Abstract
Ghrelin is a strong physiologic growth hormone secretagogue that exhibits endocrine and non-endocrine actions. In this study, ghrelin expression in humans and rats was evaluated throughout development of normal and hypoplastic lungs associated with congenital diaphragmatic hernia (CDH). Additionally, the effect of antenatal treatment with ghrelin in the nitrofen-induced CDH rat model was tested. In normal lungs, ghrelin was expressed in the primitive epithelium at early stages of development and decreased in levels of expression with gestational age. In hypoplastic lungs ghrelin was overexpressed in both human and rat CDH fetuses when compared with controls. Exogenous administration of ghrelin to nitrofen-treated dams led to an attenuation of pulmonary hypoplasia of CDH pups. Furthermore, the growth hormone, secretagogue receptor (GHSR1a), could not be amplified from human or rat fetal lungs by RT-PCR. In conclusion, of all the lungs studied so far, the fetal lung is one of the first to express ghrelin during development and might be considered a new source of circulating fetal ghrelin. Overexpression of ghrelin in hypoplastic lungs and the effect of exogenous administration of ghrelin to nitrofen-treated dams strongly suggest a role for ghrelin in mechanisms involved in attenuation of fetal lung hypoplasia, most likely through a GHSR1a-independent pathway.
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Abbreviations
- CDH:
-
congenital diaphragmatic hernia
- dpc:
-
days post-conception
- GHSR1a:
-
growth hormone secretagogue receptor 1a
- IHC:
-
immunochemistry
- ISH:
-
in situ hybridization
- NEB:
-
neuroendocrine bodies
References
Stege G, Fenton A, Jaffray B 2003 Nihilism in the 1990s: the true mortality of congenital diaphragmatic hernia. Pediatrics 112: 532–535
Harrison MR, Keller RL, Hawgood SB, Kitterman JA, Sandberg PL, Farmer DL, Lee H, Filly RA, Farrell JA, Albanese CT 2003 A randomized trial of fetal endoscopic tracheal occlusion for severe fetal congenital diaphragmatic hernia. N Engl J Med 349: 1916–1924
Baptista MJ, Melo-Rocha G, Pedrosa C, Gonzaga S, Teles A, Estevao-Costa J, Areias JC, Flake AW, Leite-Moreira AF, Correia-Pinto J 2005 Antenatal Vitamin A administration attenuates lung hypoplasia by interfering with early instead late determinants of lung underdevelopment in congenital diaphragmatic hernia. J Pediatr Surg 40: 658–665
Li J, Hu T, Liu W, Xiang B, Jiang X 2004 Effect of epidermal growth factor on pulmonary hypoplasia in experimental diaphragmatic hernia. J Pediatr Surg 39: 37–42
Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K 1999 Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402: 656–660
Wang G, Lee HM, Englander E, Greeley GH 2002 Ghrelin-not just another stomach hormone. Regul Pept 105: 75–81
Cortelazzi D, Cappiello V, Morpurgo PS, Ronzoni S, Nobile De Santis MS, Cetin I, Beck-Peccoz P, Spada A 2003 Circulating levels of ghrelin in human fetuses. Eur J Endocrinol 149: 111–116
Chanoine JP, Wong AC 2004 Ghrelin gene expression is markedly higher in fetal pancreas compared with fetal stomach: effect of maternal fasting. Endocrinology 145: 3813–3820
Hayashida T, Nakahara K, Mondal MS, Date Y, Nakazato M, Kojima M, Kangawa K, Murakami N 2002 Ghrelin in neonatal rats: distribution in stomach and its possible role. J Endocrinol 173: 239–245
Gualillo O, Caminos J, Blanco M, Garcia-Caballero T, Kojima M, Kangawa K, Dieguez C, Casanueva F 2001 Ghrelin, a novel placental-derived hormone. Endocrinology 142: 788–794
