journal of Pediatric Surgery

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The role of the glutathione antioxidant system in gut barrier failure in a rodent model of experimental necrotizing enterocolitis

Cited by 70 publications

References 14 publications

Signal Transduction Pathways Involved in Oxidative Stress-Induced Intestinal Epithelial Cell Apoptosis

Signal Transduction Pathways Involved in Oxidative Stress-Induced Intestinal Epithelial Cell Apoptosis

Unconjugated Bilirubin Modulates the Intestinal Epithelial Barrier Function in a Human-Derived In Vitro Model

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