endothelin-1 and Enterocolitis--Necrotizing

Necrotizing enterocolitis (NEC) continues to be a devastating inflammatory disease of the newborn intestine. Despite advances in management, morbidity and mortality remain high. While it is clear that intestinal ischemia plays a large role in disease pathogenesis, attempts to link NEC to intestinal macrovascular derangement have been largely unsuccessful. More recently, there has been a concerted effort to characterize the pathologic changes of the intestinal microcirculation in response to intestinal injury, including NEC. This microcirculatory regulation is controlled by a balance of vasoconstrictor and vasodilator forces. Vasoconstriction is mediated primarily by endothelin-1 (ET-1), while vasodilation is mediated primarily by nitric oxide (NO). These chemical mediators have been implicated in many aspects of intestinal ischemic injury and NEC, with the balance shifting toward increased vasoconstriction associated with intestinal injury. With a proper understanding of these antagonistic forces, potential therapeutic avenues may result from improving this pathologic microcirculatory dysregulation.

Topics: Biomarkers; Endothelin-1; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Intestines; Ischemia; Microcirculation; Nitric Oxide; Vasoconstriction; Vasodilation

Based on the observation that coagulation necrosis occurs in the majority of neonatal necrotizing enterocolitis (NEC) patients, it is clear that intestinal ischemia is a contributing factor to the pathogenesis of NEC. However, the published studies regarding the role of intestinal ischemia in NEC are controversial. The aim of this paper is to review the current studies regarding intestinal microcirculatory dysfunction and NEC, and try to elucidate the exact role of intestinal microcirculatory dysfunction in NEC.. The studies cited in this review were mainly obtained from articles listed in Medline and PubMed. The search terms used were "intestinal microcirculatory dysfunction" and "neonatal necrotizing enterocolitis".. Mainly original milestone articles and critical reviews written by major pioneer investigators in the field were selected.. Immature regulatory control of mesentery circulation makes the neonatal intestinal microvasculature vulnerable. When neonates are subjected to stress, endothelial cell dysfunction occurs and results in vasoconstriction of arterioles, inflammatory cell infiltration and activation in venules, and endothelial barrier disruption in capillaries. The compromised vasculature increases circulation resistance and therefore decreases intestinal perfusion, and may eventually progress to intestinal necrosis.. Intestinal ischemia plays an important role through the whole course of NEC. New therapeutic agents targeting intestinal ischemia, like HB-EGF, are promising therapeutic agents for the treatment of NEC.

Topics: Endothelin-1; Endothelium, Vascular; Enterocolitis, Necrotizing; Heparin-binding EGF-like Growth Factor; Humans; Infant, Newborn; Intercellular Signaling Peptides and Proteins; Intestines; Ischemia; Microcirculation; Nitric Oxide; Splanchnic Circulation

Based on the demonstration of coagulation necrosis, it is clear that intestinal ischemia plays a role in the pathogenesis of necrotizing enterocolitis (NEC). Intestinal vascular resistance is determined by a dynamic balance between vasoconstrictive and vasodilatory inputs. In the newborn, this balance heavily favors vasodilation secondary to the copious production of endothelium-derived nitric oxide (NO), a circumstance which serves to ensure adequate blood flow and thus oxygen delivery to the rapidly growing intestine. Endothelial cell injury could shift this balance in favor of endothelin (ET)-1-mediated vasoconstriction, leading to intestinal ischemia and tissue injury. Evidence obtained from animal models and from human tissue collected from infants with NEC implicates NO and ET-1 dysregulation in the pathogenesis of NEC. Strategies focused on maintaining the delicate balance favoring vasodilation in the newborn intestinal circulation may prove to be useful in the prevention and treatment of NEC.

Topics: Endothelin-1; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Intestines; Ischemia; Nitric Oxide; Regional Blood Flow; Risk Factors; Vascular Resistance; Vasoconstriction

While it is accepted that ischemia contributes to the pathogenesis of necrotizing enterocolitis (NEC), three important questions regarding this role subsist. First, where within the intestinal circulation does the vascular pathophysiology occur? It is most likely that this event begins within the intramural microcirculation, particularly the small arteries that pierce the gut wall and the submucosal arteriolar plexus insofar as these represent the principal sites of resistance regulation in the gut. Mucosal damage might also disrupt the integrity or function of downstream villous arterioles leading to damage thereto; thereafter, noxious stimuli might ascend into the submucosal vessels via downstream venules and lymphatics. Second, when during the course of pathogenesis does ischemia occur? Ischemia is unlikely to the sole initiating factor of NEC; instead, it is more likely that ischemia is triggered by other events, such as inflammation at the mucosal surface. In this context, it is likely that ischemia plays a secondary, albeit critical role in disease extension. Third, how does the ischemia occur? Regulation of vascular resistance within newborn intestine is principally determined by a balance between the endothelial production of the vasoconstrictor peptide endothelin-1 (ET-1) and endothelial production of the vasodilator free radical nitric oxide (NO). Under normal conditions, the balance heavily favors NO-induced vasodilation, leading to a low resting resistance and high rate of flow. However, factors that disrupt endothelial cell function, eg, ischemia-reperfusion, sustained low-flow perfusion, or proinflammatory mediators, alter the ET-1:NO balance in favor of constriction. The unique ET-1-NO interaction thereafter might facilitate rapid extension of this constriction, generating a viscous cascade wherein ischemia rapidly extends into larger portions of the intestine.