Wierup N, Svensson H, Mulder H, Sundler F 2002 The ghrelin cell: a novel developmentally regulated islet cell in the human pancreas. Regul Pept 107: 63–69
Rindi G, Necchi V, Savio A, Torsello A, Zoli M, Locatelli V, Raimondo F, Cocchi D, Solcia E 2002 Characterization of gastric ghrelin cells in man and other mammals: studies in adult and fetal tissues. Histochem Cell Biol 117: 511–519
Volante M, Fulcheri E, Allia E, Cerrato M, Pucci A, Papotti M 2002 Ghrelin expression in fetal, infant, and adult human lung. J Histochem Cytochem 50: 1013–1021
Henriques-Coelho T, Correia-Pinto J, Roncon-Albuquerque R Jr, Baptista MJ, Lourenco AP, Oliveira SM, Brandao-Nogueira A, Teles A, Fortunato JM, Leite-Moreira AF 2004 Endogenous production of ghrelin and beneficial effects of its exogenous administration in monocrotaline-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol 287: H2885–H2890
Correia-Pinto J, Baptista MJ, Pedrosa C, Estevao-Costa J, Flake AW, Leite-Moreira AF 2003 Fetal heart development in the nitrofen-induced CDH rat model: the role of mechanical and nonmechanical factors. J Pediatr Surg 38: 1444–1451
Strahle U, Blader P, Adam J, Ingham PW 1994 A simple and efficient procedure for non-isotopic in situ hybridization to sectioned material. Trends Genet 10: 75–76
Keijzer R, Liu J, Deimling J, Tibboel D, Post M 2000 Dual-hit hypothesis explains pulmonary hypoplasia in the nitrofen model of congenital diaphragmatic hernia. Am J Pathol 156: 1299–1306
Migliazza L, Xia H, Diez-Pardo JA, Tovar JA 1999 Skeletal malformations associated with congenital diaphragmatic hernia: experimental and human studies. J Pediatr Surg 34: 1624–1629
Sun Y, Ahmed S, Smith RG 2003 Deletion of ghrelin impairs neither growth nor appetite. Mol Cell Biol 23: 7973–7981
Baldanzi G, Filigheddu N, Cutrupi S, Catapano F, Bonissoni S, Fubini A, Malan D, Baj G, Granata R, Broglio F, Papotti M, Surico N, Bussolino F, Isgaard J, Deghenghi R, Sinigaglia F, Prat M, Muccioli G, Ghigo E, Graziani A 2002 Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT. J Cell Biol 159: 1029–1037
Muccioli G, Pons N, Ghe C, Catapano F, Granata R, Ghigo E 2004 Ghrelin and des-acyl ghrelin both inhibit isoproterenol-induced lipolysis in rat adipocytes via a non-type 1a growth hormone secretagogue receptor. Eur J Pharmacol 498: 27–35
Wollmann HA 2000 Growth hormone and growth factors during perinatal life. Horm Res 53: 50–54
Beyea JA, Olson DM, Harvey S 2005 Growth hormone expression in the perinatal and postnatal rat lung. Dev Dyn 232: 1037–1046
Edmondson SR, Werther GA, Russell A, LeRoith D, Roberts CT, Beck F 1995 Localization of growth hormone receptor/binding protein messenger ribonucleic acid (mRNA) during rat fetal development: relationship to insulin-like growth factor-I mRNA. Endocrinology 136: 4602–4609
Garcia-Aragon J, Lobie PE, Muscat GE, Gobius KS, Norstedt G, Waters MJ 1992 Prenatal expression of the growth hormone (GH) receptor/binding protein in the rat: a role for GH in embryonic and fetal development?. Development 114: 869–876
Batchelor DC, Lewis RM, Breier BH, Gluckman PD, Skinner SJ 1998 Fetal rat lung epithelium has a functional growth hormone receptor coupled to tyrosine kinase activity and insulin-like growth factor binding protein-2 production. J Mol Endocrinol 21: 73–84
