- Lung maturation
- Lung morphometry
- Vitamin A status
- Retinyl ester storage, liver
- Retinoic acid
Background: Retinyl esters (REs), the major storage form of vitamin A (retinol), provide substrates for the production of bioactive retinoids, including retinoic acid (RA), which are known to promote lung development and maturation. We previously showed that the nutrient-metabolite combination VARA (molar ratio 10 vitamin A to 1 RA), synergistically increased REs in the lungs of 1-week-old rats, compared to vitamin A or RA alone. Objectives: To test the hypotheses, first, that VARA is more effective in increasing lung RE than is vitamin A in newborn rats prior to alveolarization, and, second, that the effect of VARA is maintained during concurrent treatment with the glucocorticoid, dexamethasone (Dex). Methods: Newborn rats were treated with VARA, vitamin A alone, or oil (C) on postnatal days (P) 1–3, and RE in the lungs was quantified on P4, and again on P8 to assess retention. Additionally, neonatal rats were treated on P5–7 with VARA with and without Dex, and the lung and liver REs were quantified on P8. Results and Conclusions: Lung RE was nearly 8-fold higher in VARA compared to vitamin A-treated rats on P4 (p < 0.01) and 2.5-fold higher on P8. In neonates co-treated with Dex and VARA on P5–7, the elevation in lung RE on P8 by VARA was not antagonized by Dex, although Dex reduced growth. Lung morphology and development were not significantly altered. The VARA combination may significantly increase lung RE content even during concurrent Dex therapy. Because lung retinoids are important for lung maturation and repair, increasing lung RE may possibly have clinical benefit.
Copyright © 2007 S. Karger AG, Basel
- Short EJ, Klein NK, Lewis BA, Fulton S, Eisengart S, Kercsmar C, Baley J, Singer LT: Cognitive and academic consequences of bronchopulmonary dysplasia and very low birth weight: 8-year-old outcomes. Pediatrics 2003;112:e359.
- Ambalavanan N, Tyson JE, Kennedy KA, Hansen NI, Vohr BR, Wright LL, Carlo WA; National Institute of Child Health and Human Development Neonatal Research Network: Vitamin A supplementation for extremely low birth weight infants: outcome at 18 to 22 months. Pediatrics 2005;115:e249–e254.
- Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS, Whitfield MF: Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA 2003;289:1124–1129.
- Hustead VA, Gutcher GR, Anderson SA, Zachman RD: Relationship of vitamin A (retinol) status to lung disease in the preterm infant. J Pediatr 1984;105:610–615.
- Shenai JP, Kennedy KA, Chytil F, Stahlman MT: Clinical trial of vitamin A supplementation in infants susceptible to bronchopulmonary dysplasia. J Pediatr 1987;111:269–277.
- Shenai JP, Rush MG, Stahlman MT, Chytil F: Vitamin A supplementation and bronchopulmonary dysplasia – revisited. J Pediatr 1992;121:399–401.
- Tyson JE, Wright LL, Oh W, Kennedy KA, Mele L, Ehrenkranz RA, Stoll BJ, Lemons JA, Stevenson DK, Bauer CR, Korones SB, Fanaroff AA: Vitamin A supplementation for extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med 1999;340:1962–1968.
- Baybutt RC, Hu L, Molteni A: Vitamin A deficiency injures lung and liver parenchyma and impairs function of rat type II pneumocytes. J Nutr 2000;130:1159–1165.
- McGowan SE, Doro MM, Jackson SK: Endogenous retinoids increase perinatal elastin gene expression in rat lung fibroblasts and fetal explants. Am J Physiol 1997;273:L410–L416.
- Bland RD, Albertine KH, Pierce RA, Starcher BC, Carlton DP: Impaired alveolar development and abnormal lung elastin in preterm lambs with chronic lung injury: potential benefits of retinol treatment. Biol Neonate 2003;84:101–102.
- Takatsuka J, Takahashi N, de Luca LM: Retinoic acid metabolism and inhibition of cell proliferation: an unexpected liaison. Cancer Res 1996;56:675–678.
- Clarke N, Germain P, Altucci L, Gronemeyer H: Retinoids: potential in cancer prevention and therapy. Expert Rev Mol Med 2004;6:1–23.
- Warburton D, Schwarz M, Tefft D, Flores-Delgado G, Anderson KD, Cardoso WV: The molecular basis of lung morphogenesis. Mech Dev 2000;92:55–81.
- McGowan SE: Contributions of retinoids to the generation and repair of the pulmonary alveolus. Chest 2002;121(suppl):206S–208S.
- Chinoy MR: Lung growth and development. Front Biosci 2003;8:D392–D415.
- Chytil F: Retinoids in lung development. FASEB J 1996;10:986–992.
