Collateral Blood Flow in the Distal Ileum of Neonatal Piglets: A Clue to the Pathogenesis of Necrotizing Enterocolitis

Sibbons, Paul; Spitz, Lewis; Velzen, D. van

doi:10.3109/15513819209023278

Cited by 18 publications

(10 citation statements)

References 20 publications

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“…This is supported by the observed negative correlation between mucosal vWF density and surface density, although we cannot exclude the presence of wider capillaries in the caudal small intestine. A cranial-to-caudal decrease in intestinal blood flow has been reported in dogs (11), pigs (12,13), and humans (14). Based on our data, we suggest that blood flow gradients along the small intestine are related to the cranial-to-caudal decreasing gradients in mucosal vWF and/or eNOS, an endothelial enzyme responsible for the production of the main vasodilator NO in neonatal and premature animals (5,7,9).…”

Section: Alterations In the Intestinal Endothelium (Vwf) And Endothelsupporting

confidence: 68%

“…Since the caudal intestinal region of enterally fed piglets is characterized by a low microvascular density and low relative eNOS expression, this region is prone to develop hypoxia as soon as it becomes further stressed. This may explain why lesions in the neonatal small intestine under stressed or hypoxic conditions occur primarily in the caudal small intestine of rats (26 -28) and pigs (13,29,30). Similarly, in the present piglet model and in human NEC, lesions occur preferentially in the caudal regions, especially when the intestine has to cope with an inferior feeding such as formula (2,31).…”

Section: Alterations In the Intestinal Endothelium (Vwf) And Endothelmentioning

confidence: 55%

“…Although eNOS is constitutively expressed in the endothelium, both eNOS mRNA and protein expression can be modulated (10), including by nutrient intake (7). Furthermore, intestinal blood flow shows a cranial-tocaudal decrease along the small intestine in neonatal and adult dogs (11), pigs (12,13), and humans (14). It is, however, unknown whether this functional gradient in the small intestine is associated with a similar gradient in microvessel distribution and/or eNOS protein expression.…”

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confidence: 99%

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Enteral Feeding Reduces Endothelial Nitric Oxide Synthase in the Caudal Intestinal Microvasculature of Preterm Piglets

et al. 2008

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ABSTRACT:The initiation of enteral feeding represents a challenge to the neonatal intestinal microcirculation, especially in preterms where it predisposes to necrotizing enterocolitis (NEC). We hypothesized that a structural microvascular deficiency may occur when enteral feeding is initiated in preterm piglets susceptible to NEC. Stereologic volume densities of a pan-endothelial marker (vWF), and the main vasodilator endothelial nitric oxide synthase (eNOS), were determined along the small intestine of 1) unfed preterm piglets, 2) piglets receiving total parenteral nutrition (TPN) for 2-3 d, and 3) piglets fed 2 d sow's colostrum (TPNϩSOW) or milk formula (TPNϩFOR) following TPN. In the mucosa, vWF-density decreased in a cranio-caudal direction. A corresponding mucosal eNOS gradient appeared only after initiating enteral feeding. In TPNϩSOW, eNOS induction may lag behind the mucosal growth of the caudal region. In TPNϩFOR, formula-related factors (i.e. bacteria, cytokines) may suppress mucosal eNOS, indicated by increased stresssensitive nuclear HIF1␣ staining. The low mucosal endothelial eNOS density was related to the presence of NEC lesions, maybe via increased hypoxia-sensitivity, especially in the caudal region as indicated by nuclear HIF1␣-staining. Our results suggest an insufficient structural adaptation of the microvasculature to enteral feeding, especially of mucosal eNOS, which may lead to NEC. T he birth process converts the relatively dormant fetal intestine into an organ of intense metabolic activity and associated abundant perfusion, as it becomes the sole site for nutrient absorption. This profound transition is particularly problematic at premature birth, where it may result in NEC, a severe inflammatory bowel disease associated with the initiation of enteral feeding, especially formula (1-3). Therefore, a period of total parenteral nutrition (TPN) in preterm infants is often required before enteral feeding is tolerated (4). The etiology of NEC is unknown, but a dysfunctional intestinal microcirculation could contribute to the etiopathogenesis (5,6).The newborn intestinal circulation shows some unique features, up to now intensely studied from a functional point of view (5,7). Nitric oxide (NO), a gaseous free radical produced mainly by endothelial nitric oxide synthase (eNOS), is the most important vasodilator during the perinatal period in sheep (8) and pig (9). Although eNOS is constitutively expressed in the endothelium, both eNOS mRNA and protein expression can be modulated (10), including by nutrient intake (7). Furthermore, intestinal blood flow shows a cranial-tocaudal decrease along the small intestine in neonatal and adult dogs (11), pigs (12,13), and humans (14). It is, however, unknown whether this functional gradient in the small intestine is associated with a similar gradient in microvessel distribution and/or eNOS protein expression. Histologic analyses of the regional morphometrics of the intestinal endothelium and eNOS expression during the first days of life are therefore inte...

