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Adaptation of the Oxygen Sensing System during Lung Development

  • During gestation, the most drastic change in oxygen supply occurs with the onset of ventilation after birth. As the too early exposure of premature infants to high arterial oxygen pressure leads to characteristic diseases, we studied the adaptation of the oxygen sensing system and its targets, the hypoxia-inducible factor- (HIF-) regulated genes (HRGs) in the developing lung. We draw a detailed picture of the oxygen sensing system by integrating information from qPCR, immunoblotting, in situ hybridization, and single-cell RNA sequencing data in ex vivo and in vivo models. HIF1α protein was completely destabilized with the onset of pulmonary ventilation, but did not coincide with expression changes in bona fide HRGs. We observed a modified composition of the HIF-PHD system from intrauterine to neonatal phases: Phd3 was significantly decreased, while Hif2a showed a strong increase and the Hif3a isoform Ipas exclusively peaked at P0. Colocalization studies point to the Hif1a-Phd1 axis as the main regulator of the HIF-PHD system in mouse lung development, complemented by the Hif3a-Phd3 axis during gestation. Hif3a isoform expression showed a stepwise adaptation during the periods of saccular and alveolar differentiation. With a strong hypoxic stimulus, lung ex vivo organ cultures displayed a functioning HIF system at every developmental stage. Approaches with systemic hypoxia or roxadustat treatment revealed only a limited in vivo response of HRGs. Understanding the interplay of the oxygen sensing system components during the transition from saccular to alveolar phases of lung development might help to counteract prematurity-associated diseases like bronchopulmonary dysplasia.

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Author:Karin Michaela KirschnerORCiD, Simon KelterbornORCiD, Herrmann Stehr, Johanna L. T. PenzlinORCiD, Charlotte L. J. JacobiORCiD, Stefanie EndesfelderORCiD, Miriam SiegORCiD, Jochen Kruppa-ScheetzORCiD, Christof DameORCiD, Lina Katrin SciesielskiORCiD
Title (English):Adaptation of the Oxygen Sensing System during Lung Development
Parent Title (English):Oxidative Medicine and Cellular Longevity : Special Issue
Document Type:Article
Year of Completion:2022
Release Date:2024/04/22
Article Number:9714669
Page Number:15
Faculties:Fakultät AuL
DDC classes:600 Technik, Medizin, angewandte Wissenschaften / 610 Medizin, Gesundheit
Review Status:Veröffentlichte Fassung/Verlagsversion
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International