- Zachman RD, Grummer MA: Retinoids and lung development; in Zachman RD, Grummer MA (eds): Contemporary Endocrinology. Endocrinology of the Lung: Development and surfactant synthesis. Totowa, Humana Press, 2000, pp 161–179.
- Pierce RA, Shipley JM: Retinoid-enhanced alveolization. Identifying relevant downstream targets. Am J Respir Cell Mol Biol 2000;23:137–141.
- Belloni PN, Garvin L, Mao CP, Bailey-Healy I, Leaffer D: Effects of all-trans-retinoic acid in promoting alveolar repair. Chest 2000;117(suppl 1):235S–241S.
- Massaro D, Massaro GD: Invited review: pulmonary alveoli: formation, the ‘call for oxygen’, and other regulators. Am J Physiol Lung Cell Mol Physiol 2002;282:L345–L358.
- Maden M, Hind M: Retinoic acid in alveolar development, maintenance and regeneration. Philos Trans R Soc Lond B Biol Sci 2004;359:799–808.
- Napoli JL: Enzymology and biogenesis of retinoic acid; in Livrea MA (ed): Vitamin A and Retinoids: An Update of Biological Aspects and Clinical Applications. Basel, Birkhäuser, 2000, pp 17–27.
- Ross AC, Harrison EH: Vitamin A and carotenoids; in McCormick DB, Rucker RR, Suttie JW, Zempleni J (eds): Handbook of Vitamins. Boca Raton, CRC Press, 2006, pp 5–28.
- Shenai JP, Chytil F, Stahlman MT: Liver vitamin A reserves of very low birth weight neonates. Pediatr Res 1985;19:892–893.
- Shenai JP, Rush MG, Stahlman MT, Chytil F: Plasma retinol-binding protein response to vitamin A administration in infants susceptible to bronchopulmonary dysplasia. J Pediatr 1990;116:607–614.
- Zachman RD, Samuels DP, Brand JM, Winston JF, Pi JT: Use of the intramuscular relative-dose-response test to predict bronchopulmonary dysplasia in premature infants. Am J Clin Nutr 1996;63:123–129.
- Shenai JP, Chytil F: Vitamin A storage in lungs during perinatal development in the rat. Biol Neonate 1990;57:126–132.
- Shenai JP, Chytil F: Effect of maternal vitamin-A administration on fetal lung vitamin-A stores in the perinatal rat. Biol Neonate 1990b;58:318–325.
- Ross AC, Ambalavanan N, Zolfaghari R, Li NQ: Vitamin A combined with retinoic acid increases retinol uptake and lung retinyl ester formation in neonatal rats. J Lipid Res 2006;47:1844–1851.
- Roth-Kleiner M, Post M: Similarities and dissimilarities of branching and septation during lung development. Pediatr Pulmonol 2005;40:113–134.
- Grier DG, Halliday HL: Management of bronchopulmonary dysplasia in infants: guidelines for corticosteroid use. Drugs 2005;65:15–29.
- Purdy IB: Perinatal corticosteroids: a review of the research. Part II: Postnatal administration. Neonatal Netw 2004;23:13–25.
- Whitney D, Massaro GD, Massaro D, Clerch LB: Gene expression of cellular retinoid-binding proteins: Modulation by retinoic acid and dexamethasone in postnatal rat lung. Pediatr Res 1999;45:2–7.
- Grummer MA, Zachman RD: Postnatal rat lung retinoic acid receptor (RAR) mRNA expression and effects of dexamethasone on RAR β mRNA. Pediatr Pulmonol 1995;20:234–240.
- Humphrey JH, Agoestina T, Wu L, Usman A, Nurachim M, Subardja D, Hidayat S, Tielsch J, West KP Jr, Sommer A: Impact of neonatal vitamin A supplementation on infant morbidity and mortality. J Pediatr 1996;128:489–496.
- Rahmathullah L, Tielsch JM, Thulasiraj RD, Katz J, Coles C, Devi S, John R, Prakash K, Sadanand AV, Edwin N, Kamaraj C: Impact of supplementing newborn infants with vitamin A on early infant mortality: community based randomised trial in southern India. BMJ 2003;327:254–260.
- Massaro GD, Massaro D: Postnatal treatment with retinoic acid increases the number of pulmonary alveoli in rats. Am J Physiol Lung Cell Mol Physiol 1996;270:L305–L310.
- Massaro D, Massaro GD: Dexamethasone accelerates postnatal alveolar wall thinning and alters wall composition. Am J Physiol Lung Cell Mol Physiol 1986;251:R218–R224.
- Dawson HD, Li NQ, DeCicco KL, Nibert JA, Ross AC: Chronic marginal vitamin A status reduces natural killer cell number and function in aging Lewis rats. J Nutr 1999;129:1510–1517.
