Abstract
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.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- CVs:
-
collecting venules
- DF:
-
dam fed
- ET:
-
endothelin
- FMD:
-
functional microvascular density
- NEC:
-
necrotizing enterocolitis
References
Neu J 1996 Necrotizing enterocolitis: the search for a unifying pathogenic theory leading to prevention. Pediatr Clin North Am 43: 409–432
Lee JS, Polin RA 2003 Treatment and prevention of necrotizing enterocolitis. Semin Neonatol 8: 449–459
Nowicki PT 2005 Ischemia and necrotizing enterocolitis: where, when, and how. Semin Pediatr Surg 14: 152–158
Barnett CP, Perlman M, Ekert PG 1997 Clinicopathological correlations in postasphyxial organ damage: a donor organ perspective. Pediatrics 99: 797–799
Martin-Ancel A, Garcia-Alix A, Gaya F, Cabanas F, Burgueros M, Quero J 1995 Multiple organ involvement in perinatal asphyxia. J Pediatr 127: 786–793
Alward CT, Hook JB, Helmrath TA, Mattson JC, Bailie MD 1978 Effects of asphyxia on cardiac output and organ blood flow in the newborn piglet. Pediatr Res 12: 824–827
Karna P, Senagore A, Chou CC 1986 Comparison of the effect of asphyxia, hypoxia, and acidosis on intestinal blood flow and O2 uptake in newborn piglets. Pediatr Res 20: 929–932
Papparella A, DeLuca FG, Oyer CE, Pinar H, Stonestreet BS 1997 Ischemia-reperfusion injury in the intestines of newborn pigs. Pediatr Res 42: 180–188
Touloukian RJ, Posch JN, Spencer R 1972 The pathogenesis of ischemic gastroenterocolitis of the neonate: selective gut mucosal ischemia in asphyxiated neonatal piglets. J Pediatr Surg 7: 194–205
Nankervis CA, Nowicki PT 2000 Role of endothelin-1 in regulation of the postnatal intestinal circulation. Am J Physiol Gastrointest Liver Physiol 278: G367–G375
King-VanVlack CE, Mewburn JD, Chapler CK, MacDonald PH 2003 Hemodynamic and proinflammatory actions of endothelin-1 in guinea pig small intestine submucosal microcirculation. Am J Physiol Gastrointest Liver Physiol 284: G940–G948
Nowicki PT, Dunaway DJ, Nankervis CA, Giannnone PJ, Reber KM, Hammond SB, Besner GE, Caniano DA 2005 Endothelin-1 in human intestine resected for necrotizing enterocolitis. J Pediatr 146: 805–810
Caplan MS, Hedlund E, Adler L, Hsueh W 1994 Role of asphyxia and feeding in a neonatal rat model of necrotizing enterocolitis. Pediatr Pathol 14: 1017–1028
Clark JA, Lane RH, Maclennan NK, Holubec H, Dvorakova K, Halpern MD, Williams CS, Payne CM, Dvorak B 2005 Epidermal growth factor reduces intestinal apoptosis in an experimental model of necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 288: G755–G762
Dvorak B, Halpern MD, Holubec H, Williams CS, McWilliam DL, Dominguez JA, Stepankova R, Payne CM, McCuskey RS 2002 Epidermal growth factor reduces the development of necrotizing enterocolitis in a neonatal rat model. Am J Physiol Gastrointest Liver Physiol 282: G156–G164
Halpern MD, Clark JA, Saunders TA, Doelle SM, Hosseini DM, Stagner AM, Dvorak B 2006 Reduction of experimental necrotizing enterocolitis with anti-TNF-α. Am J Physiol Gastrointest Liver Physiol 290: G757–G764
Halpern MD, Holubec H, Saunders TA, Dvorak K, Clark JA, Doelle SM, Ballatori N, Dvorak B 2006 Bile acids induce ileal damage during experimental necrotizing enterocolitis. Gastroenterology 130: 359–372
McCuskey RS 1986 Microscopic methods for studying the microvasculature of internal organs. In: Baker CH, Nastuk WF (eds) Physical Techniques in Biology and Medicine Microvascular Technology. Academic Press, New York, pp 247–264.
