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Enteral intestinal alkaline phosphatase administration in newborns decreases iNOS expression in a neonatal necrotizing enterocolitis rat model.

ABSTRACT: To determine if intestinal alkaline phosphatase (IAP) decreases intestinal injury resulting from experimentally induced necrotizing enterocolitis (NEC). We hypothesized that IAP administration prevents the initial development of NEC related intestinal inflammation.Pre- and full-term newborn Sprague-Dawley rat pups were sacrificed on day 1 of life. Pre-term pups were exposed to intermittent hypoxia and formula containing LPS to induce NEC. Select NEC pups were given 40, 4 or 0.4 units/kg of bovine IAP (NEC+IAP40u, IAP4u or IAP0.4u) enterally, once daily. Ileal sections were evaluated by real-time PCR (qRT-PCR) for IAP, iNOS, IL-1?, IL-6, and TNF-? mRNA and immunofluorescence for 3-nitrotyrosine (3-NT).Experimentally induced NEC decreased IAP mRNA expression by 66% (p ? 0.001). IAP supplementation increased IAP mRNA expression to control. Supplemental enteral IAP decreased nitrosative stress as measured by iNOS mRNA expression and 3-NT staining in the NEC stressed pups (p ? 0.01), as well as decreased intestinal TNF-? mRNA expression. In addition, IAP decreased LSP translocation into the serum in the treated pups.We conclude that enterally administered IAP prevents NEC-related intestinal injury and inflammation. Enteral IAP may prove a useful strategy in the prevention of NEC in preterm neonates.

SUBMITTER: Rentea RM

PROVIDER: S-EPMC5664149 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Enteral intestinal alkaline phosphatase administration in newborns decreases iNOS expression in a neonatal necrotizing enterocolitis rat model.

Rentea Rebecca M RM Liedel Jennifer L JL Liedel Jennifer L JL Fredrich Katherine K Pritchard Kirkwood K Oldham Keith T KT Simpson Pippa M PM Gourlay David M DM

Journal of pediatric surgery 20130101 1

<h4>Purpose</h4>To determine if intestinal alkaline phosphatase (IAP) decreases intestinal injury resulting from experimentally induced necrotizing enterocolitis (NEC). We hypothesized that IAP administration prevents the initial development of NEC related intestinal inflammation.<h4>Methods</h4>Pre- and full-term newborn Sprague-Dawley rat pups were sacrificed on day 1 of life. Pre-term pups were exposed to intermittent hypoxia and formula containing LPS to induce NEC. Select NEC pups were give ...[more]

PMID: 23331804

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Project description:Inflammation in the premature intestine is a key factor that leads to the development of necrotizing enterocolitis (NEC). Activation of nuclear factor kappa B (NF-?B) and subsequent inflammation increases the severity of NEC. The aim of this study was to investigate the early temporal expression of inflammatory markers and activation of NF-?B in a neonatal rat model of NEC.Pre- and full-term newborn Sprague-Dawley rat pups were sacrificed at birth, 1.5, 4, 8, and 24 hours after receiving their first feed. Control pups were vaginally delivered and mother fed; NEC was induced by a combination of gavage feeding formula, hypoxia, and enteral lipopolysaccharide (LPS); and formula fed pups were fed every 4 hours with infant formula. Ileal tissue was collected for immunohistochemistry, real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay. Serum was collected for cytokine content. Fold change of expression of inducible nitric oxide synthase (iNOS), interleukin (IL)-1?, IL-6, tumor necrosis factor-? (TNF-?), IL-10, NF-?B p65, and I?B? used RT-PCR. Data were analyzed by paired two-tailed t test, expressed as mean ± standard error of the mean, and p ? 0.05 considered significant.No histologic injury was evident in ileal sections. At 1.5 h, iNOS expression increased twofold over control in NEC pups (2.1 vs. 1.0, p ? 0.05) and remained elevated at 24 h (0.7 vs. 9.4, p ? 0.05). IL-1? and IL-6 reached a peak at 24 h in NEC tissue compared with control. IL-10 expression rose in NEC pups after 4 h of insult and remained elevated in formula and NEC stressed pups. Coincident with an increase in p65 translocation into the nucleus and a reduction of I?B? detected in the cytoplasm, increased transcription of I?B? occurs.These findings suggest that NF-?B activation initiates inflammation early in the course of NEC resulting in increased proinflammatory protein expression, underscoring the importance of the inflammatory response in this NEC model, which precedes evidence of histological injury.

