Abnormal Intestinal Histology in Neonates with Congenital Anomalies of the Gastrointestinal Tract

Condino, Adria A.; Barleycorn, Aaron A.; Lu, Wenzhe; Maheshwari, Akhil; Christensen, Robert D.; Calhoun, Darlene A

doi:10.1159/000075064

Cited by 31 publications

(23 citation statements)

References 32 publications

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“…Using a fetal sheep model, Trahair and Harding (36) showed that experimental obstruction of the fetal esophagus or the small intestine caused ultrastructural abnormalities in IECs such as delayed disappearance of the apical endocytic network, disrupted or absent microvilli, glycogen accumulation, and inappropriate cell extrusion. Similarly, we have previously shown that human neonates with congenital intestinal obstruction have histopathological abnormalities such as villus blunting and loss of crypt depth with abnormal crypt organization (10). In undifferentiated 15-day murine fetal duodenal explants, rat amniotic fluid extracts have been shown to induce IEC proliferation and promote crypt and villus formation (23).…”

Section: Discussionmentioning

confidence: 85%

Amniotic fluid-borne hepatocyte growth factor protects rat pups against experimental necrotizing enterocolitis

Jain

Baggerman

MohanKumar

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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fluid-borne hepatocyte growth factor protects rat pups against experimental necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 306: G361-G369, 2014. First published January 9, 2014; doi:10.1152/ajpgi.00272.2013.-Fetal swallowing of amniotic fluid, which contains numerous cytokines and growth factors, plays a key role in gut mucosal development. Preterm birth interrupts this exposure to amniotic fluid-borne growth factors, possibly contributing to the increased risk of necrotizing enterocolitis (NEC) in premature infants. We hypothesized that supplementation of formula feeds with amniotic fluid can provide amniotic fluid-borne growth factors and prevent experimental NEC in rat pups. We compared NEC-like injury in rat pups fed with infant formula vs. formula supplemented either with 30% amniotic fluid or recombinant hepatocyte growth factor (HGF). Cytokines/growth factors in amniotic fluid were measured by immunoassays. Amniotic fluid and HGF effects on enterocyte migration, proliferation, and survival were measured in cultured IEC6 intestinal epithelial cells. Finally, we used an antibody array to investigate receptor tyrosine kinase (RTK) activation and immunoblots to measure phosphoinositide 3-kinase (PI3K) signaling. Amniotic fluid supplementation in oral feeds protected rat pups against NEC-like injury. HGF was the most abundant growth factor in rat amniotic fluid in our panel of analytes. Amniotic fluid increased cell migration, proliferation, and cell survival in vitro. These effects were reproduced by HGF and blocked by anti-HGF antibody or a PI3K inhibitor. HGF transactivated several RTKs in IEC6 cells, indicating that its effects extended to multiple signaling pathways. Finally, similar to amniotic fluid, recombinant HGF also reduced the frequency and severity of NEC-like injury in rat pups. Amniotic fluid supplementation protects rat pups against experimental NEC, which is mediated, at least in part, by HGF. amniotic fluid; NEC; HGF; inflammation; phosphoinositide 3-kinase NECROTIZING ENTEROCOLITIS (NEC), an inflammatory bowel necrosis of preterm infants, is a leading cause of death among neonates born before 32 wk of gestation or with a birth weight Ͻ1,500 g (20, 27). Although the etiology of NEC remains unclear, epidemiological studies show an association with diverse risk factors such as maternal chorioamnionitis, perinatal asphyxia, indomethacin therapy, viral infections, and blood transfusions (20). Current pathophysiological models suggest that NEC occurs when altered/disrupted epithelial barrier in the preterm intestine allows luminal bacteria to translocate across the epithelial barrier into the lamina propria, triggering a severe mucosal inflammatory response and tissue damage (21).During intrauterine development, the fetus ingests progressively large volumes of amniotic fluid, which contains several cytokines and growth factors known to promote gut mucosal development (19). In the third trimester, the human fetus swallows nearly 550 ml/day amniotic fluid (29, 40). We hypothesiz...

