Prevention of necrotizing enterocolitis in the rat with prenatal cortisone

Israël, E; Schiffrin, E.J.; Carter, E A; Freiberg, E.K.; Walker, W. Allan

doi:10.1016/0016-5085(90)91158-3

Cited by 74 publications

(26 citation statements)

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“…Examples of this include glucocorticoidinduced expression of digestive enzymes, glucocorticoid increased goblet cell numbers, and glucocorticoid-induced thickening of the mucosa (4 -8). Administration of glucocorticoids also has been associated with a decreased incidence of necrotizing enterocolitis in premature infants and rat pups (9,10). Taken together, these findings suggest that steroids can induce precocious maturation of the bowel mucosa.…”

mentioning

confidence: 74%

Dexamethasone Administration to Newborn Mice Alters Mucosal and Muscular Morphology in the Ileum and Modulates IGF-I Localization

2001

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Glucocorticoid exposure accelerates the maturation of small bowel mucosa. We hypothesized that IGF-I, a mitogen and differentiating peptide expressed in small bowel, mediates steroid-induced change within the developing ileum. To investigate this possibility, we intraperitoneally administered 1 g/gm/d of dexamethasone (DEX) or equal volumes of saline to litter-mate newborn mice. The animals were killed on d 1-3 of life and their ileums were harvested and prepared for microscopy. Tissue sections of ileum were examined for morphologic analyses, mucin staining, immunolocalization of IGF-I and -II, proliferating cell nuclear antigen (PCNA), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and in situ hybridization for IGF-I transcripts. Morphologic comparisons showed increases in goblet cell number, total cell number, and TUNEL-positive cells within the mucosa of DEX-treated animals. In contrast, the number of smooth muscle nuclei per cross-section was unchanged with DEX treatment despite a reduction in the number of PCNA-positive nuclei and an increased bowel circumference. These findings suggest the muscularis stretches to accommodate increasing bowel diameter. IGF-I peptide was localized to the mesenchyme of all control animals. After 48 h of DEX treatment, IGF-I was detected in the epithelia whereas mesenchymal IGF-I localization appeared diminished. In situ hybridization analyses for IGF-I transcripts showed no differences in localization between the groups. We conclude that DEX administration differentially affects adjacent tissues in the newborn ileum and that the associated changes in IGF-I localization are consistent with its participation in this process. The fetal small bowel undergoes rapid maturation during the latter third of gestation by increasing villus length, mucosal thickness, goblet cell number, lumen diameter, and smooth muscle thickness. Cell proliferation, differentiation, and turnover must be coordinated by local growth factors for these changes to occur. The IGFs, with their known actions on cell proliferation, cell differentiation, cell motility, matrix production, and cell survival are logical candidates for participation in this process.There are two forms of IGF. IGF-II is abundant in fetal tissue but rapidly wanes around the time of birth and is increasingly difficult to detect thereafter. IGF-I has been shown to be important for both growth and repair within developing and mature bowel models (1-3). For example, transgenic mice that overexpress IGF-I have longer small bowel length and increased mucosal mass when compared with controls. Likewise, i.v. IGF-I has been shown to rescue mucosal and villus atrophy in mature rodents receiving prolonged parental nutrition. Finally, IGF-I has been demonstrated to be a potent promoter of mucosal growth after bowel resection. Collectively, these findings suggest a central role for IGF-I in growthrelated phenomena of the bowel mucosa.Glucocorticoids also affect the growth and differentiation of the bowel mucosa. Examp...

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confidence: 74%

Dexamethasone Administration to Newborn Mice Alters Mucosal and Muscular Morphology in the Ileum and Modulates IGF-I Localization

2001

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“…In support of these mucosal changes are reports that steroids accelerate maturation of the mucosa in rats 14 and reduce the incidence of NEC in premature infants and in rat pups by enhancing mucosal barrier function. 15,16 In support of smooth muscle developmental perturbation is a report that dexamethasone alters collagen and collagenase mRNA expression in human intestinal smooth muscle cells 17 and collagen expression in rat small intestine. 14 The developmental effects of dexamethasone might also be compounded by other agents that affect cell signaling or second messenger function, such as indomethacin, caffeine, betamethasone, or ranitidine.…”