McCuskey RS, Ekataksin W, LeBouton AV, Nishida J, McCuskey MK, McDonnell D, Williams C, Bethea NW, Dvorak B, Koldovsky O 2003 Hepatic microvascular development in relation to the morphogenesis of hepatocellular plates in neonatal rats. Anat Rec A Discov Mol Cell Evol Biol 275: 1019–1030
Gore RW, Bohlen HG 1977 Microvascular pressures in rat intestinal muscle and mucosal villi. Am J Physiol 233: H685–H693
Gonzalez AP, Sepulveda S, Massberg S, Baumeister R, Menger MD 1994 In vivo fluorescence microscopy for the assessment of microvascular reperfusion injury in small bowel transplants in rats. Transplantation 58: 403–408
McCuskey RS, Vonnahme FJ, Grun M 1983 In vivo and electron microscopic observations of the hepatic microvasculature in the rat following portacaval anastomosis. Hepatology 3: 96–104
Pham TD, MacLennan NK, Chiu CT, Laksana GS, Hsu JL, Lane RH 2003 Uteroplacental insufficiency increases apoptosis and alters p53 gene methylation in the full-term IUGR rat kidney. Am J Physiol Regul Integr Comp Physiol 285: R962–R970
Menon RK, Shaufl A, Yu JH, Stephan DA, Friday RP 2001 Identification and characterization of a novel transcript of the murine growth hormone receptor gene exhibiting development- and tissue-specific expression. Mol Cell Endocrinol 172: 135–146
Bradford MM 1976 A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248–254
Barlow B, Santulli TV, Heird WC, Pitt J, Blanc WA, Schullinger JN 1974 An experimental study of acute neonatal enterocolitis–the importance of breast milk. J Pediatr Surg 9: 587–595
Egidy G, Juillerat-Jeanneret L, Jeannin JF, Korth P, Bosman FT, Pinet F 2000 Modulation of human colon tumor-stromal interactions by the endothelin system. Am J Pathol 157: 1863–1874
Halpern MD, Holubec H, Dominguez JA, Meza YG, Williams CS, Ruth MC, McCuskey RS, Dvorak B 2003 Hepatic inflammatory mediators contribute to intestinal damage in necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 284: G695–G702
Halpern MD, Holubec H, Dominguez JA, Williams CS, Meza YG, McWilliam DL, Payne CM, McCuskey RS, Besselsen DG, Dvorak B 2002 Up-regulation of IL-18 and IL-12 in the ileum of neonatal rats with necrotizing enterocolitis. Pediatr Res 51: 733–739
Woods M, Mitchell JA, Wood EG, Barker S, Walcot NR, Rees GM, Warner TD 1999 Endothelin-1 is induced by cytokines in human vascular smooth muscle cells: evidence for intracellular endothelin-converting enzyme. Mol Pharmacol 55: 902–909
Kuchan MJ, Frangos JA 1993 Shear stress regulates endothelin-1 release via protein kinase C and cGMP in cultured endothelial cells. Am J Physiol 264: H150–H156
Thakali K, Fink GD, Watts SW 2004 Arteries and veins desensitize differently to endothelin. J Cardiovasc Pharmacol 43: 387–393
Nowicki PT 1999 Effects of sustained low-flow perfusion on the response to vasoconstrictor agents in postnatal intestine. Am J Physiol 276: 1408–1416
Nowicki PT 1998 Effects of sustained flow reduction on postnatal intestinal circulation. Am J Physiol 275: G758–G768
Author information
Authors and Affiliations
Corresponding author
Additional information
This work was supported by the National Institute of Child Health and Human Development grant HD39657 (to B. Dvorak).
Rights and permissions
About this article
Cite this article
Ito, Y., Doelle, S., Clark, J. et al. Intestinal Microcirculatory Dysfunction During the Development of Experimental Necrotizing Enterocolitis. Pediatr Res 61, 180–184 (2007). https://doi.org/10.1203/pdr.0b013e31802d77db
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/pdr.0b013e31802d77db
This article is cited by
-
Anemia of prematurity: how low is too low?
Journal of Perinatology (2021)
-
Remote ischemic conditioning counteracts the intestinal damage of necrotizing enterocolitis by improving intestinal microcirculation
Nature Communications (2020)
-
Endothelin receptor B affects the perfusion of newborn intestine: possible mechanism of necrotizing enterocolitis development
Pediatric Surgery International (2019)
-
Pathogenesis of neonatal necrotizing enterocolitis
Pediatric Surgery International (2015)
-
A comparison of combination dopamine and epinephrine treatment with high-dose dopamine alone in asphyxiated newborn piglets after resuscitation
Pediatric Research (2013)