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Section: Alterations In the Intestinal Endothelium (Vwf) And Endothelsupporting

confidence: 68%

Section: Alterations In the Intestinal Endothelium (Vwf) And Endothelmentioning

confidence: 55%

mentioning

confidence: 99%

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Enteral Feeding Reduces Endothelial Nitric Oxide Synthase in the Caudal Intestinal Microvasculature of Preterm Piglets

et al. 2008

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“…The commensal microbiota has been implicated in the inflammation, mucosal disruption, and bacterial translocation that are associated with necrotizing enterocolitis (NEC) (2); however, the cellular interaction of premature intestinal mucosa with newly colonized bacteria is still unknown. In addition, although the pathogenesis of NEC is unknown, ischemia/reperfusion injury (I/R) has been considered a major contributing factor (3,4).…”

mentioning

confidence: 99%

Toll-like receptor 2 is protective of ischemia–reperfusion-mediated small-bowel injury in a murine model

Aprahamian

Lorenz

Harmon

et al. 2008

Pediatric Critical Care Medicine

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TLR2-/- mice have a dysregulated mucosal innate immune response and fail to mount a protective response after ischemia-reperfusion compared with wild-type mice. This murine model of intestinal injury may correlate with the early postnatal course of premature infants who may have decreased TLR2 expression and/or decreased luminal commensal bacteria secondary to antibiotic therapy, thus decreasing TLR2-mediated signaling.

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“…Endogenous release is induced by both proximal enteric neuronal signaling and direct stimulation from nutrients in the distal bowel, especially long-chain fatty acids (14)(15)(16)(17). Because necrotizing enterocolitis and other common causes of neonatal SBS are often associated with damage to or loss of ileum, we hypothesized that deficient endogenous GLP-2 release is a factor contributing to poor outcomes in neonates with SBS, by limiting adaptation (13,18).…”

mentioning

confidence: 99%

Role of glucagon-like peptide–2 deficiency in neonatal short-bowel syndrome using neonatal piglets

et al. 2013

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Background: Short-bowel syndrome (SBS) is the most common cause of neonatal intestinal failure. Recovery requires intestinal adaptation, dependent on enteral nutrition (EN) and growth factors such as glucagon-like peptide-2 (GLP-2), which is secreted from L cells in the ileum. Neonatal SBS often results in loss of ileum; therefore, we hypothesized that without ileum, endogenous GLP-2 production would be inadequate to promote adaptation. We compared endogenous GLP-2 production and adaptation in neonatal animals with SBS, with and without ileum. Methods: Neonatal piglets (4-6 d) were randomized to 75% mid-intestinal resection, 75% distal-intestinal resection, or sham control without resection. Postoperatively, all piglets commenced parenteral nutrition (PN), tapering as EN was increased to maintain specific growth. results: The resected SBS piglets developed intestinal failure, requiring a longer duration of PN support and experiencing fat malabsorption. The piglets without ileum were not able to wean from PN during the study and did not show adaptation, specifically growth in intestinal length or crypt hyperplasia on histology of the jejunum. Adaptation was observed in the resected SBS piglets with ileum, and these piglets also had an increased plasma GLP-2 level that was not observed in piglets without ileum. conclusion: SBS piglets with ileum undergo adaptation associated with increased endogenous GLP-2 production. SBS piglets without ileum undergo limited adaptation and severe intestinal failure, requiring prolonged PN support. This appears to be related to a deficiency in endogenous GLP-2 production. n eonatal intestinal failure secondary to short-bowel syndrome (SBS) has a particularly poor outcome. It is most common in preterm infants, and necrotizing enterocolitis is the most common cause (1-3). Necrotizing enterocolitis usually results in loss of ileum and right colon and carries a significant mortality (4).After intestinal resection, adaptation of the remnant intestine is essential for survival, compensating for the reduced absorptive surface area, both structurally and functionally (5). This process is regulated by several factors, including the stage of intestinal development, site and length of resection, the underlying disease, nutritional status, and gut-derived hormones and growth factors (6). Among the growth factors, glucagon-like peptide-2 (GLP-2) is considered to have an important role in inducing small-intestinal adaptation after resection. GLP-2 acts specifically at the GLP-2 receptor (GLP-2R), which is expressed throughout the small and large intestines but with greatest concentration in the jejunum (7). GLP-2 is uniquely trophic for the intestine (8). It can stimulate residual small-intestinal adaptation by increasing crypt cell proliferation and inhibiting apoptosis, thereby increasing villus height, crypt depth, mucosal mass, and overall small-intestinal length and weight (9-11). Functionally, GLP-2 increases activities of mucosal enzymes and therefore increases digestion and absorption (...

show abstract

Collateral Blood Flow in the Distal Ileum of Neonatal Piglets: A Clue to the Pathogenesis of Necrotizing Enterocolitis

Cited by 18 publications

References 20 publications

Enteral Feeding Reduces Endothelial Nitric Oxide Synthase in the Caudal Intestinal Microvasculature of Preterm Piglets

Enteral Feeding Reduces Endothelial Nitric Oxide Synthase in the Caudal Intestinal Microvasculature of Preterm Piglets

Toll-like receptor 2 is protective of ischemia–reperfusion-mediated small-bowel injury in a murine model

Role of glucagon-like peptide–2 deficiency in neonatal short-bowel syndrome using neonatal piglets

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