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The thioredoxin reductase inhibitor auranofin induces heme oxygenase-1 in lung epithelial cells via Nrf2-dependent mechanisms.
Am J Physiol Lung Cell Mol Physiol. 2018 10 01; 315(4):L545-L552.AJ

Abstract

Thioredoxin reductase-1 (TXNRD1) inhibition effectively activates nuclear factor (erythroid-derived 2)-like 2 (Nrf2) responses and attenuates lung injury in acute respiratory distress syndrome (ARDS) and bronchopulmonary dysplasia (BPD) models. Upon TXNRD1 inhibition, heme oxygenase-1 (HO-1) is disproportionally increased compared with Nrf2 target NADPH quinone oxidoreductase-1 (Nqo1). HO-1 has been investigated as a potential therapeutic target in both ARDS and BPD. TXNRD1 is predominantly expressed in airway epithelial cells; however, the mechanism of HO-1 induction by TXNRD1 inhibitors is unknown. We tested the hypothesis that TXNRD1 inhibition induces HO-1 via Nrf2-dependent mechanisms. Wild-type (WT), Nrf2KO1.3, and Nrf2KO2.2 cells were morphologically indistinguishable, indicating that Nrf2 can be deleted from murine-transformed club cells (mtCCs) using CRISPR/Cas9 gene editing. Hemin, a Nrf2-independent HO-1-inducing agent, significantly increased HO-1 expression in WT, Nrf2KO1.3, and Nrf2KO2.2. Auranofin (AFN) (0.5 µM) inhibited TXNRD1 activity by 50% and increased Nqo1 and Hmox1 mRNA levels by 6- and 24-fold, respectively, in WT cells. Despite similar levels of TXNRD1 inhibition, Nqo1 mRNA levels were not different between control and AFN-treated Nrf2KO1.3 and Nrf2KO2.2. AFN slightly increased Hmox1 mRNA levels in Nrf2KO1.3 and Nrf2KO2.2 cells compared with controls. AFN failed to increase HO-1 protein in Nrf2KO1.3 and Nrf2KO2.2 compared with a 36-fold increase in WT mtCCs. Our data indicate that Nrf2 is the primary mechanism by which TXNRD1 inhibitors increase HO-1 in lung epithelia. Future studies will use ARDS and BPD models to define the role of HO-1 in attenuation of lung injury by TXNRD1 inhibitors.

Authors+Show Affiliations

Neonatal Redox Biology Laboratory, Division of Neonatology, Department of Pediatrics, University of Alabama at Birmingham , Birmingham, Alabama. University of Alabama at Birmingham , Birmingham, Alabama.Neonatal Redox Biology Laboratory, Division of Neonatology, Department of Pediatrics, University of Alabama at Birmingham , Birmingham, Alabama. University of Alabama at Birmingham , Birmingham, Alabama.Neonatal Redox Biology Laboratory, Division of Neonatology, Department of Pediatrics, University of Alabama at Birmingham , Birmingham, Alabama. University of Alabama at Birmingham , Birmingham, Alabama.University of Alabama at Birmingham , Birmingham, Alabama.Neonatal Redox Biology Laboratory, Division of Neonatology, Department of Pediatrics, University of Alabama at Birmingham , Birmingham, Alabama. University of Alabama at Birmingham , Birmingham, Alabama.Neonatal Redox Biology Laboratory, Division of Neonatology, Department of Pediatrics, University of Alabama at Birmingham , Birmingham, Alabama. University of Alabama at Birmingham , Birmingham, Alabama.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