- Bruce MC, Bruce EN, Janiga K, Chetty A: Hyperoxic exposure of developing rat lung decreases tropoelastin mRNA levels that rebound postexposure. Am J Physiol Lung Cell Mol Physiol 1993;265:L293–L300.
- Auten RL, Whorton MH, Mason SN: Blocking neutrophil influx reduces DNA damage in hyperoxia-exposed newborn rat lung. Am J Resp Cell Mol Biol 2002;26:391–397.
- Simma B, Luz G, Trawoger R, Hormann C, Klima G, Kreczy A, Baum M: Comparison of different modes of high-frequency ventilation in surfactant-deficient rabbits. Pediatr Pulmonol 1996;22:263–270.
- McGowan S, Jackson SK, Jenkins-Moore M, Dai HH, Chambon P, Snyder JM: Mice bearing deletions of retinoic acid receptors demonstrate reduced lung elastin and alveolar numbers. Am J Respir Cell Mol Biol 2000;23:162–167.
- Cooney TP, Thurlbeck WM: The radial alveolar count method of Emery and Mithal: a reappraisal 1 – postnatal lung growth. Thorax 1982;37:572–579.
- Zachman RD, Kakkad B, Chytil F: Perinatal rat lung retinol (vitamin A) and retinyl palmitate. Pediatr Res 1984;18:1297–1299.
- McMenamy KR, Anderson MJ, Zachman RD: Efffect of dexamethasone and oxygen exposure on neonatal rat lung retinoic acid receptor proteins. Pediatr Pulmonol 1994;18:232–238.
- Grummer MA, Zachman RD: Retinoic acid and dexamethasone affect RAR-beta and surfactant protein C mRNA in the MLE lung cell line. Am J Physiol Lung Cell Mol Physiol 1998;274:L1–L7.
- Okajima S, Matsuda T, Cho K, Matsumoto Y, Kobayashi Y, Fujimoto S: Antenatal dexamethasone administration impairs normal postnatal lung growth in rats. Pediatr Res 2001;49:777–781.
- Villamor E, Fawzi WW: Effects of vitamin A supplementation on immune responses and correlation with clinical outcomes. Clin Microbiol Rev 2005;18:446–464.
- Stephensen CB: Vitamin A, infection, and immune function. Annu Rev Nutr 2001;21:167–192.
- Ching P, Birmingham M, Goodman T, Sutter R, Loevinsohn B: Childhood mortality impact and costs of integrating vitamin A supplementation into immunization campaigns. Am J Public Health 2000;90:1526–1529.
- Ross AC, Zolfaghari R: Regulation of hepatic retinol metabolism: perspectives from studies on vitamin A status. J Nutr 2004;134:269S–275S.
- Valentine AR, Tanumihardjo SA: One-time vitamin A supplementation of lactating sows enhances hepatic retinol in their offspring independent of dose size. Am J Clin Nutr 2005;81:427–433.
- Ross AC, Zolfaghari R, Weisz J: Vitamin A: recent advances in the biotransformation, transport, and metabolism of retinoids. Curr Opin Gastroenterol 2001;17:184–192.
- Georgieff MK, Radmer WJ, Sowell AL, Yeager PR, Blaner WS, Gunter EW, Johnson DE: The effect of glucocorticosteroids on serum, liver, and lung vitamin A and retinyl ester concentrations. J Pediatr Gastroenterol Nutr 1991;382:376–382.
- Massaro GD, Massaro D: Retinoic acid treatment partially rescues failed septation in rats and in mice. Am J Physiol Lung Cell Mol Physiol 2000;278:L955–L960.
- Srinivasan G, Bruce EN, Houtz PK, Bruce MC: Dexamethasone-induced changes in lung function are not prevented by concomitant treatment with retinoic acid. Am J Physiol Lung Cell Mol Physiol 2002;283:L275–L287.
Dr. A. Catharine Ross
Department of Nutritional Sciences and Huck Institute for Life Sciences
126-S Henderson Building, Pennsylvania State University
University Park, PA 16802 (USA)
Tel. +1 814 865 4721, Fax +1 814 865 4723, E-Mail email@example.com
Received: July 17, 2006
Accepted after revision: September 25, 2006
Published online: February 23, 2007
Number of Print Pages : 7
Number of Figures : 2, Number of Tables : 1, Number of References : 57
Neonatology (Fetal and Neonatal Research)
Vol. 92, No. 1, Year 2007 (Cover Date: June 2007)
Journal Editor: Halliday, H.L. (Belfast)
ISSN: 1661–7800 (print), 1661–7819 (Online)
For additional information: http://www.karger.com/NEO
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.