Topics: Endothelin-1; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Intestinal Mucosa; Ischemia; Microcirculation; Nitric Oxide; Splanchnic Circulation

Necrotizing enterocolitis (NEC) has high morbidity in premature infants. Hypoxia-ischemia, infection, and enteral feeding are risk factors associated with NEC, whereas feeding human milk is protective. Vasoactive and inflammatory mediators in NEC remain elusive. Gangliosides are found in human milk and enterocyte membranes. An infant bowel model of NEC was developed to test the hypothesis that gangliosides modulate the inflammatory response to infection and hypoxia.. Viable, noninflamed bowel was obtained from 9 infants between 26 and 40 weeks' gestational age. Infant bowel was treated in culture with Escherichia coli lipopolysaccharide (LPS) and hypoxia in the presence or absence of preexposure to gangliosides. Bowel necrosis and production of nitric oxide, endothelin-1, serotonin, eicosanoids, hydrogen peroxide, and proinflammatory cytokines were measured.. Ganglioside preexposure reduced bowel necrosis and endothelin-1 production in response to LPS. Gangliosides suppressed infant bowel production of nitric oxide, leukotriene B4, prostaglandin E2, hydrogen peroxide, interleukin-1beta, interleukin-6, and interleukin-8 in response to LPS exposure and hypoxia.. A bowel protective effect of gangliosides is indicated by modulation of vasoactive mediators and proinflammatory signal suppression.

Topics: Animals; Anti-Inflammatory Agents; Colon; Endothelin-1; Enterocolitis, Necrotizing; Escherichia coli; Gangliosides; Humans; Hypoxia; In Vitro Techniques; Infant, Newborn; Inflammation; Inflammation Mediators; Lipopolysaccharides; Milk; Necrosis

The aim of this study was to evaluate changes in intestinal microcirculation during necrotizing enterocolitis (NEC) and to examine the effect of endothelin (ET)-1 on the intestinal microcirculation. Prematurely born rats were either hand-fed formula (NEC) or dam fed (DF) and were exposed to asphyxia and cold stress twice daily to induce disease. At 0, 2, 3, and 4 d after the birth, the microcirculation in the ileum was examined using in vivo microscopic methods. The nutritive microvascular perfusion in the NEC group was progressively compromised from d 3 to d 4 (35% and 50% decrease, respectively) when compared with DF rats. Concomitantly, intestinal blood flow assessed by laser Doppler flowmetry was significantly reduced at d 2, 3, and 4 (by 31%, 36%, and 73%, respectively). Levels of ET-1 mRNA in the ileum were increased 3.7-fold. Microvascular responses to topically applied ET-1 were significantly increased in the NEC group, which was associated with decreased expression of ETB receptor. These results suggest that microcirculatory dysfunction in the distal ileum of neonatal rats with NEC contributes to disease progression and that enhanced microvascular responsiveness to ET-1 may participate in these microcirculatory disturbances.

Topics: Animals; Animals, Newborn; Asphyxia; Disease Models, Animal; Disease Progression; Endothelin-1; Enterocolitis, Necrotizing; Ileum; Laser-Doppler Flowmetry; Microcirculation; Rats; Rats, Sprague-Dawley; Receptors, Endothelin

We asked if the tissue concentration of the potent vasoconstrictor endothelin-1 (ET-1) is greater in areas of human preterm intestine that demonstrate histologic evidence of necrotizing enterocolitis (NEC) when compared with relatively healthy areas within the same resection specimen. We then evaluated if ET-1 participates in hemodynamic regulation within intestinal subserosal arterioles harvested from portions of human preterm intestine that demonstrate NEC.. Human preterm intestine resected for NEC was divided into three zones based on proximity to the perforation (zone 1 most proximal, zone 3 most distal). Histologic evidence of NEC was determined in each zone (normal = 0, advanced necrosis = 6). The tissue concentration of ET-1 was determined by enzyme-linked immunosorbent assay within intestinal homogenates prepared from each zone. Arteriolar hemodynamics were determined in vitro on subserosal arterioles harvested from different zones. Arteriolar flow rate, diameter, and resistance were determined at pressure gradients (DeltaP) of 20 and 40 mmHg under control conditions and again after blockade of endothelin ET A receptors with BQ610 (10 -9 mol/L).. The tissue concentration of ET-1 (pg/mg protein) and histologic score in the three zones were: zone 1: 84 +/- 14, 5.5 +/- 0.3; zone 2: 99 +/- 12, 4.7 +/- 0.4, and zone 3: 33 +/- 9, 0.8 +/- 0.6, respectively (M +/- SD, n = 10 resection specimens, P < .05, zone 3 vs zones 1 and 2). Zone 2 arterioles demonstrated significantly lower flow rate and diameter and increased resistance under control conditions than zone 3 arterioles when DeltaP was either 20 or 40 mmHg (n = 7, P < .05). Treatment with BQ610 had no effect on zone 3 arterioles but significantly vasodilated zone 2 arterioles, increasing flow rate and vessel diameter, and decreasing vascular resistance (n = 7, P < .05).. The tissue concentration of ET-1 is greater in human preterm intestine that demonstrates histologic evidence of NEC. Arterioles harvested from intestine exhibiting histologic evidence of NEC demonstrate vasoconstriction when compared with arterioles from relatively healthy intestine in the same resection specimen. This vasoconstriction was reversed by blockade of endothelin ET A receptors.

Topics: Arterioles; Blood Flow Velocity; Endothelin A Receptor Antagonists; Endothelin-1; Enterocolitis, Necrotizing; Enzyme-Linked Immunosorbent Assay; Humans; In Vitro Techniques; Infant; Intestinal Mucosa; Intestines; Oligopeptides; Vasoconstriction; Vasodilator Agents