title: Gene expression profiles in preterm infants on continuous long‑term oxygen therapy suggest reduced oxidative stress‑dependent signaling during hypoxia.
abstract: Preterm infants are susceptible to neonatal inflammatory/infective diseases requiring drug therapy. The present study hypothesized that mRNA expression in the blood may be modulated by signaling pathways during treatment. The current study aimed to explore changes in global gene expression in the blood from preterm infants with the objective of identifying patterns or pathways of potential relevance to drug therapy. The infants involved were selected based on maternal criteria indicating increased risk for therapeutic intervention. Global mRNA expression was measured in 107 longitudinal whole blood samples using Affymetrix Human‑Genome‑U133 Plus 2.0‑arrays; samples were obtained from 20 preterm infants. Unsupervised clustering revealed a distinct homogeneous gene expression pattern in 13 samples derived from seven infants undergoing continuous oxygen therapy. At these sampling times, all but one of the seven infants exhibited severe drops in peripheral capillary saturation levels below 60%. The infants were reoxygenated with 100% inspired oxygen concentration. The other samples (n=94) represented the infants from the cohort at time points when they did not undergo continuous oxygen therapy. Comparing these two sets of samples identified a distinct gene expression pattern of 5,986 significantly differentially expressed genes, of which 5,167 genes exhibited reduced expression levels during transient hypoxia. This expression pattern was reversed when the infants became stable, i.e., when they were not continuously oxygenated and had no events of hypoxia. To identify signaling pathways involved in gene regulation, the Database for Annotation, Visualization and Integrated Discovery online tool was used. Mitogen‑activated protein kinases, which are normally induced by oxidative stress, exhibited reduced gene expression during hypoxia. In addition, nuclear factor erythroid 2‑related factor 2‑antioxidant response element target genes involved in oxidative stress protection were also expressed at lower levels, suggesting reduced transcription of this pathway. The findings of the present study suggest that oxidative stress‑dependent signaling is reduced during hypoxia. Understanding the molecular response in preterm infants during continuous oxygenation may aid in refining therapeutic strategies for oxygen therapy.
authors.affiliation: University of Oslo, Institute of Clinical Medicine, Women and Children's Clinic, Rikshospitalet, 0372 Oslo, Norway.
authors.forename: Betty
authors.initials: B
authors.lastname: Kalikstad
authors.affiliation: Department of Medical Sciences, Science for Life Laboratory, Uppsala University, 751 23 Uppsala, Sweden.
authors.forename: Hanna Göransson
authors.initials: HG
authors.lastname: Kultima
authors.affiliation: Department of Molecular Biology, Institute of Medical Microbiology, Oslo University Hospital, Rikshospitalet, 0372 Oslo, Norway.
authors.forename: Terese Kristoffersen
authors.initials: TK
authors.lastname: Andersstuen
authors.affiliation: Department of Molecular Biology, Institute of Medical Microbiology, Oslo University Hospital, Rikshospitalet, 0372 Oslo, Norway.
authors.forename: Arne
authors.initials: A
authors.lastname: Klungland
authors.affiliation: Department of Medical Sciences, Science for Life Laboratory, Uppsala University, 751 23 Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Isaksson
mesh_terms: D061745:Antioxidant Response Elements / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D000860:Hypoxia / Q000235:genetics*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature / Q000378:metabolism*; D008297:Male; D058977:Molecular Sequence Annotation; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics*; D010100:Oxygen / Q000627:therapeutic use*; D015398:Signal Transduction / Q000235:genetics*; D013997:Time Factors; D059467:Transcriptome
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010100:Oxygen