Neonatal necrotizing enterocolitis: an overview

Kafetzis, Dimitris A.; Skevaki, Chrysanthi; Costalos, Christos

doi:10.1097/00001432-200308000-00007

Cited by 128 publications

(99 citation statements)

References 73 publications

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“…3). Other proinflammatory cytokines may act to impair enterocyte migration as well, 2 suggesting that the combined effects of the proinflammatory milieu adversely affect intestinal restitution. The current study focuses on the specific role of endotoxin, since it is expected to act much earlier than the other cytokines and is likely to be present at very high levels after bacterial translocation has occurred.…”

Section: Discussionmentioning

confidence: 99%

“…Necrotizing enterocolitis (NEC) 1 is the leading cause of death from gastrointestinal disease in neonates and is second to respiratory disease as the overall leading cause of morbidity and mortality in this population (1)(2)(3). Clinical manifestations of NEC include abdominal distention, feeding intolerance, and systemic sepsis, which result from the destruction of the intestinal barrier (4,5).…”

mentioning

confidence: 99%

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Endotoxin Inhibits Intestinal Epithelial Restitution through Activation of Rho-GTPase and Increased Focal Adhesions

Çetin

Ford

Sysko

et al. 2004

Journal of Biological Chemistry

130

145

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Diseases of gut inflammation such as neonatal necrotizing enterocolitis (NEC) result after an injury to the mucosal lining of the intestine, leading to translocation of bacteria and endotoxin (lipopolysaccharide). Intestinal mucosal defects are repaired by the process of intestinal restitution, during which enterocytes migrate from healthy areas to sites of injury. In an animal model of NEC, we determined that intestinal restitution was significantly impaired compared with control animals. We therefore sought to determine the mechanisms governing enterocyte migration under basal conditions and after an endotoxin challenge. Here we show that the cytoskeletal reorganization and stress fiber formation required for migration in IEC-6 enterocytes requires RhoA. Enterocytes were found to express the endotoxin receptor Toll-like receptor 4, which served to bind and internalize lipopolysaccharide. Strikingly, endotoxin treatment significantly inhibited intestinal restitution, as measured by impaired IEC-6 cell migration across a scraped wound. Lipopolysaccharide was found to increase RhoA activity in a phosphatidylinositol 3-kinasedependent manner, leading to an increase in phosphorylation of focal adhesion kinase and an enhanced number of focal adhesions. Importantly, endotoxin caused a progressive, RhoA-dependent increase in cell matrix tension/contractility, which correlated with the observed impairment in enterocyte migration. We therefore conclude that endotoxin inhibits enterocyte migration through a RhoA-dependent increase in focal adhesions and enhanced cell adhesiveness, which may participate in the impaired restitution observed in experimental NEC.Necrotizing enterocolitis (NEC) 1 is the leading cause of death from gastrointestinal disease in neonates and is second to respiratory disease as the overall leading cause of morbidity and mortality in this population (1-3). Clinical manifestations of NEC include abdominal distention, feeding intolerance, and systemic sepsis, which result from the destruction of the intestinal barrier (4, 5). Mucosal breakdown may occur as a result of a perinatal insult, such as hypoxia, which allows bacteria and bacterial by-products to breach the normally impermeable mucosal barrier and initiate a local and systemic inflammatory response (4,6,7,9). This causes the release of proinflammatory cytokines, including tumor necrosis factor, platelet-activating factor, nitric oxide, and endotoxin, which lead to further epithelial injury (10 -13). Following mucosal damage, healing occurs initially through the process of epithelial restitution, in which healthy enterocytes adjacent to the sites of injury migrate toward the denuded mucosa to bridge the defect (14 -18). We hypothesize that the intestinal barrier defect in NEC does not result from epithelial injury alone but also from impaired restitution. This paper focuses specifically on the process of enterocyte migration, which is the sine qua non of epithelial restitution and mucosal healing.Although a variety of cytokines may be importan...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Endotoxin Inhibits Intestinal Epithelial Restitution through Activation of Rho-GTPase and Increased Focal Adhesions

Çetin

Ford

Sysko

et al. 2004

Journal of Biological Chemistry

130

145

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“…Initial symptoms may be subtle and can include feeding intolerance (gastric residuals, bilious vomiting), bloody diarrhea, temperature instability, letharg y, apnea, bradycardia, decreased peripheral perfusion, delayed gastric emptying, ileus, abdominal distension, or tenderness and respiratory stress [1,9,10] . Nonspecific laboratory abnormalities can include neutropenia, thrombocytopenia, hyponatriemia, hyperglycemia, metabolic acidosis, and bacteria or infectious products isolated from blood, urine, or stool [9,11] . Serial C-reactive protein could be useful in the management of the disease.…”

