Mifepristone-inducible recombinant adenovirus attenuates paraquat-induced lung injury in rats.
Hum Exp Toxicol
; 34(1): 32-43, 2015 Jan.
Article
em En
| MEDLINE
| ID: mdl-24812154
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-1ß (IL-1ß) 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).CONCLUSION:
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Paraquat
/
Adenoviridae
/
Fator 2 Relacionado a NF-E2
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Lesão Pulmonar
/
Herbicidas
Limite:
Animals
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article