Section: Discussionmentioning

confidence: 99%

Early Postnatal Dexamethasone Increases the Risk of Focal Small Bowel Perforation in Extremely Low Birth Weight Infants

et al. 1999

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OBJECTIVE:We observed two clusters of spontaneous pneumoperitoneums in extremely low birth weight infants during the use of a protocol for early dexamethasone prophylaxis (EDP) for bronchopulmonary dysplasia from 1996 to 1997. During surgery, focal small bowel perforation (FSBP) was found in eight of nine cases. A retrospective study was designed to identify risk factors for FSBP in these extremely low birth weight infants. METHODS:A case-controlled analysis was performed using all infants born weighing Ͻ1001 gm and admitted to the University of Washington Medical Center Neonatal Intensive Care Unit during a 13-month period. A total of 51 infants were identified and divided into groups based on treatment or not with dexamethasone and indomethacin. These cohorts were homogeneous for gestational age, birth weight, and perinatal stability. Relative risk and confidence intervals were calculated for each of the comparisons. Routine pathology was performed on all surgical specimens and additional sections were cut and stained for further study. RESULTS:Infants who received EDP had a relative risk of perforation that was 12.3 times that of untreated infants. Those treated with indomethacin had a risk that was comparable with that for infants who did not receive indomethacin. Infants who received both EDP and indomethacin tended to have higher rates of pneumoperitoneum than infants who received EDP alone but comprised a cohort too small for valid analysis. The pathology of surgical specimens revealed FSBP with segmental loss of the muscularis externa. There was no evidence of fungal or bacterial infection in any of the surgical specimens. CONCLUSION:These findings implicate EDP, but not indomethacin, as a significant risk factor for FSBP.Focal small bowel perforation (FSBP) is a sporadic problem occurring in premature infants. It is often clinically mistaken for perforation secondary to necrotizing enterocolitis (NEC). 1 Case reports of FSBP have associated this disorder with hypoxic-ischemic injury, 2,3 congenital absence of the muscularis externa, 4 -6 indomethacin, 7,8 dexamethasone, 9,10 and candidal infection. 11 Risk factors for FSBP have also been postulated to be multifactorial. 1 Unfortunately, evidencebased research on FSBP is scant.In late 1996 and mid 1997, two clusters of FSBP occurred in extremely low birth weight (ELBW) infants at the University of Washington Medical Center (UWMC) neonatal intensive care unit (NICU). These clusters coincided with the onset of a standardized protocol for early dexamethasone prophylaxis (EDP) in premature infants at risk for bronchopulmonary dysplasia. During the first month, four infants who received EDP required urgent surgery for pneumoperitoneum and were found to have FSBP. The EDP protocol was suspended pending review of the cases and literature.Review of the literature failed to find any reports of FSBP occurring in clusters. Review of all neonatal surgical cases in the previous 6 months revealed two more infants with FSBP who also weighed Ͻ1001 gm. Indomethacin proph...

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“…Antenatal glucocorticoid therapy has beneficial effects by suppressing inflammation and promoting gastrointestinal maturation and function including reduced mucosal uptake of macromolecules, decreased colonization with aerobic bacteria, reduced bacterial translocation, and increased activity of enzymes such as lactase, maltase, sucrase, and Na/K-ATPase [148,149] . A significant reduction in the incidence and risk of NEC following antenatal glucocorticoid therapy has been reported in several large, randomized control trials [150,151] .…”

Section: Antenatal Glucocorticoidsmentioning

confidence: 99%

Necrotizing enterocolitis: A multifactorial disease with no cure

Schnabl

Aerde²,

Thomson³

et al. 2008

WJG

163

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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Prevention of necrotizing enterocolitis in the rat with prenatal cortisone

Cited by 74 publications

References 20 publications

Dexamethasone Administration to Newborn Mice Alters Mucosal and Muscular Morphology in the Ileum and Modulates IGF-I Localization

Dexamethasone Administration to Newborn Mice Alters Mucosal and Muscular Morphology in the Ileum and Modulates IGF-I Localization

Early Postnatal Dexamethasone Increases the Risk of Focal Small Bowel Perforation in Extremely Low Birth Weight Infants

Necrotizing enterocolitis: A multifactorial disease with no cure

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