Abstract
Necrotizing enterocolitis (NEC) afflicts extremely low birth weight neonates, and probiotics reduces its incidence and severity. NO is involved in the pathogenesis of NEC, and caveolin-1 regulates NO signaling. We tested the hypothesis that intestinal caveolin-1 and NOS are deficient in formula-fed neonatal rats and that supplementation with “Florastar Kids” and/or galacto-oligosaccharides and fructo-oligosaccharides preserves caveolin-1 and NOS. At birth (P0), neonatal rat pups were maternally fed or hand-gavaged with or without supplemented formula. Samples from the terminal ileum were analyzed for total NO metabolites, growth factors, and gene expression of caveolin-1, NOS isoforms, and antioxidants. Our data showed that formula feeding with and without supplementation resulted in significant growth restriction. Despite suboptimal nutrition, growth factors involved in intestinal repair and regeneration were increased in the neonatal rat ileum. Caveolin-1, endothelial NOS, and neuronal NOS were simultaneously down-regulated with formula feeding while inducible NOS was up-regulated. Superoxide dismutase and glutathione peroxidase were up-regulated with supplementation. These data provide a probable mechanism for the benefits of supplemented formula for decreasing the severity of NEC by preserving the antioxidant systems.
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Abbreviations
- eNOS:
-
endothelial NOS
- FOS:
-
fructo-oligosaccharides
- GOS:
-
galactoligosaccharides
- GPX:
-
glutathione peroxidase
- iNOS:
-
inducible NOS
- NEC:
-
necrotizing enterocolitis
- nNOS:
-
neuronal NO synthase
- NOx:
-
NO metabolites
- O2−:
-
superoxide anion
- ROS:
-
reactive oxygen species
- SOD:
-
superoxide dismutase
References
Srinivasan PS, Brandler MD, D'Souza A 2008 Necrotizing enterocolitis. Clin Perinatol 35: 251–272
Levy RM, Prince JM, Billiar TR 2005 Nitric oxide: a clinical primer. Crit Care Med 33: S492–S495
Alderton WK, Cooper CE, Knowles RG 2001 Nitric oxide synthases: structure, function and inhibition. Biochem J 357: 593–615
Nathan C, Xie QW 1994 Nitric oxide synthases: roles, tolls, and controls. Cell 78: 915–918
Tepperman BL, Brown JF, Whittle BJ 1993 Nitric oxide synthase induction and intestinal epithelial cell viability in rats. Am J Physiol 265: G214–G218
Ford H, Watkins S, Reblock K, Rowe M 1997 The role of inflammatory cytokines and nitric oxide in the pathogenesis of necrotizing enterocolitis. J Pediatr Surg 32: 275–282
Beckman JS, Koppenol WH 1996 Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 271: C1424–C1437
Upperman JS, Potoka D, Grishin A, Hackam D, Zamora R, Ford HR 2005 Mechanisms of nitric oxide-mediated intestinal barrier failure in necrotizing enterocolitis. Semin Pediatr Surg 14: 159–166
Bautista AP, Spitzer JJ 1994 Inhibition of nitric oxide formation in vivo enhances superoxide release by the perfused liver. Am J Physiol 266: G783–G788
Grande-García A, del Pozo MA 2008 Caveolin-1 in cell polarization and directional migration. Eur J Cell Biol 87: 641–647
Hu G, Ye RD, Dinauer MC, Malik AB, Minshall RD 2008 Neutrophil caveolin-1 expression contributes to mechanism of lung inflammation and injury. Am J Physiol Lung Cell Mol Physiol 294: L178–L186
Salanueva IJ, Cerezo A, Guadamillas MC, del Pozo MA 2007 Integrin regulation of caveolin function. J Cell Mol Med 11: 969–980
Warner BW, Warner BB 2005 Role of epidermal growth factor in the pathogenesis of neonatal necrotizing enterocolitis. Semin Pediatr Surg 14: 175–180
Hirai C, Ichiba H, Saito M, Shintaku H, Yamano T, Kusuda S 2002 Trophic effect of multiple growth factors in amniotic fluid or human milk on cultured human fetal small intestinal cells. J Pediatr Gastroenterol Nutr 34: 524–528
Maggi D, Biedi C, Segat D, Barbero D, Panetta D, Cordera R 2002 IGF-I induces caveolin 1 tyrosine phosphorylation and translocation in the lipid rafts. Biochem Biophys Res Commun 295: 1085–1089
