Necrotizing Enterocolitis Risk

Gephart, Sheila M.; McGrath, Jacqueline M.; Effken, Judith A.; Halpern, Melissa D.

doi:10.1097/anc.0b013e31824cee94

Cited by 210 publications

(205 citation statements)

References 79 publications

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“…The defining pathological feature of NEC is the presence of patchy areas of ischemia and necrosis of the small and large intestine (2). Although prematurity is the leading risk factor for NEC development, breast milk administration has been identified as the most important protective strategy (3). Importantly, the mechanisms that lead to the acute development of intestinal necrosis in the premature intestine and factors within breast milk that may prevent NEC remain largely unexplored.…”

mentioning

confidence: 99%

Endothelial TLR4 activation impairs intestinal microcirculatory perfusion in necrotizing enterocolitis via eNOS–NO–nitrite signaling

Yazji

Sodhi²,

Lee³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

199

171

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Necrotizing enterocolitis (NEC) is a devastating disease of premature infants characterized by severe intestinal necrosis and for which breast milk represents the most effective protective strategy. Previous studies have revealed a critical role for the lipopolysaccharide receptor toll-like receptor 4 (TLR4) in NEC development through its induction of mucosal injury, yet the reasons for which intestinal ischemia in NEC occurs in the first place remain unknown. We hypothesize that TLR4 signaling within the endothelium plays an essential role in NEC development by regulating perfusion to the small intestine via the vasodilatory molecule endothelial nitric oxide synthase (eNOS). Using a unique mouse system in which we selectively deleted TLR4 from the endothelium, we now show that endothelial TLR4 activation is required for NEC development and that endothelial TLR4 activation impairs intestinal perfusion without effects on other organs and reduces eNOS expression via activation of myeloid differentiation primary response gene 88. NEC severity was significantly increased in eNOS −/− mice and decreased upon administration of the phosphodiesterase inhibitor sildenafil, which augments eNOS function. Strikingly, compared with formula, human and mouse breast milk were enriched in sodium nitrate-a precursor for enteral generation of nitrite and nitric oxide-and repletion of formula with sodium nitrate/nitrite restored intestinal perfusion, reversed the deleterious effects of endothelial TLR4 signaling, and reduced NEC severity. These data identify that endothelial TLR4 critically regulates intestinal perfusion leading to NEC and reveal that the protective properties of breast milk involve enhanced intestinal microcirculatory integrity via augmentation of nitrate-nitrite-NO signaling.neonatal inflammation | prematurity | infant formula | neonatal nutrition | sepsis N ecrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in the premature infant and is gradually increasing in frequency (1). The defining pathological feature of NEC is the presence of patchy areas of ischemia and necrosis of the small and large intestine (2). Although prematurity is the leading risk factor for NEC development, breast milk administration has been identified as the most important protective strategy (3). Importantly, the mechanisms that lead to the acute development of intestinal necrosis in the premature intestine and factors within breast milk that may prevent NEC remain largely unexplored.In seeking to understand the underlying biological mechanisms that lead to NEC, we and others have identified a critical role for the innate immune receptor toll-like receptor 4 (TLR4) in NEC pathogenesis, because mice deficient in TLR4 showed reduced mucosal inflammation and reduced intestinal necrosis in experimental NEC (4, 5). Microcirculatory perfusion of the premature intestine is primarily regulated by the vasodilator nitric oxide (NO), which is generated through the activity of endothelial NO synthase (eNOS) (6). ...

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mentioning

confidence: 99%

Endothelial TLR4 activation impairs intestinal microcirculatory perfusion in necrotizing enterocolitis via eNOS–NO–nitrite signaling

Yazji

Sodhi²,

Lee³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

199

171

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“…Three factors are generally present when NEC occurs: (i) an immature intestinal barrier and immune system; (ii) enteral feedings; and (iii) a putative bacterial component. A genetic predisposition, an in utero maternal or fetal insult (hypoxia), and/or a highly immune-reactive intestinal mucosa may then cause the initial inflammation that precedes NEC (2).…”

