Molecular Mechanisms Contributing to Necrotizing Enterocolitis

Chung, Dai H.; Ethridge, Richard T.; Kim, Sung Hoon; Owens-Stovall, Sharla; Hernandez, Ambrosio; Kelly, David R.; Evers, B. Mark

doi:10.1097/00000658-200106000-00014

Cited by 57 publications

(46 citation statements)

References 36 publications

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“…However, the role of COX-2 in NEC pathogenesis is still not clear. High levels of intestinal COX-2 are reported in animal models of NEC, suggesting its pathogenic effects during intestinal inflammation (6,17). Conversely, administration of a COX-2 inhibitor results in a higher degree of intestinal inflammation in the rat NEC model (17), and studies with COX-2 knockout mice describe increased intestinal damage compared with wildtype controls (40).…”

Section: Discussionmentioning

confidence: 99%

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Bifidobacterium bifidum reduces apoptosis in the intestinal epithelium in necrotizing enterocolitis

Khailová

Patrick

Arganbright

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

132

100

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Necrotizing enterocolitis (NEC) is a devastating intestinal disease of neonates, and clinical studies suggest the beneficial effect of probiotics in NEC prevention. Recently, we have shown that administration of Bifidobacterium bifidum protects against NEC in a rat model. Intestinal apoptosis can be suppressed by activation of cyclooxygenase-2 (COX-2) and increased production of prostaglandin E2 (PGE2). The present study investigates the effect of B. bifidum on intestinal apoptosis in the rat NEC model and in an intestinal epithelial cell line (IEC-6), as a mechanism of protection against mucosal injury. Premature rats were divided into the following three groups: dam fed, hand fed with formula (NEC), or hand fed with formula supplemented with B. bifidum (NEC + B. bifidum ). Intestinal Toll-like receptor-2 (TLR-2), COX-2, PGE2, and apoptotic regulators were measured. The effect of B. bifidum was verified in IEC-6 cells using a model of cytokine-induced apoptosis. Administration of B. bifidum increased expression of TLR-2, COX-2, and PGE2 and significantly reduced apoptosis in the intestinal epithelium of both in vivo and in vitro models. The Bax-to-Bcl-w ratio was shifted toward cell survival, and the number of cleaved caspase-3 positive cells was markedly decreased in B. bifidum -treated rats. Experiments in IEC-6 cells showed anti-apoptotic effect of B. bifidum . Inhibition of COX-2 signaling blocked the protective effect of B. bifidum treatment in both in vivo and in vitro models. In conclusion, oral administration of B. bifidum activates TLR-2 in the intestinal epithelium. B. bifidum increases expression of COX-2, which leads to higher production of PGE2 in the ileum and protects against intestinal apoptosis associated with NEC. This study indicates the ability of B. bifidum to downregulate apoptosis in the rat NEC model and in IEC-6 cells by a COX-2-dependent matter and suggests a molecular mechanism by which this probiotic reduces mucosal injury and preserves intestinal integrity.

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Section: Discussionmentioning

confidence: 99%

“…Whereas high levels of intestinal COX-2 are reported in both human (6) and experimental (6,17) NEC, the role of COX-2 and PGE 2 in NEC pathogenesis is still controversial and not fully understood (31).…”

mentioning

confidence: 99%

Bifidobacterium bifidum reduces apoptosis in the intestinal epithelium in necrotizing enterocolitis

Khailová

Patrick

Arganbright

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

132

100

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“…These include inducing hypoxia for 5 min followed by 10 min with 100% oxygen [133] , hypoxia for 50 s followed by cold exposure [134] , superior mysenteric artery clamping with or without PAF [135] , intraarterial injection of TNF-α [136] , and placing rats into a 100% nitrogen or 10% oxygen environment [24] . Finally, a rat model has been described by Chan [137] who created intestinal ischemia by increasing intraluminal pressure and injecting E. coli into the lumen.…”

Section: Nec Modelsmentioning

confidence: 99%

Necrotizing enterocolitis: A multifactorial disease with no cure

Schnabl

Aerde²,

Thomson³

et al. 2008

WJG

160

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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“…However, in response to various proinflammatory stimuli, COX-2 is rapidly induced. An increase in COX-2 protein expression was noted in the perforated intestinal sections of all 36 neonates examined in the study by Chung et al (13). High intestinal COX levels have been identified in an animal model of NEC (7,13).…”

Section: Discussionmentioning

confidence: 86%

“…NEC is predominately a disease of premature infants. In recent years, its incidence has become more prevalent with the increasing survival of low-birth weight premature infants (13). The pathogenesis of NEC continues to be investigated, however, the unifying hypothesis includes mucosal injury of the small intestine, followed by bacterial translocation and an amplified inflammatory response to endotoxin (14).…”

Section: Discussionmentioning

confidence: 99%

Role of cyclooxygenase-2 in intestinal injury in neonatal rats

Lü

Zhu

2014

Biomedical Reports

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Abstract. Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in premature neonates. The pathogenesis of NEC remains poorly understood. The present study aimed to investigate the dynamic change and role of cyclooxygenase-2 (COX-2) in neonatal rats with intestinal injury. Wistar rats, <24 h in age, received an intraperitoneal injection with 5 mg/kg lipopolysaccharide (LPS). Ileal tissues were collected at 1, 3, 6, 12 and 24 h following the LPS challenge for histological evaluation of NEC and for measurements of COX-2 mRNA. The correlation between the degree of intestinal injury and expression of COX-2 mRNA was determined. The LPS-injected pups showed a significant increase in injury scores compared to the control, and the most deteriorating change was at 12 h. COX-2 mRNA expression was upregulated following LPS injection. There was a significantly positive correlation between COX-2 mRNA and the grade of intestinal injury within 12 h, whereas COX-2 mRNA expression had a significantly negative correlation with the severity of intestinal injury at 24 h. COX-2 plays an important role in LPS-induced intestinal injury and the repair processes. Caution should be exerted concerning the potential therapeutic uses of COX-2 inhibitors or promoters in NEC.

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Molecular Mechanisms Contributing to Necrotizing Enterocolitis

Cited by 57 publications

References 36 publications

Bifidobacterium bifidum reduces apoptosis in the intestinal epithelium in necrotizing enterocolitis

Bifidobacterium bifidum reduces apoptosis in the intestinal epithelium in necrotizing enterocolitis

Necrotizing enterocolitis: A multifactorial disease with no cure

Role of cyclooxygenase-2 in intestinal injury in neonatal rats

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