Guarino N, Solari V, Shima H, Puri P 2004 Upregulated expression of EGF and TGF-alpha in the proximal respiratory epithelium in the human hypoplastic lung in congenital diaphragmatic hernia. Pediatr Surg Int 19: 755–759
Ohshiro K, Miyazaki E, Taira Y, Puri P 1998 Upregulated tumor necrosis factor-alpha gene expression in the hypoplastic lung in patients with congenital diaphragmatic hernia. Pediatr Surg Int 14: 21–24
Unemoto K, Sakai M, Shima H, Guarino N, Puri P 2003 Increased expression of ICAM-1 and VCAM-1 in the lung of nitrofen-induced congenital diaphragmatic hernia in rats. Pediatr Surg Int 19: 365–370
Adriaensen D, Brouns I, Van Genechten J, Timmermans JP 2003 Functional morphology of pulmonary neuroepithelial bodies: extremely complex airway receptors. Anat Rec A Discov Mol Cell Evol Biol 270: 25–40
Cutz E, Gillan JE, Perrin DG 1995 Pulmonary neuroendocrine cell system: an overview of cell biology and pathology with emphasis on pediatric lung disease. In: Askin FB, Langston C, Rosenberg HS, and Berstein J (eds) Perspectives in Pediatric Pathology. Basel Karger 32–70
Ijsselstijn H, Gaillard JL, de Jongste JC, Tibboel D, Cutz E 1997 Abnormal expression of pulmonary bombesin-like peptide immunostaining cells in infants with congenital diaphragmatic hernia. Pediatr Res 42: 715–20
Sunday ME, Kaplan LM, Motoyama E, Chin WW, Spindel ER 1988 Gastrin-releasing peptide (mammalian bombesin) gene expression in health and disease. Lab Invest 59: 5–24
Van Lommel A 2001 Pulmonary neuroendocrine cells (PNEC) and neuroepithelial bodies (NEB): chemoreceptors and regulators of lung development. Paediatr Respir Rev 2: 171–176
Youngson C, Nurse C, Yeger H, Cutz E 1993 Oxygen sensing in airway chemoreceptors. Nature 365: 153–155
King KA, Torday JS, Sunday ME 1995 Bombesin and [Leu8]phyllolitorin promote fetal mouse lung branching morphogenesis via a receptor-mediated mechanism. Proc Natl Acad Sci U S A 92: 4357–4361
IJsselstijn H, Perrin DG, de Jongste JC, Cutz E, Tibboel D 1995 Pulmonary neuroendocrine cells in neonatal rats with congenital diaphragmatic hernia. J Pediatr Surg 30: 413–415
Acknowledgements
We would like to thank Dr. Tena-Sempere for providing the plasmid with ghrelin for the riboprobe synthesis.
Note added in proof: After this manuscript had been accepted, a paper describing abnormalities in norepinephrine and respiratory systems in Mecp2-/y mice was published: Viemari JC, Roux JC, Tryba AK, Saywell V, Burnet H, Pena F, Zanella S, Bevengut M, Barthelemy-Requin M, Herzing LB, Moncla A, Mancini J, Ramirez JM, Villard L, Hilaire G 2006 Mecp2 deficiency disrupts norepinephrine and respiratory systems in mice. J Neurosci 2005 Dec 14;25:11521–11530.
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This project was funded by Fundação para a Ciência e a Tecnologia (POCI/SAU-OBS/56428/2004). M.S. was supported by the Fundação para a Ciência e a Tecnologia (SFRH/BD/9631/2002) through the G.A.B.B.A. Programme, University of Porto, Portugal. S.G. was funded by Fundação para a Ciência e a Tecnologia (SFR/BI/9763/2003).
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Santos, M., Bastos, P., Gonzaga, S. et al. Ghrelin Expression in Human and Rat Fetal Lungs and the Effect of Ghrelin Administration in Nitrofen-Induced Congenital Diaphragmatic Hernia. Pediatr Res 59, 531–537 (2006). https://doi.org/10.1203/01.pdr.0000202748.66359.a9
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DOI: https://doi.org/10.1203/01.pdr.0000202748.66359.a9
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