title: NRF2 deficiency reduces life span of mice administered thoracic irradiation.
abstract: Subsets of cancer survivors who have been subjected to thoracic irradiation face the prospect of developing pulmonary injury. Radiation-induced pulmonary fibrosis is an insidious injury that presents 6 to 24 months after irradiation and continues to progress over a period of years. TGF-β and reactive oxygen species contribute significantly to the pathogenesis of this injury. The transcription factor NRF2 controls antioxidant gene expression and therefore regulates the cellular oxidant burden. This work demonstrates an additional paradigm for NRF2: suppression of TGF-β-mediated signaling, assessed by measuring expression of a surrogate TGF-β1 target gene (PAI-1) in lung fibroblasts. Thoracic irradiation of Nfe2l2(-/-) mice resulted in rapid expression of PAI-1 and FSP-1 compared to irradiated wild-type mice. Examination of lung tissue 16 weeks after thoracic irradiation of Nfe2l2(-/-) mice revealed the presence of distended alveoli and decreased numbers of alveoli compared to wild-type mice. Suppression of NRF2 expression shortened life span in mice administered 16 Gy to the thorax. Nfe2l2(+/-) and Nfe2l2(-/-) mice exhibited a mean life span of 176 days compared to wild-type mice, which lived an average of 212 days. These novel results identify NRF2 as a susceptibility factor for the development of late tissue injury.
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Travis
authors.forename: Girish
authors.initials: G
authors.lastname: Rachakonda
authors.forename: Xinhui
authors.initials: X
authors.lastname: Zhou
authors.forename: Katrina
authors.initials: K
authors.lastname: Korhonen
authors.forename: Konjeti R
authors.initials: KR
authors.lastname: Sekhar
authors.forename: Swati
authors.initials: S
authors.lastname: Biswas
authors.forename: Michael L
authors.initials: ML
authors.lastname: Freeman
mesh_terms: D000818:Animals; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D006801:Humans; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000528:radiation effects; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D011833:Radiation Injuries, Experimental / Q000378:metabolism* / Q000473:pathology; D017564:Radiation Pneumonitis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D011839:Radiation, Ionizing; D011878:Radiotherapy / Q000009:adverse effects; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000528:radiation effects; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D051267:NF-E2-Related Factor 2; D017395:Plasminogen Activator Inhibitor 1; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D016212:Transforming Growth Factor beta