In this work, we evaluate the lung retinoids content to study the possible difference between male and female mice during prenatal development and to comprehend if the vitamin A metabolism is similar in both genders. The study occurred between developmental days E15 and E19, and the retinol and retinyl palmitate lung contents were determined by HPLC analysis. We established two main groups: the control, consisting of foetuses obtained from pregnant females without any manipulation, and vitamin A, composed of foetuses from pregnant females submitted to vitamin A administration on developmental day E14. Each of these groups was subdivided by gender, establishing the four final groups. In the lung of control group, retinol was undetected in both genders and retinyl palmitate levels exhibited a sexual dimorphism. In the vitamin A group, we detected retinol and retinyl palmitate in both genders, and we observed a more evident sexual dimorphism for both retinoids. Our study also indicates that, from developmental day E15 to E19, there is an increase in the retinoids content in foetal lung and a gender difference in the retinoids metabolism. In conclusion, there is a sexual dimorphism in the lung retinoids content and in its metabolism during mice development. 1. Introduction Vitamin A has been regarded as a major contributor in the differentiation and maturation of the lung [1–3], and there is no doubt that retinoids, especially retinoic acid, are essential for the lung development [4]. Until now, little is known about the acquisition and use of stored retinoids, but functionally they are involved in lung differentiation and maturation [2, 3], surfactant production [5, 6], inducing the formation of alveolar septa [7–9], cell differentiation [1, 2, 10, 11], elastin synthesis and deposition [12–17], homeostasis and lung repair [18, 19], and alveolar regeneration capacity [20, 21]. Some studies showed the potential usefulness of retinoids in reducing the incidence of bronchopulmonary dysplasia (BPD) in newborns, because indirectly retinoic acid is able to inhibit the effect of glucocorticoids that are often used to treat this pathology [22, 23]. The administration of vitamin A to premature newborns with low birth weight subjected to mechanical ventilation promotes the regeneration of lung injury by reducing the morbidity associated with BPD [22, 23]. Administration of a vitamin A supplement 48 hours after birth significantly reduced the mortality of newborns during the first 3-4 months of life, and the greatest benefit occurs in children with low birth weight
References
[1]
H. K. Biesalski and D. Nohr, “Importance of vitamin-A for lung function and development,” Molecular Aspects of Medicine, vol. 24, no. 6, pp. 431–440, 2003.
[2]
F. Chytil, “The lungs and vitamin A,” American Journal of Physiology, vol. 262, no. 5, pp. L517–L527, 1992.
[3]
F. Chytil, “Retinoids in lung development,” The FASEB Journal, vol. 10, no. 9, pp. 986–992, 1996.
[4]
M. L. Pinto, P. Rodrigues, A. Honório, C. Gon？alves, and V. Bairos, “Vitamin A and lung development,” in Vitamin A: Nutrition, Side Effects and Supplements, L. P. Scott, Ed., pp. 1–46, Nova Science, 2010.
[5]
C. Fraslon and J. R. Bourbon, “Retinoids control surfactant phospholipid biosynthesis in fetal rat lung,” American Journal of Physiology, vol. 266, no. 6, pp. L705–L712, 1994.
[6]
M. D. Metzler and J. M. Snyder, “Retinoic acid differentially regulates expression of surfactant-associated proteins in human fetal lung,” Endocrinology, vol. 133, no. 5, pp. 1990–1998, 1993.
[7]
G. D. Massaro and D. Massaro, “Postnatal treatment with retinoic acid increases the number of pulmonary alveoli in rats,” American Journal of Physiology, vol. 270, no. 2, pp. L305–L310, 1996.
[8]
G. D. Massaro and D. Massaro, “Retinoic acid treatment partially rescues failed septation in rats and in mice,” American Journal of Physiology, vol. 278, no. 5, pp. L955–L960, 2000.
[9]
G. D. C. Massaro, D. Massaro, W. Y. Chan et al., “Retinoic acid receptor-β: an endogenous inhibitor of the perinatal formation of pulmonary alveoli,” Physiological Genomics, vol. 4, no. 1, pp. 51–57, 2000.
[10]
R. H. Costa, V. V. Kalinichenko, and L. Lim, “Transcription factors in mouse lung development and function,” American Journal Respiratory Cell Molecular Biology, vol. 280, no. 5, pp. L823–L838, 2001.
