title: Oxidative stress mediates radiation lung injury by inducing apoptosis.
abstract: OBJECTIVE
  Apoptosis in irradiated normal lung tissue has been observed several weeks after radiation. However, the signaling pathway propagating cell death after radiation remains unknown.
  
  
  METHODS
  C57BL/6J mice were irradiated with 15 Gy to the whole thorax. Pro-apoptotic signaling was evaluated 6 weeks after radiation with or without administration of AEOL10150, a potent catalytic scavenger of reactive oxygen and nitrogen species.
  
  
  RESULTS
  Apoptosis was observed primarily in type I and type II pneumocytes and endothelium. Apoptosis correlated with increased PTEN expression, inhibition of downstream PI3K/AKT signaling, and increased p53 and Bax protein levels. Transforming growth factor-β1, Nox4, and oxidative stress were also increased 6 weeks after radiation. Therapeutic administration of AEOL10150 suppressed pro-apoptotic signaling and dramatically reduced the number of apoptotic cells.
  
  
  CONCLUSIONS
  Increased PTEN signaling after radiation results in apoptosis of lung parenchymal cells. We hypothesize that upregulation of PTEN is influenced by Nox4-derived oxidative stress. To our knowledge, this is the first study to highlight the role of PTEN in radiation-induced pulmonary toxicity.
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiuwu
authors.initials: X
authors.lastname: Zhang
authors.forename: Zahid N
authors.initials: ZN
authors.lastname: Rabbani
authors.forename: Isabel L
authors.initials: IL
authors.lastname: Jackson
authors.forename: Zeljko
authors.initials: Z
authors.lastname: Vujaskovic
mesh_terms: D056809:Alveolar Epithelial Cells / Q000502:physiology / Q000528:radiation effects; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D004727:Endothelium / Q000503:physiopathology / Q000528:radiation effects; D005260:Female; D020287:In Situ Nick-End Labeling / Q000379:methods; D008168:Lung / Q000528:radiation effects*; D055370:Lung Injury / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011832:Radiation Injuries / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000099200:Scaffold Protein ILK
chemical_list: D000975:Antioxidants; D053148:Caspase 3; D008665:Metalloporphyrins; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D000099200:Scaffold Protein ILK; C472668:AEOL 10150; C422943:Nox4 protein, mouse; C487757:Pten protein, mouse