TY - JOUR
T1 - Molecular regulation of lung maturation in near-term fetal sheep by maternal daily vitamin C treatment in late gestation
AU - McGillick, Erin V.
AU - Orgeig, Sandra
AU - Allison, Beth J.
AU - Brain, Kirsty L.
AU - Niu, Youguo
AU - Itani, Nozomi
AU - Skeffington, Katie L.
AU - Kane, Andrew D.
AU - Herrera, Emilio A.
AU - Morrison, Janna L.
AU - Giussani, Dino A.
N1 - Funding Information:
We acknowledge the support of staff from University Biological Services at The Barcroft Centre, University of Cambridge and the Early Origins of Adult Health Research Group, Emma Bradshaw and Stacey Holman, in performing the Western blots. This work was funded by a program grant (RG/17/8/32924) from The British Heart Foundation (DG) and a National Health and Medical Research Council (NHMRC) Project Grant (APP1030853, J.L.M. and S.O.). E.V.M. is supported by an NHMRC Peter Doherty Biomedical Early Career Fellowship (APP1138049). D.A.G. is Professor of Cardiovascular Physiology and Medicine at the Department of Physiology Development and Neuroscience at the University of Cambridge, Professorial Fellow and Director of Studies in Medicine at Gonville and Caius College, a Lister Institute Fellow, and a Royal Society Wolfson Research Merit Award Holder. J.L.M. is funded by an NHMRC Career Development Fellowship (APP1066916) and an Australian Research Council Future Fellowship (Level 3; FT170100431).
Publisher Copyright:
© 2021, The Author(s).
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2022/3
Y1 - 2022/3
N2 - Background: In the fetus, the appropriate balance of prooxidants and antioxidants is essential to negate the detrimental effects of oxidative stress on lung maturation. Antioxidants improve respiratory function in postnatal life and adulthood. However, the outcomes and biological mechanisms of antioxidant action in the fetal lung are unknown. Methods: We investigated the effect of maternal daily vitamin C treatment (200 mg/kg, intravenously) for a month in late gestation (105–138 days gestation, term ~145 days) on molecular regulation of fetal lung maturation in sheep. Expression of genes and proteins regulating lung development was quantified in fetal lung tissue. The number of surfactant-producing cells was determined by immunohistochemistry. Results: Maternal vitamin C treatment increased fetal lung gene expression of the antioxidant enzyme SOD-1, hypoxia signaling genes (HIF-2α, HIF-3α, ADM, and EGLN-3), genes regulating sodium movement (SCNN1-A, SCNN1-B, ATP1-A1, and ATP1-B1), surfactant maturation (SFTP-B and ABCA3), and airway remodeling (ELN). There was no effect of maternal vitamin C treatment on the expression of protein markers evaluated or on the number of surfactant protein-producing cells in fetal lung tissue. Conclusions: Maternal vitamin C treatment in the last third of pregnancy in sheep acts at the molecular level to increase the expression of genes that are important for fetal lung maturation in a healthy pregnancy. Impact: Maternal daily vitamin C treatment for a month in late gestation in sheep increases the expression of gene-regulating pathways that are essential for normal fetal lung development.Following late gestation vitamin C exposure in a healthy pregnancy, an increase in lung gene but not protein expression may act as a mechanism to aid in the preparation for exposure to the air-breathing environment after birth.In the future, the availability/development of compounds with greater antioxidant properties than vitamin C or more specific targets at the site of oxidative stress in vivo may translate clinically to improve respiratory outcomes in complicated pregnancies at birth.
AB - Background: In the fetus, the appropriate balance of prooxidants and antioxidants is essential to negate the detrimental effects of oxidative stress on lung maturation. Antioxidants improve respiratory function in postnatal life and adulthood. However, the outcomes and biological mechanisms of antioxidant action in the fetal lung are unknown. Methods: We investigated the effect of maternal daily vitamin C treatment (200 mg/kg, intravenously) for a month in late gestation (105–138 days gestation, term ~145 days) on molecular regulation of fetal lung maturation in sheep. Expression of genes and proteins regulating lung development was quantified in fetal lung tissue. The number of surfactant-producing cells was determined by immunohistochemistry. Results: Maternal vitamin C treatment increased fetal lung gene expression of the antioxidant enzyme SOD-1, hypoxia signaling genes (HIF-2α, HIF-3α, ADM, and EGLN-3), genes regulating sodium movement (SCNN1-A, SCNN1-B, ATP1-A1, and ATP1-B1), surfactant maturation (SFTP-B and ABCA3), and airway remodeling (ELN). There was no effect of maternal vitamin C treatment on the expression of protein markers evaluated or on the number of surfactant protein-producing cells in fetal lung tissue. Conclusions: Maternal vitamin C treatment in the last third of pregnancy in sheep acts at the molecular level to increase the expression of genes that are important for fetal lung maturation in a healthy pregnancy. Impact: Maternal daily vitamin C treatment for a month in late gestation in sheep increases the expression of gene-regulating pathways that are essential for normal fetal lung development.Following late gestation vitamin C exposure in a healthy pregnancy, an increase in lung gene but not protein expression may act as a mechanism to aid in the preparation for exposure to the air-breathing environment after birth.In the future, the availability/development of compounds with greater antioxidant properties than vitamin C or more specific targets at the site of oxidative stress in vivo may translate clinically to improve respiratory outcomes in complicated pregnancies at birth.
UR - https://www.scopus.com/pages/publications/85104725366
U2 - 10.1038/s41390-021-01489-4
DO - 10.1038/s41390-021-01489-4
M3 - Article
C2 - 33859366
AN - SCOPUS:85104725366
SN - 0031-3998
VL - 91
SP - 828
EP - 838
JO - Pediatric Research
JF - Pediatric Research
IS - 4
ER -