[11]
C. Wongtrakool, S. Malpel, J. Gorenstein et al., “Down-regulation of retinoic acid receptor α signaling is required for sacculation and type I cell formation in the developing lung,” Journal of Biological Chemistry, vol. 278, no. 47, pp. 46911–46918, 2003.
[12]
R. Liu, C. S. Harvey, and S. E. McGowan, “Retinoic acid increases elastin in neonatal rat lung fibroblast cultures,” American Journal of Physiology, vol. 265, no. 5, pp. L430–L437, 1993.
[13]
G. D. Massaro and D. Massaro, “Formation of pulmonary alveoli and gas-exchange surface area: quantitation and regulation,” Annual Review of Physiology, vol. 58, pp. 73–92, 1996.
[14]
S. E. McGowan, C. S. Harvey, and S. K. Jackson, “Retinoids, retinoic acid receptors, and cytoplasmic retinoid binding proteins in perinatal rat lung fibroblasts,” American Journal of Physiology, vol. 269, no. 4, pp. L463–L472, 1995.
[15]
S. E. McGowan and J. S. Torday, “The pulmonary lipofibroblast (lipid interstitial cell) and its contributions to alveolar development,” Annual Review of Physiology, vol. 59, pp. 43–62, 1997.
[16]
S. E. McGowan, M. M. Doro, and S. K. Jackson, “Endogenous retinoids increase perinatal elastin gene expression in rat lung fibroblasts and fetal explants,” American Journal of Physiology, vol. 273, no. 2, pp. L410–L416, 1997.
[17]
S. McGowan, S. K. Jackson, M. Jenkins-Moore, H. H. Dai, P. Chambon, and J. M. Snyder, “Mice bearing deletions of retinoic acid receptors demonstrate reduced lung elastin and alveolar numbers,” American Journal of Respiratory Cell and Molecular Biology, vol. 23, no. 2, pp. 162–167, 2000.
[18]
W. Shi, F. Chen, and W. V. Cardoso, “Mechanisms of lung development: contribution to adult lung disease and relevance to chronic obstructive pulmonary disease,” Proceedings of the American Thoracic Society, vol. 6, no. 7, pp. 558–563, 2009.
[19]
J. S. Torday and V. K. Rehan, “Does “A” stand for alveolization?” European Respiratory Journal, vol. 23, no. 1, pp. 3–4, 2004.
[20]
M. Hind and M. Maden, “Retinoic acid induces alveolar regeneration in the adult mouse lung,” European Respiratory Journal, vol. 23, no. 1, pp. 20–27, 2004.
[21]
M. Maden, “Retinoids have differing efficacies on alveolar regeneration in a dexamethasone-treated mouse,” American Journal of Respiratory Cell and Molecular Biology, vol. 35, no. 2, pp. 260–267, 2006.
[22]
J. P. Shenai, K. A. Kennedy, F. Chytil, and M. T. Stahlman, “Clinical trial of vitamin A supplementation in infants susceptible to bronchopulmonary dysplasia,” Journal of Pediatrics, vol. 111, no. 2, pp. 269–277, 1987.
[23]
J. P. Shenai, M. G. Rush, M. T. Stahlman, and F. Chytil, “Plasma retinol-binding protein response to vitamin A administration in infants susceptible to bronchopulmonary dysplasia,” Journal of Pediatrics, vol. 116, no. 4, pp. 607–614, 1990.
[24]
L. Rahmathullah, J. M. Tielsch, R. D. Thulasiraj et al., “Impact of supplementing newborn infants with vitamin A on early infant mortality: community based randomised trial in southern India,” BMJ, vol. 327, no. 7409, pp. 254–257, 2003.
[25]
K. A. Kennedy, B. J. Stoll, R. A. Ehrenkranz et al., “Vitamin A to prevent bronchopulmonary dysplasia in very-low-birth-weight infants: has the dose been too low?” Early Human Development, vol. 49, no. 1, pp. 19–31, 1997.
[26]
M. C. Bruce, C. E. Honaker, and R. J. Cross, “Lung fibroblasts undergo apoptosis following alveolarization,” American Journal of Respiratory Cell and Molecular Biology, vol. 20, no. 2, pp. 228–236, 1999.
[27]
M. Nakajoh, T. Fukushima, T. Suzuki et al., “Retinoic acid inhibits elastase-induced injury in human lung epithelial cell lines,” American Journal of Respiratory Cell and Molecular Biology, vol. 28, no. 3, pp. 296–304, 2003.
