title: Transcriptome profiling of the newborn mouse lung after hypoxia and reoxygenation: hyperoxic reoxygenation affects mTOR signaling pathway, DNA repair, and JNK-pathway regulation.
abstract: BACKGROUND
  The use of oxygen in acute treatment of asphyxiated term newborns is associated with increased mortality. It is unclear how hyperoxic reoxygenation after hypoxia affects transcriptional changes in the newborn lung.
  
  
  METHODS
  On postnatal day 7, C57BL/6 mice (n = 62) were randomized to 120-min hypoxia (fraction of inspired oxygen (FiO2) 0.08) or normoxia. The hypoxia group was further randomized to reoxygenation for 30 min with FiO2 0.21, 0.40, 0.60, or 1.00, and the normoxia group to FiO2 0.21 or 1.00. Transcriptome profiling was performed on homogenized lung tissue using the Affymetrix 750k expression array, and validation was carried out by real-time polymerase chain reaction and enzyme-linked immunosorbent assay.
  
  
  RESULTS
  The hypoxia-reoxygenation model induced hypoxia-inducible factor 1 (HIF-1) targets like Vegfc, Adm, and Aqp1. In total, ~70% of the significantly differentially expressed genes were detected in the two high hyperoxic groups (FiO2 0.60 and 1.00). Reoxygenation with 100% oxygen after hypoxia uniquely upregulated Gadd45g, Dusp1, Peg3, and Tgm2. Pathway analysis identified mammalian target of rapamycin (mTOR) signaling pathway, DNA repair, c-jun N-terminal kinase (JNK)-pathway regulation, and cell cycle after hyperoxic reoxygenation was applied.
  
  
  CONCLUSIONS
  Acute hypoxia induces HIF-1 targets independent of the reoxygenation regime applied. Hyperoxic reoxygenation affects pathways regulating cell growth and survival. DNA-damage-responsive genes are restricted to reoxygenation with 100% oxygen.
authors.affiliation: Department of Pediatric Research, Women and Children's Division, Oslo University Hospital, Rikshospitalet, University of Oslo, Oslo, Norway.
authors.forename: Embjørg J
authors.initials: EJ
authors.lastname: Wollen
authors.forename: Yngve
authors.initials: Y
authors.lastname: Sejersted
authors.forename: Marianne S
authors.initials: MS
authors.lastname: Wright
authors.forename: Miroslaw
authors.initials: M
authors.lastname: Bik-Multanowski
authors.forename: Anna
authors.initials: A
authors.lastname: Madetko-Talowska
authors.forename: Clara-Cecilie
authors.initials: CC
authors.lastname: Günther
authors.forename: Ståle
authors.initials: S
authors.lastname: Nygård
authors.forename: Przemko
authors.initials: P
authors.lastname: Kwinta
authors.forename: Jacek J
authors.initials: JJ
authors.lastname: Pietrzyk
authors.forename: Ola D
authors.initials: OD
authors.lastname: Saugstad
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000235:genetics / Q000378:metabolism*; D016000:Cluster Analysis; D017931:DNA Primers / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D000860:Hypoxia / Q000628:therapy*; D016014:Linear Models; D008168:Lung / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D010100:Oxygen / Q000009:adverse effects* / Q000627:therapeutic use; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D017931:DNA Primers; D058570:TOR Serine-Threonine Kinases; D010100:Oxygen