Lin HC, Hsu CH, Chen HL, Chung MY, Hsu JF, Lien RI, Tsao LY, Chen CH, Su BH 2008 Oral probiotics prevent necrotizing enterocolitis in very low birth weight preterm infants: a multicenter randomized controlled trial. Pediatrics 122: 693–700
Khailova L, Dvorak K, Arganbright KM, Williams CS, Halpern MD, Dvorak B 2009 Changes in hepatic cell junctions structure during experimental necrotizing enterocolitis: effect of EGF treatment. Pediatr Res 66: 140–144
Zani A, Ghionzoli M, Lauriti G, Cananzi M, Smith VV, Pierro A, De Coppi P, Eaton S 2010 Does intestinal permeability lead to organ failure in experimental necrotizing enterocolitis?. Pediatr Surg Int 26: 85–89
Liu Y, Zhu L, Fatheree NY, Liu X, Pacheco SE, Tatevian N, Rhoads JM 2009 Changes in intestinal toll-like receptors and cytokines precede histological injury in a rat model of necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 297: G442–G450
Repetto S, Salani B, Maggi D, Cordera R 2005 Insulin and IGF-I phosphorylate eNOS in HUVECs by a caveolin-1 dependent mechanism. Biochem Biophys Res Commun 337: 849–852
Tremblay E, Chailler P, Ménard D 2001 Coordinated control of fetal gastric epithelial functions by insulin-like growth factors and their binding proteins. Endocrinology 142: 1795–1803
Gordon PV 2009 Understanding intestinal vulnerability to perforation in the extremely low birth weight infant. Pediatr Res 65: 138–144
Fruchtman S, Simmons JG, Michaylira CZ, Miller ME, Greenhalgh CJ, Ney DM, Lund PK 2005 Suppressor of cytokine signaling-2 modulates the fibrogenic actions of GH and IGF-I in intestinal mesenchymal cells. Am J Physiol Gastrointest Liver Physiol 289: G342–G350
Murali SG, Nelson DW, Draxler AK, Liu X, Ney DM 2005 Insulin-like growth factor-I (IGF-I) attenuates jejunal atrophy in association with increased expression of IGF-I binding protein-5 in parenterally fed mice. J Nutr 135: 2553–2559
Huo H, Guo X, Hong S, Jiang M, Liu X, Liao K 2003 Lipid rafts/caveolae are essential for insulin-like growth factor-1 receptor signaling during 3T3-L1 preadipocyte differentiation induction. J Biol Chem 278: 11561–11569
Matthews LC, Taggart MJ, Westwood M 2008 Modulation of caveolin-1 expression can affect signalling through the phosphatidylinositol 3-kinase/Akt pathway and cellular proliferation in response to insulin-like growth factor I. Endocrinology 149: 5199–5208
Bennett WR, Crew TE, Slack JM, Ward A 2003 Structural-proliferative units and organ growth: effects of insulin-like growth factor 2 on the growth of colon and skin. Development 130: 1079–1088
Gordon PV, Herman AC, Marcinkiewicz M, Gaston BM, Laubach VE, Aschner JL 2007 A neonatal mouse model of intestinal perforation: Investigating the harmful synergism between glucocorticoids and indomethacin. J Pediatr Gastroenterol Nutr 45: 509–519
Acknowledgements
We thank the staff of the Department of Laboratory Animal Research, State University of New York, Brooklyn, NY, for their assistance and technical support and the Pathology Department at State University of New York Downstate Medical Center, Brooklyn, NY, for their technical assistance.
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Supported by a grant from the Department of Pediatrics, SUNY Downstate Medical Center, Brooklyn, NY.
Presented, in part, at the Pediatric Academic Societies 2009 Annual Meeting, Baltimore, MD, May 2–5, 2009.
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D'Souza, A., Fordjour, L., Ahmad, A. et al. Effects of Probiotics, Prebiotics, and Synbiotics on Messenger RNA Expression of Caveolin-1, NOS, and Genes Regulating Oxidative Stress in the Terminal Ileum of Formula-Fed Neonatal Rats. Pediatr Res 67, 526–531 (2010). https://doi.org/10.1203/PDR.0b013e3181d4ff2b
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DOI: https://doi.org/10.1203/PDR.0b013e3181d4ff2b
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