[28]
S. K. Geevarghese and F. Chytil, “Depletion of retinyl esters in the lungs coincides with lung prenatal morphological maturation,” Biochemical and Biophysical Research Communications, vol. 200, no. 1, pp. 529–535, 1994.
[29]
T. J. Desai, S. Malpel, G. R. Flentke, S. M. Smith, and W. V. Cardoso, “Retinoic acid selectively regulates Fgf10 expression and maintains cell identity in the prospective lung field of the developing foregut,” Developmental Biology, vol. 273, no. 2, pp. 402–415, 2004.
[30]
C. Mendelsohn, D. Lohnes, D. Décimo et al., “Function of the retinoic acid receptors (RARs) during development. (II) Multiple abnormalities at various stages of organogenesis in RAR double mutants,” Development, vol. 120, no. 10, pp. 2749–2771, 1994.
[31]
Z. Wang, P. Dollé, W. V. Cardoso, and K. Niederreither, “Retinoic acid regulates morphogenesis and patterning of posterior foregut derivatives,” Developmental Biology, vol. 297, no. 2, pp. 433–445, 2006.
[32]
P. Rodrigues, C. Gon？alves, and V. Bairos, “Metabolic pathways and modulating effects of vitamin A,” Current Medicinal Chemistry: Immunology, Endocrine and Metabolic Agents, vol. 4, no. 2, pp. 119–142, 2004.
[33]
R. Blomhoff, M. H. Green, T. Berg, and K. R. Norum, “Transport and storage of vitamin A,” Science, vol. 250, no. 4979, pp. 399–404, 1990.
[34]
D. S. Goodman, “Vitamin A and retinoids in health and disease,” The New England Journal of Medicine, vol. 310, no. 16, pp. 1023–1031, 1984.
[35]
M. E. Newcomer and D. E. Ong, “Plasma retinol binding protein: structure and function of the prototypic lipocalin,” Biochimica et Biophysica Acta, vol. 1482, no. 1-2, pp. 57–64, 2000.
[36]
N. Noy, “Retinoid-binding proteins: mediators of retinoid action,” Biochemical Journal, vol. 348, no. 3, pp. 481–495, 2000.
[37]
J. L. Napoli, “Retinoic acid biosynthesis and metabolism,” The FASEB Journal, vol. 10, no. 9, pp. 993–1001, 1996.
[38]
T. Okabe, H. Yorifuji, E. Yamada, and F. Takaku, “Isolation and characterization of vitamin-A-storing lung cells,” Experimental Cell Research, vol. 154, no. 1, pp. 125–135, 1984.
[39]
J. P. Shenai and F. Chytil, “Vitamin A storage in lungs during perinatal development in the rat,” Biology of the Neonate, vol. 57, no. 2, pp. 126–132, 1990.
[40]
H. J. Maksvytis, C. Vaccaro, and J. S. Brody, “Isolation and characterization of the lipid-containing interstitial cell from the developing rat lung,” Laboratory Investigation, vol. 45, no. 3, pp. 248–259, 1981.
[41]
W. V. Cardoso, “Lung morphogenesis, role of growth factors and transcription factors,” in The Lung Development, Aging and the Environment, R. Harding, K. E. Pinkerton, and C. G. Plopper, Eds., cap. 1, pp. 3–11, Elsevier, London, UK, 2004.
[42]
T. J. Desai, F. Chen, J. Lü et al., “Distinct roles for retinoic acid receptors alpha and beta in early lung morphogenesis,” Developmental Biology, vol. 291, no. 1, pp. 12–24, 2006.
[43]
S. Malpel, C. Mendelsohn, and W. V. Cardoso, “Regulation of retinoic acid signaling during lung morphogenesis,” Development, vol. 127, no. 14, pp. 3057–3067, 2000.
[44]
S. Bellusci, J. Grindley, H. Emoto, N. Itoh, and B. L. M. Hogan, “Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung,” Development, vol. 124, no. 23, pp. 4867–4878, 1997.
[45]
F. Chen, T. J. Desai, J. Qian, K. Niederreither, J. Lü, and W. V. Cardoso, “Inhibition of Tgfβ signaling by endogenous retinoic acid is essential for primary lung bud induction,” Development, vol. 134, no. 16, pp. 2969–2979, 2007.
