Article

Prenatal lipopolysaccharide increases postnatal intestinal injury in a rat model of necrotizing enterocolitis.

Department of Pediatrics at Centers for Cardiovascular Medicine, Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
Journal of pediatric gastroenterology and nutrition (impact factor: 2.18). 04/2009; 48(3):276-82. pp.276-82
Source: PubMed

ABSTRACT An increased incidence of necrotizing enterocolitis (NEC) has been noted in infants who are born to mothers with chorioamnionitis.
Our objective was to test the hypothesis that newborn rat pups born to mothers exposed to prenatal lipopolysaccharide during pregnancy would be more susceptible to intestinal injury in a rat model of NEC and that the increased intestinal injury is mediated by dysregulation of inducible nitric oxide synthase.
Time-dated pregnant Sprague-Dawley dams were given an intraperitoneal injection of either 2 mg/kg of lipopolysaccharide or vehicle. Rat pups from each group of dams were delivered at term and placed in a rat NEC model. A subset of pups was given either vehicle or aminoguanidine. Intestines were harvested and graded for degree of intestinal injury.
Maternal prenatal lipopolysaccharide exposure increased the frequency and severity of intestinal injury in the neonatal rat NEC model. Treatment with aminoguanidine significantly decreased plasma nitric oxide levels. Additionally, aminoguanidine significantly decreased intestinal injury.
Intestinal injury observed may be mediated via nitric oxide synthase dysregulation.

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    Article: Chorioamnionitis as a Risk Factor for Necrotizing Enterocolitis: A Systematic Review and Meta-Analysis.
    Jasper V Been, Sanne Lievense, Luc J I Zimmermann, Boris W Kramer, Tim G A M Wolfs
    [show abstract] [hide abstract]
    ABSTRACT: OBJECTIVE: To accumulate available evidence regarding the association between antenatal inflammation and necrotizing enterocolitis (NEC). STUDY DESIGN: A systematic literature search was performed using Medline, Embase, Cochrane Library, ISI Web of Knowledge, and reference hand searches. Human studies published in English that reported associations between chorioamnionitis or other indicators of antenatal inflammation and NEC were eligible. Relevant associations were extracted and reported. Studies reporting associations between histological chorioamnionitis (HC) and NEC, HC with fetal involvement and NEC, and clinical chorioamnionitis and NEC were pooled in separate meta-analyses. RESULTS: A total of 33 relevant studies were identified. Clinical chorioamnionitis was significantly associated with NEC (12 studies; n = 22 601; OR, 1.24; 95% CI, 1.01-1.52; P = .04; I(2) = 12%), but the association between HC and NEC was not statistically significant (13 studies; n = 5889; OR, 1.39; 95% CI, 0.95-2.04; P = .09; I(2) = 49%). However, HC with fetal involvement was highly associated with NEC (3 studies; n = 1640; OR, 3.29; 95% CI, 1.87-5.78; P ≤ .0001; I(2) = 10%). Selection based on study quality did not affect the results. No indications of publication bias were apparent. Multivariate analyses in single studies generally attenuated the reported associations. Several associations between other markers of antenatal inflammation and NEC are reported. CONCLUSION: Currently available evidence supports a role for antenatal inflammation in NEC pathophysiology. This finding emphasizes the need to further study the underlying mechanisms and evaluate potential interventions to improve postnatal intestinal outcomes.
    The Journal of pediatrics 08/2012; · 4.02 Impact Factor
  • Article: Poly(ADP-ribose) polymerase-1: a novel therapeutic target in necrotizing enterocolitis.
    Peter J Giannone, Alicia A Alcamo, Brandon L Schanbacher, Craig A Nankervis, Gail E Besner, John A Bauer
    [show abstract] [hide abstract]
    ABSTRACT: Necrotizing enterocolitis (NEC) is the most common gastrointestinal disease of infancy, afflicting 11% of infants born 22-28 wk GA. Both inflammation and oxidation may be involved in NEC pathogenesis through reactive nitrogen species production, protein oxidation, and DNA damage. Poly(ADP-ribose) polymerase-1 (PARP-1) is a critical enzyme activated to facilitate DNA repair using nicotinamide adenine dinucleotide (NAD+) as a substrate. However, in the presence of severe oxidative stress and DNA damage, PARP-1 overactivation may ensue, depleting cells of NAD+ and ATP, killing them by metabolic catastrophe. Here, we tested the hypothesis that NO dysregulation in intestinal epithelial cells during NEC leads to marked PARP-1 expression and that administration of a PARP-1 inhibitor (nicotinamide) attenuates intestinal injury in a newborn rat model of NEC. In this model, 56% of control pups developed NEC (any stage) versus 14% of pups receiving nicotinamide. Forty-four percent of control pups developed high-grade NEC (grades 3-4), whereas only 7% of pups receiving nicotinamide developed high-grade NEC. Nicotinamide treatment protects pups against intestinal injury incurred in the newborn rat NEC model. We speculate that PARP-1 overactivation in NEC may drive mucosal cell death in this disease and that PARP-1 may be a novel therapeutic target in NEC.
    Pediatric Research 03/2011; 70(1):67-71. · 2.70 Impact Factor
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Keywords

aminoguanidine
 
increased incidence
 
increased intestinal injury
 
inducible nitric oxide synthase
 
intestinal injury
 
Intestines
 
intraperitoneal injection
 
Maternal prenatal lipopolysaccharide exposure
 
necrotizing enterocolitis
 
neonatal rat NEC model
 
newborn rat pups
 
nitric oxide synthase dysregulation
 
plasma nitric oxide levels
 
pups
 
rat model
 
rat NEC model
 
Rat pups
 
subset
 
susceptible
 
Time-dated pregnant Sprague-Dawley dams
 

Peter J Giannone