30024305

Citation

Dunigan, Katelyn, et al. "The Thioredoxin Reductase Inhibitor Auranofin Induces Heme Oxygenase-1 in Lung Epithelial Cells Via Nrf2-dependent Mechanisms." American Journal of Physiology. Lung Cellular and Molecular Physiology, vol. 315, no. 4, 2018, pp. L545-L552.
Dunigan K, Li Q, Li R, et al. The thioredoxin reductase inhibitor auranofin induces heme oxygenase-1 in lung epithelial cells via Nrf2-dependent mechanisms. Am J Physiol Lung Cell Mol Physiol. 2018;315(4):L545-L552.
Dunigan, K., Li, Q., Li, R., Locy, M. L., Wall, S., & Tipple, T. E. (2018). The thioredoxin reductase inhibitor auranofin induces heme oxygenase-1 in lung epithelial cells via Nrf2-dependent mechanisms. American Journal of Physiology. Lung Cellular and Molecular Physiology, 315(4), L545-L552. https://doi.org/10.1152/ajplung.00214.2018
Dunigan K, et al. The Thioredoxin Reductase Inhibitor Auranofin Induces Heme Oxygenase-1 in Lung Epithelial Cells Via Nrf2-dependent Mechanisms. Am J Physiol Lung Cell Mol Physiol. 2018 10 1;315(4):L545-L552. PubMed PMID: 30024305.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The thioredoxin reductase inhibitor auranofin induces heme oxygenase-1 in lung epithelial cells via Nrf2-dependent mechanisms. AU - Dunigan,Katelyn, AU - Li,Qian, AU - Li,Rui, AU - Locy,Morgan L, AU - Wall,Stephanie, AU - Tipple,Trent E, Y1 - 2018/07/19/ PY - 2018/7/20/pubmed PY - 2019/8/23/medline PY - 2018/7/20/entrez KW - acute respiratory distress syndrome KW - auranofin KW - bronchopulmonary dysplasia KW - club cells KW - heme oxygenase-1 KW - nuclear factor E2-related factor 2 KW - thioredoxin reductase SP - L545 EP - L552 JF - American journal of physiology. Lung cellular and molecular physiology JO - Am. J. Physiol. Lung Cell Mol. Physiol. VL - 315 IS - 4 N2 - Thioredoxin reductase-1 (TXNRD1) inhibition effectively activates nuclear factor (erythroid-derived 2)-like 2 (Nrf2) responses and attenuates lung injury in acute respiratory distress syndrome (ARDS) and bronchopulmonary dysplasia (BPD) models. Upon TXNRD1 inhibition, heme oxygenase-1 (HO-1) is disproportionally increased compared with Nrf2 target NADPH quinone oxidoreductase-1 (Nqo1). HO-1 has been investigated as a potential therapeutic target in both ARDS and BPD. TXNRD1 is predominantly expressed in airway epithelial cells; however, the mechanism of HO-1 induction by TXNRD1 inhibitors is unknown. We tested the hypothesis that TXNRD1 inhibition induces HO-1 via Nrf2-dependent mechanisms. Wild-type (WT), Nrf2KO1.3, and Nrf2KO2.2 cells were morphologically indistinguishable, indicating that Nrf2 can be deleted from murine-transformed club cells (mtCCs) using CRISPR/Cas9 gene editing. Hemin, a Nrf2-independent HO-1-inducing agent, significantly increased HO-1 expression in WT, Nrf2KO1.3, and Nrf2KO2.2. Auranofin (AFN) (0.5 µM) inhibited TXNRD1 activity by 50% and increased Nqo1 and Hmox1 mRNA levels by 6- and 24-fold, respectively, in WT cells. Despite similar levels of TXNRD1 inhibition, Nqo1 mRNA levels were not different between control and AFN-treated Nrf2KO1.3 and Nrf2KO2.2. AFN slightly increased Hmox1 mRNA levels in Nrf2KO1.3 and Nrf2KO2.2 cells compared with controls. AFN failed to increase HO-1 protein in Nrf2KO1.3 and Nrf2KO2.2 compared with a 36-fold increase in WT mtCCs. Our data indicate that Nrf2 is the primary mechanism by which TXNRD1 inhibitors increase HO-1 in lung epithelia. Future studies will use ARDS and BPD models to define the role of HO-1 in attenuation of lung injury by TXNRD1 inhibitors. SN - 1522-1504 UR - https://www.unboundmedicine.com/medline/citation/30024305/The_thioredoxin_reductase_inhibitor_auranofin_induces_heme_oxygenase_1_in_lung_epithelial_cells_via_Nrf2_dependent_mechanisms_ L2 - http://journals.physiology.org/doi/full/10.1152/ajplung.00214.2018?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -