Date Published: September 26, 2017
Publisher: Public Library of Science
Author(s): Jia Yin Soo, Sandra Orgeig, Erin Victoria McGillick, Song Zhang, I Caroline McMillen, Janna L. Morrison, Rory Edward Morty.
Intrauterine growth restriction (IUGR) induced by placental restriction (PR) in the sheep negatively impacts lung and pulmonary surfactant development during fetal life. Using a sheep model of low birth weight (LBW), we found that there was an increase in mRNA expression of surfactant protein (SP)-A, -B and -C in the lung of LBW lambs but no difference in the protein expression of SP-A or -B. LBW also resulted in increased lysosome-associated membrane glycoprotein (LAMP)-3 mRNA expression, which may indicate an increase in either the density of type II Alveolar epithelial cells (AEC) or maturity of type II AECs. Although there was an increase in glucocorticoid receptor (GR) and 11β-hydroxysteroid dehydrogenase (11βHSD)-1 mRNA expression in the lung of LBW lambs, we found no change in the protein expression of these factors, suggesting that the increase in SP mRNA expression is not mediated by increased GC signalling in the lung. The increase in SP mRNA expression may, in part, be mediated by persistent alterations in hypoxia signalling as there was an increase in lung HIF-2α mRNA expression in the LBW lamb. The changes in the hypoxia signalling pathway that persist within the lung after birth may be involved in maintaining SP production in the LBW lamb.
Intrauterine lung development and maturation are critically important for postnatal survival of the neonate. An important step in fetal lung development in late gestation is the maturation of the pulmonary surfactant system, which consists of a complex mixture of ∼90% lipids and 8–10% surfactant proteins (SP) . Pulmonary surfactant is synthesised in type II alveolar epithelial cells (AEC), stored in lamellar bodies and under appropriate conditions is secreted via exocytosis into the alveolar space . SP-B and -C, which are hydrophobic surfactant proteins, interact with the lipid component to facilitate adsorption of the surfactant film to the air-liquid interface of the alveoli. This film reduces the work of breathing by maintaining stability between alveolar units and preventing adherence of the alveolar walls during expiration . SP-A and -D play important roles as effectors of the pulmonary innate immune system [4,5].
All procedures were approved by the University of Adelaide Animal Ethics Committee and conformed to the NHMRC Australian code of practice for the care and use of animals for scientific purposes.
In this study, we have shown that there is an increase in lung mRNA expression of SP-A, -B and -C in LBW compared with ABW lambs at 21 days after birth which is in contrast to the decrease in SP-A, SP-B and SP-C mRNA expression and protein abundance in the lung of the PR fetus in late gestation [27,28]. Despite the an absolute fold change of ~2.0-fold increase in SP-Aand absolute fold change of ~1.7-fold increase in -B mRNA expression in the lung of LBW lambs in this study, there was no difference in the protein expression of either SP-A or -B. Hence, the deficit in lung tissue SP in the PR fetus observed in late gestation was normalised by 21d after birth in the LBW lamb, possibly as a result of the persistent elevation in SP mRNA expression. In this study, we have further examined the role of a range of intrapulmonary signalling pathways, including regulation by GCs, hypoxia, PPARγ, cellular proliferation and global methylation, which may be responsible for the altered regulation of surfactant maturation in the LBW lamb.