Project description:Importance:Necrotizing enterocolitis (NEC) in preterm infants is an often-fatal gastrointestinal tract emergency. A robust NEC biomarker that is not confounded by sepsis could improve bedside management, lead to lower morbidity and mortality, and permit patient selection in randomized clinical trials of possible therapeutic approaches. Objective:To evaluate whether aberrant intestinal alkaline phosphatase (IAP) biochemistry in infant stool is a molecular biomarker for NEC and not associated with sepsis. Design, Setting, and Participants:This multicenter diagnostic study enrolled 136 premature infants (gestational age, <37 weeks) in 2 hospitals in Louisiana and 1 hospital in Missouri. Data were collected and analyzed from May 2015 to November 2018. Exposures:Infant stool samples were collected between 24 and 40 or more weeks postconceptual age. Enrolled infants underwent abdominal radiography at physician and hospital site discretion. Main Outcomes and Measures:Enzyme activity and relative abundance of IAP were measured using fluorometric detection and immunoassays, respectively. After measurements were performed, biochemical data were evaluated against clinical entries from infants' hospital stay. Results:Of 136 infants, 68 (50.0%) were male infants, median (interquartile range [IQR]) birth weight was 1050 (790-1350) g, and median (IQR) gestational age was 28.4 (26.0-30.9) weeks. A total of 25 infants (18.4%) were diagnosed with severe NEC, 19 (14.0%) were suspected of having NEC, and 92 (66.9%) did not have NEC; 26 patients (19.1%) were diagnosed with late-onset sepsis, and 14 (10.3%) had other non-gastrointestinal tract infections. For severe NEC, suspected NEC, and no NEC samples, median (IQR) fecal IAP content, relative to the amount of IAP in human small intestinal lysate, was 99.0% (51.0%-187.8%) (95% CI, 54.0%-163.0%), 123.0% (31.0%-224.0%) (95% CI, 31.0%-224.0%), and 4.8% (2.4%-9.8%) (95% CI, 3.4%-5.9%), respectively. For severe NEC, suspected NEC, and no NEC samples, median (IQR) enzyme activity was 183 (56-507) μmol/min/g (95% CI, 63-478 μmol/min/g) of stool protein, 355 (172-608) μmol/min/g (95% CI, 172-608 μmol/min/g) of stool protein, and 613 (210-1465) μmol/min/g (95% CI, 386-723 μmol/min/g) of stool protein, respectively. Mean (SE) area under the receiver operating characteristic curve values for IAP content measurements were 0.97 (0.02) (95% CI, 0.93-1.00; P < .001) at time of severe NEC, 0.97 (0.02) (95% CI, 0.93-1.00; P < .001) at time of suspected NEC, 0.52 (0.07) (95% CI, 0.38-0.66; P = .75) at time of sepsis, and 0.58 (0.08) (95% CI, 0.42-0.75; P = .06) at time of other non-gastrointestinal tract infections. Mean (SE) area under the receiver operating characteristic curve values for IAP activity were 0.76 (0.06) (95% CI, 0.64-0.86; P < .001), 0.62 (0.07) (95% CI, 0.48-0.77; P = .13), 0.52 (0.07) (95% CI, 0.39-0.67; P = .68), and 0.57 (0.08) (95% CI, 0.39-0.69; P = .66), respectively. Conclusions and Relevance:In this diagnostic study, high amounts of IAP protein in stool and low IAP enzyme activity were associated with diagnosis of NEC and may serve as useful biomarkers for NEC. Our findings indicated that IAP biochemistry was uniquely able to distinguish NEC from sepsis.

Dataset Information

Enteral intestinal alkaline phosphatase administration in newborns decreases iNOS expression in a neonatal necrotizing enterocolitis rat model.

Publications

Enteral intestinal alkaline phosphatase administration in newborns decreases iNOS expression in a neonatal necrotizing enterocolitis rat model.

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