title: Mifepristone-inducible recombinant adenovirus attenuates paraquat-induced lung injury in rats.
abstract: OBJECTIVE
  To investigate the effects of overexpression of nuclear factor E2-related factor-2 (NRF2) on lung injury in rats exposed to paraquat (PQ) poisoning.
  
  
  METHODS
  A mifepristone (RU486)-inducible recombinant adenoviral vector carrying the human NRF2 gene (Ad-RUNRF2) was constructed and transfected via airway into the rats 7 days before the administration of RU486. Rats were orally challenged with PQ at 20 mg/kg 24 h after the injection of RU486. On days 0.5, 3 and 21 after PQ poisoning, the expressions of NRF2 and cytokines related to inflammation and oxidation in lung tissue were examined.
  
  
  RESULTS
  RU486 remarkably enhanced NRF2 mRNA and NRF2 protein levels in Ad-RUNRF2-transfected rats in a dose-dependent manner (p < 0.01). PQ stimulated compensatory overexpression of NRF2, heme oxygenase 1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO-1) in lungs on days 0.5 and 3 after exposure (p < 0.05), but depleted the expression of catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione (GSH), with an increased malondialdehyde (MDA) (p < 0.05). However, pretreatment with Ad-RUNRF2 and RU486 strongly enhanced the expression levels of NRF2, HO-1, NQO-1, CAT and GSH-Px in the lungs of PQ intoxicated rats, with increased GSH and decreased MDA (p < 0.05). Pretreatment with Ad-RUNRF2 and RU486 also strongly suppressed the PQ-induced activation of nuclear factor κB (NF-κB) and decreased the levels of tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). In addition, Ad-RUNRF2 and RU486 induction significantly reduced PQ-induced pathological changes in lungs and attenuated lung oedema and protein leakage caused by PQ (p < 0.05).
  
  
  CONCLUSIONS
  RU486-induced overexpression of NRF2 in lungs transfected with Ad-RUNRF2 can ameliorate PQ-induced lung injury by the activation of the NRF2-antioxidant response element (ARE) pathway.
authors.affiliation: Department of Emergency Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: G-L
authors.initials: GL
authors.lastname: Hong
authors.affiliation: Emergency Intensive Care Unit, The First People's Hospital, Taizhou, Zhejiang, China.
authors.forename: Q-Q
authors.initials: QQ
authors.lastname: Cai
authors.affiliation: Department of Emergency Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: J-P
authors.initials: JP
authors.lastname: Tan
authors.affiliation: Department of Emergency Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: X-Z
authors.initials: XZ
authors.lastname: Jiang
authors.affiliation: Department of Emergency Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: G-J
authors.initials: GJ
authors.lastname: Zhao
authors.affiliation: Department of Emergency Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: B
authors.initials: B
authors.lastname: Wu
authors.affiliation: Department of Emergency Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: M-F
authors.initials: MF
authors.lastname: Li
authors.affiliation: Department of Emergency Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Q-M
authors.initials: QM
authors.lastname: Qiu
authors.affiliation: Department of Emergency Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China honggl98@163.com lzq640815@163.com.
authors.forename: Z-Q
authors.initials: ZQ
authors.lastname: Lu
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002374:Catalase / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006540:Herbicides / Q000633:toxicity*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008297:Male; D015735:Mifepristone; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D010269:Paraquat / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D016207:Cytokines; D006540:Herbicides; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D015735:Mifepristone; D002374:Catalase; D005979:Glutathione Peroxidase; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat; D005978:Glutathione; D010269:Paraquat
keywords: NF-κB; NRF2; PQ poisoning; RU486 inducible regulation system