Section: Introductionmentioning

confidence: 99%

Necrotizing enterocolitis: A multifactorial disease with no cure

Schnabl

Aerde²,

Thomson³

et al. 2008

WJG

161

120

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INTRODUCTIONNecrotizing enterocolitis (NEC) is an inflammatory bowel disease of neonates and remains one of the most common gastrointestinal emergencies in newborn infants [1] . Onset of NEC is often within the first three months of life and neonates who are of extremely low birth weight (< 1000 g) and under 28 wk gestation are the most susceptible [2] . Full term neonates account for 10% of all NEC cases while premature infants account for 90% [3] . With an incidence rate of 1%-5% for all newborns admitted to the NICU [1] , a prevalence of 7%-14% of very low birth weight infants (VLBW, 500-1500 g) [4] and a mortality rate approaching 20%-50% [5] , NEC continues to represent a significant clinical problem. In Canada, the incidence rate is 1.8 per 100 live births with a prevalence of 7% of VLBW infants [1] . Advances in obstetric and neonatal care have improved survival rates for smaller, more immature infants, and as more VLBW preterm infants survive the neonatal period, the population at risk for NEC increases [1] .No consistent association between sex, race, and rates of NEC has been identified. However, male VLBW infants and black infants are at greater risk of death [6] . Due to inadequate treatments and no effective preventative strategy, an estimated 20%-40% of babies with NEC require surgery [1] and 10%-30% experience significant morbidity including neurodevelopmental impairment, vision and hearing impairment, failure to thrive, feeding abnormalities, diarrhea, bowel obstruction, and short bowel syndrome [1,2,7] . The case fatality rate with surgical intervention is as high as 50% [1] . NEC is also a financial burden to the health care system with yearly hospital charges reported to be as high as $6.5 million in the US [8] . Thus, NEC continues to be an important health issue for preterm neonates. DIAGNOSIS Clinical signs and symptomsThe onset of NEC can occur suddenly within a few AbstractNecrotizing enterocolitis is an inflammatory bowel disease of neonates with significant morbidity and mortality in preterm infants. Due to the multifactorial nature of the disease and limitations in disease models, early diagnosis remains challenging and the pathogenesis elusive. Although preterm birth, hypoxic-ischemic events, formula feeding, and abnormal bacteria colonization are established risk factors, the role of genetics and vasoactive/inflammatory mediators is unclear. Consequently, treatments do not target the specific underlying disease processes and are symptomatic and surgically invasive. Breast-feeding is the most effective preventative measure. Recent advances in the prevention of necrotizing enterocolitis have focused on bioactive nutrients and trophic factors in human milk. Development of new disease models including the aspect of prematurity that consistently predisposes neonates to the disease with multiple risk factors will improve our understanding of the pathogenesis and lead to discovery of innovative therapeutics.

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“…The increasing awareness of the potential adverse effects of being born early to immature organ systems has led to many studies over recent years looking at the consequences of preterm birth on fetal organ development, such as in the lungs [12], brain [13,14], gastrointestinal tract [15], and the kidney [16][17][18][19]. The effects of preterm birth in the neonatal kidney form the focus of this review.…”

Section: Preterm Birthmentioning

confidence: 99%

Preterm Birth and/or Factors that Lead to Preterm Delivery: Effects on the Neonatal Kidney

Ryan¹,

Black²

2015

J Neonatal Biol

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Preterm birth (defined as birth prior to 37 completed weeks of gestation), occurs in approximately 10% of all births and is one of the leading causes of neonatal morbidity and mortality worldwide. Preterm infants are born at a time when kidney development is still ongoing, and consequently can lead to renal impairment (in both the short-term and long-term), as well as severe glomerular abnormalities in some preterm infants. Since the glomerular abnormalities are not present in all preterm kidneys, this suggests that it is not preterm birth per se that leads to the glomerular abnormalities but may relate to factors associated with the etiology of the premature delivery, or factors in neonatal care. In this review, we provide an overview of what is currently known of how prenatal and postnatal factors can potentially impact on the immature kidneys of infants born preterm.

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Neonatal necrotizing enterocolitis: an overview

Abstract: Keeping in mind that the key to confronting such a devastating disorder as necrotizing enterocolitis is early diagnosis and prevention, both clinically applicable and experimental advances are presented with the hope of improving the survival rates of patients affected.

Cited by 128 publications

References 73 publications

Endotoxin Inhibits Intestinal Epithelial Restitution through Activation of Rho-GTPase and Increased Focal Adhesions

Endotoxin Inhibits Intestinal Epithelial Restitution through Activation of Rho-GTPase and Increased Focal Adhesions

Necrotizing enterocolitis: A multifactorial disease with no cure

Preterm Birth and/or Factors that Lead to Preterm Delivery: Effects on the Neonatal Kidney

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