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confidence: 99%

Heme oxygenase-1 confers protection and alters T-cell populations in a mouse model of neonatal intestinal inflammation

et al. 2015

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Background: Necrotizing enterocolitis (NEC), an intestinal inflammatory disease affecting premature infants, is associated with low regulatory T (Treg) to effector T (Teff ) cell ratios. We recently demonstrated that heme oxygenase-1 (HO-1) deficiency leads to increased NEC development. Here, we investigated the effects of HO-1 on T-cell proportions in a murine NEC-like injury model. Methods: Intestinal injury was induced in 7-d-old wildtype (WT) or HO-1 heterozygous (HO-1 Het) pups by formulafeeding every 4 h for 24-78 h by oral gavage and exposures to 5%O 2 . Controls remained breastfed. HO-1 was induced in WT pups by administering heme preinjury induction. Lamina propria T cells were identified by flow cytometry. For adoptive transfer studies, WT splenic/thymic Tregs were injected intraperitoneally into HO-1 Het pups 12-24 h preinduction. results: Het mice showed increased intestinal injury and decreased Treg/Teff ratios. Genes for pattern recognition (Toll-like receptor-4, C-reactive protein, MyD88) and neutrophil recruitment increased in Het pups after NEC induction. Inducing intestinal HO-1 decreased NEC scores and incidence, and increased Treg/Teff ratios. Moreover, adoptive transfer of Tregs from WT to HO-1 Het pups decreased NEC scores and incidence and restored Treg/Teff ratios. conclusion: HO-1 can change Treg proportions in the lamina propria of young mice under inflammatory conditions, which might, in part, confer intestinal protection.n EC is a devastating disease of premature infants.Characterized by intestinal inflammation, it can progress rapidly to intestinal necrosis. Its incidence correlates inversely with low birth weight and gestational age, reaching ~7% in infants weighing 500-1,500 g. Unfortunately, 20-40% of NEC patients need to undergo surgery, which increases mortality up to 50% and places these infants at higher risk for developing long-term sequelae, such as short bowel syndrome and neurodevelopmental impairments (1).Although advances in the understanding of its pathophysiology have been made in the last decades, the pathogenesis of NEC remains incompletely understood. Thus, current prevention and treatment strategies are limited. Three factors are generally present when NEC occurs: (i) an immature intestinal barrier and immune system; (ii) enteral feedings; and (iii) a putative bacterial component. A genetic predisposition, an in utero maternal or fetal insult (hypoxia), and/or a highly immune-reactive intestinal mucosa may then cause the initial inflammation that precedes NEC (2).Several studies have demonstrated the importance of the innate immune system in the pathophysiology of NEC. For example, a significant component is the pattern recognition of pathogens through Toll-like receptor (TLR)-4 (3,4). Also, a reduction in Paneth and in mucin-producing goblet cells (5,6) and an increase in proinflammatory mediators (i.e., TNF-α, IL-1, -6, -8, and platelet-activating factor) are associated with NEC (7).However, less attention has been given to the adaptive immune system. The fact th...

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“…NEC is observed primarily in premature infants although 10% of those affected are infants born at full term or near term. The incidence is inversely proportional to birth weight and gestational age with more common in infants of younger gestational age [8]. According to Neu and Walker, NEC does not occur until at least 8-10 days postpartum.…”

Section: Editorialmentioning

confidence: 99%

“…Despite advances in perinatal care over the recent years, the incidence and prognosis of newborns with NEC have not improved showing a mortality rate nearing 30% [8]. Furthermore, survivors of NEC have poorer long-term growth and neuro developmental outcomes.…”

Section: Editorialmentioning

confidence: 99%

Necrotizing Enterocolitis: Refocusing Efforts on Prevention

Codipilly¹

2016

MOJI

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Necrotizing enterocolitis (NEC) is a life-threatening disease affecting preterm, very low birth weight infants which warrants emergency medical and/or surgical intervention, often in Neonatal Intensive Care Units (NICU). NEC incidence is inversely proportional to birth weight and is more common in infants of younger gestational age. Though its etiology is not well understood, research suggests a bacterial element as the major role player in its pathogenesis. Among other causatives diet, under developed intestines, and use of enteral feedings are some being implied. To date, many preventive approaches have been suggested, introduced, and implemented though with no real success achieved.

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Necrotizing Enterocolitis Risk

Cited by 210 publications

References 79 publications

Endothelial TLR4 activation impairs intestinal microcirculatory perfusion in necrotizing enterocolitis via eNOS–NO–nitrite signaling

Endothelial TLR4 activation impairs intestinal microcirculatory perfusion in necrotizing enterocolitis via eNOS–NO–nitrite signaling

Heme oxygenase-1 confers protection and alters T-cell populations in a mouse model of neonatal intestinal inflammation

Necrotizing Enterocolitis: Refocusing Efforts on Prevention

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