title: Mitochondrial DNA damage mediates hyperoxic dysmorphogenesis in rat fetal lung explants.
abstract: BACKGROUND
  Numerous studies in cultured cells indicate that damage to mitochondrial DNA (mtDNA) dictates cellular responses to oxidant stress, yet the consequences of mtDNA damage have not been studied directly in the preterm lung.
  
  
  OBJECTIVE
  We sought to determine whether hyperoxia-induced fetal lung dysmorphogenesis is linked to mtDNA damage and establish mtDNA repair as a potential therapeutic approach for treating lung dysplasia in the preterm neonate.
  
  
  METHODS
  Hyperoxia-induced mtDNA damage was assessed by quantitative alkaline gel electrophoresis in normoxic (3% O2) and hyperoxic (21% O2) fetal rat lung explants. A fusion protein construct targeting the DNA repair enzyme endonuclease III (Endo III) to the mitochondria was used to augment mtDNA repair. Fetal lung branching and surfactant protein C (SFPTC) were assessed in these tissues.
  
  
  RESULTS
  Hyperoxia induced mtDNA damage in lung explants and was accompanied by impaired branching morphogenesis and decreased SFPTC mRNA expression. Treatment of lung explants with Endo III fusion protein prevented hyperoxia-induced mtDNA damage and restored normal branching morphogenesis and SFPTC mRNA expression.
  
  
  CONCLUSIONS
  These findings support the concept that mtDNA governs cellular responses to oxidant stress in the fetal lung and suggest that modulation of mtDNA repair is a potential pharmacologic strategy in the prevention of hyperoxic lung injury.
authors.affiliation: Department of Cell Biology and Neuroscience, University of South Alabama College of Medicine, Mobile, AL 36688, USA. sgebb@usouthal.edu
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Gebb
authors.forename: Ashley
authors.initials: A
authors.lastname: Decoux
authors.forename: Alicia
authors.initials: A
authors.lastname: Waggoner
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Wilson
authors.forename: Mark N
authors.initials: MN
authors.lastname: Gillespie
mesh_terms: D000818:Animals; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000502:physiology*; D043224:Deoxyribonuclease (Pyrimidine Dimer); D004706:Endodeoxyribonucleases / Q000008:administration & dosage / Q000235:genetics; D018496:Hyperoxia / Q000150:complications*; D008168:Lung / Q000196:embryology* / Q000648:ultrastructure; D008171:Lung Diseases / Q000196:embryology* / Q000209:etiology*; D009024:Morphogenesis / Q000187:drug effects; D010100:Oxygen / Q000008:administration & dosage; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D046509:Tissue Culture Techniques
chemical_list: D004272:DNA, Mitochondrial; D011993:Recombinant Fusion Proteins; D004706:Endodeoxyribonucleases; D043224:Deoxyribonuclease (Pyrimidine Dimer); D010100:Oxygen