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Mifepristone-inducible recombinant adenovirus attenuates paraquat-induced lung injury in rats.
Hum Exp Toxicol. 2015 Jan; 34(1):32-43.HE

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).

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.

Authors+Show Affiliations

Department of Emergency Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.Emergency Intensive Care Unit, The First People's Hospital, Taizhou, Zhejiang, China.Department of Emergency Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.Department of Emergency Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.Department of Emergency Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.Department of Emergency Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.Department of Emergency Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.Department of Emergency Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.Department of Emergency Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China honggl98@163.com lzq640815@163.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24812154

Citation

Hong, G-L, et al. "Mifepristone-inducible Recombinant Adenovirus Attenuates Paraquat-induced Lung Injury in Rats." Human & Experimental Toxicology, vol. 34, no. 1, 2015, pp. 32-43.
Hong GL, Cai QQ, Tan JP, et al. Mifepristone-inducible recombinant adenovirus attenuates paraquat-induced lung injury in rats. Hum Exp Toxicol. 2015;34(1):32-43.
Hong, G. L., Cai, Q. Q., Tan, J. P., Jiang, X. Z., Zhao, G. J., Wu, B., Li, M. F., Qiu, Q. M., & Lu, Z. Q. (2015). Mifepristone-inducible recombinant adenovirus attenuates paraquat-induced lung injury in rats. Human & Experimental Toxicology, 34(1), 32-43. https://doi.org/10.1177/0960327114532381
Hong GL, et al. Mifepristone-inducible Recombinant Adenovirus Attenuates Paraquat-induced Lung Injury in Rats. Hum Exp Toxicol. 2015;34(1):32-43. PubMed PMID: 24812154.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mifepristone-inducible recombinant adenovirus attenuates paraquat-induced lung injury in rats. AU - Hong,G-L, AU - Cai,Q-Q, AU - Tan,J-P, AU - Jiang,X-Z, AU - Zhao,G-J, AU - Wu,B, AU - Li,M-F, AU - Qiu,Q-M, AU - Lu,Z-Q, Y1 - 2014/05/08/ PY - 2014/5/10/entrez PY - 2014/5/9/pubmed PY - 2015/9/1/medline KW - NF-κB KW - NRF2 KW - PQ poisoning KW - RU486 inducible regulation system SP - 32 EP - 43 JF - Human & experimental toxicology JO - Hum Exp Toxicol VL - 34 IS - 1 N2 - 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). 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. SN - 1477-0903 UR - https://www.unboundmedicine.com/medline/citation/24812154/Mifepristone_inducible_recombinant_adenovirus_attenuates_paraquat_induced_lung_injury_in_rats_ L2 - https://journals.sagepub.com/doi/10.1177/0960327114532381?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -