title: Regulation of lung maturation by prolyl hydroxylase domain inhibition in the lung of the normally grown and placentally restricted fetus in late gestation.
abstract: Intrauterine growth restriction induced by placental restriction (PR) in sheep leads to chronic hypoxemia and reduced surfactant maturation. The underlying molecular mechanism involves altered regulation of hypoxia signaling by increased prolyl hydroxylase domain (PHD) expression. Here, we evaluated the effect of intratracheal administration of the PHD inhibitor dimethyloxalylglycine (DMOG) on functional, molecular, and structural determinants of lung maturation in the control and PR sheep fetus. There was no effect of DMOG on fetal blood pressure or fetal breathing movements. DMOG reduced lung expression of genes regulating hypoxia signaling (HIF-3α, ACE1), antioxidant defense (CAT), lung liquid reabsorption (SCNN1-A, ATP1-A1, AQP-1, AQP-5), and surfactant maturation (SFTP-A, SFTP-B, SFTP-C, PCYT1A, LPCAT, ABCA3, LAMP3) in control fetuses. There were very few effects of DMOG on gene expression in the PR fetal lung (reduced lung expression of angiogenic factor ADM, water channel AQP-5, and increased expression of glucose transporter SLC2A1). DMOG administration in controls reduced total lung lavage phosphatidylcholine to the same degree as in PR fetuses. These changes appear to be regulated at the molecular level as there was no effect of DMOG on the percent tissue, air space, or numerical density of SFTP-B positive cells in the control and PR lung. Hence, DMOG administration mimics the effects of PR in reducing surfactant maturation in the lung of control fetuses. The limited responsiveness of the PR fetal lung suggests a potential biochemical limit or reduced plasticity to respond to changes in regulation of hypoxia signaling following exposure to chronic hypoxemia in utero.
authors.affiliation: Early Origins of Adult Health Research Group and Molecular and Evolutionary Physiology of the Lung Laboratory, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia.
authors.forename: Erin V
authors.identifier: 0000-0002-9849-5958
authors.initials: EV
authors.lastname: McGillick
authors.affiliation: Molecular and Evolutionary Physiology of the Lung Laboratory, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Orgeig
authors.affiliation: Early Origins of Adult Health Research Group and janna.morrison@unisa.edu.au.
authors.forename: Janna L
authors.identifier: 0000-0002-8602-8519
authors.initials: JL
authors.lastname: Morrison
mesh_terms: D000818:Animals; D005260:Female; D005317:Fetal Growth Retardation / Q000201:enzymology*; D005865:Gestational Age; D008168:Lung / Q000196:embryology / Q000201:enzymology* / Q000254:growth & development*; D064828:Prolyl Hydroxylases / Q000737:chemistry / Q000378:metabolism*; D064800:Prolyl-Hydroxylase Inhibitors / Q000378:metabolism*; D000072417:Protein Domains; D017382:Reactive Oxygen Species / Q000378:metabolism; D012756:Sheep; D013329:Structure-Activity Relationship
chemical_list: D064800:Prolyl-Hydroxylase Inhibitors; D017382:Reactive Oxygen Species; D064828:Prolyl Hydroxylases
keywords: DMOG; chronic hypoxemia; fetal lung; intrauterine growth restriction; surfactant