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Section: Discussionmentioning

confidence: 85%

Amniotic fluid-borne hepatocyte growth factor protects rat pups against experimental necrotizing enterocolitis

Jain

Baggerman

MohanKumar

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Consistent with these findings, human neonates with congenital intestinal obstruction also show villus blunting and shallow, poorly organized crypts distal to the site of obstruction. 13 In Trahair’s model, the mucosal defects were gradually reversed following the removal of esophageal ligatures and restitution of AF ingestion but not by the infusion of Ringer’s lactate, indicating that the “trophic” effects of AF were secondary to the bioactive molecules present in AF and not merely due to the flow of fluid through the gut lumen. 14 …”

Section: Cytokines In the Developing Intestinementioning

confidence: 99%

Cytokines and growth factors in the developing intestine and during necrotizing enterocolitis

MohanKumar¹,

Namachivayam²,

Ho³

et al. 2017

Seminars in Perinatology

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Cytokines and growth factors play diverse roles in the uninflamed fetal/neonatal intestinal mucosa and in the development of inflammatory bowel injury during necrotizing enterocolitis (NEC). During gestational development and the early neonatal period, the fetal/premature intestine is exposed to high levels of many “inflammatory” cytokines and growth factors, first via swallowed amniotic fluid in utero and then, after birth, in colostrum and mother’s milk. This article reviews the dual, seemingly counter-intuitive roles of cytokines, where these agents play a “trophic” role and promote maturation of the uninflamed mucosa, but can also cause inflammation and promote intestinal injury during NEC.

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“…[15][16][17] Experiments of Karnak 16 and Trahair 17 showed that the beneficial effect of swallowed amniotic fluid on bowel development comes from the enterocyte growth factors within the fluid, not from the liquid itself. The enterocyte growth factors present in amniotic fluid are also present in colostrum and human milk.…”

Section: Discussionmentioning

confidence: 99%

Treating feeding intolerance with an enteral solution patterned after human amniotic fluid: a randomized, controlled, masked trial

et al. 2006

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Objective: Feeding intolerance is a common problem in the neonatal intensive care unit (NICU) and some cases might be causally related to atrophic changes in the small bowel mucosa. We speculated that for such patients, feeding tolerance might improve after oral administration of enterocyte growth factors in a sterile, isotonic solution patterned after amniotic fluid.Study Design: Twenty neonates meeting criteria for feeding intolerance were eligible for this trial. They were randomized to either Group 1 (test solution) or Group 2 (control). Group 1 received 2.5 ml of test solution/kg every 3 h by oral-gastric or nasal-gastric (OG/NG) tube. This was begun when the patient was NPO because of feeding intolerance and continued until 80 ml/k/day of milk feedings were tolerated, or for a maximum of 7 days. Group 2 received a sham OG/NG administration every 3 h, until 80 ml/k/day of milk feedings were tolerated, or for a maximum of 7 days. Only the bedside nurse and the NICU pharmacist were aware which patients received the test solution and which received the sham administrations. The volumes of milk feedings were increased by order of the attending neonatologist and nurse practitioner. The study outcome was enteral calories/kg/day during and for 7 days after the cessation of the treatments.Results: Eleven patients were randomized to receive the test solution and nine to receive sham administrations. At study entry, the two groups were not different in gestational age, postnatal age, signs of feeding intolerance or cal/k/day taken enterally during the previous 3 days. The study doses were given for an average of just under 6 days (range, 2 to 7 days). During the week following the administrations, the test solution recipients trended toward more enteral calories. Specifically, they had an increase averaging 78±20.8 cal/k/day more than before the study, whereas the sham recipients had an increase averaging 55.9±33 cal/k/day more than before the study (P ¼ 0.05 for a one-sided test and P ¼ 0.10 for a two-sided test). The test solution recipients also had a trend toward fewer formula changes than did the sham recipients (P ¼ 0.10). Conclusion:In this small, randomized, controlled, masked trial, the administration of a sterile, non-caloric, growth factor containing solution patterned after human amniotic fluid was associated with trends that we interpret as reflecting better tolerance of milk feedings. On this basis, we suggest that a phase III efficacy trial should be accomplished, using the present data for sample size calculations.

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Abnormal Intestinal Histology in Neonates with Congenital Anomalies of the Gastrointestinal Tract

Cited by 31 publications

References 32 publications

Amniotic fluid-borne hepatocyte growth factor protects rat pups against experimental necrotizing enterocolitis

Amniotic fluid-borne hepatocyte growth factor protects rat pups against experimental necrotizing enterocolitis

Cytokines and growth factors in the developing intestine and during necrotizing enterocolitis

Treating feeding intolerance with an enteral solution patterned after human amniotic fluid: a randomized, controlled, masked trial

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