The thioredoxin reductase inhibitor auranofin induces heme oxygenase-1 in lung epithelial cells via Nrf2-dependent mechanisms.

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: Katelyn Dunigan, Qian Li, Rui Li, Morgan L Locy, Stephanie Wall, Trent E Tipple
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 315 Issue 4 Pg. L545-L552 (10 01 2018) ISSN: 1522-1504 [Electronic] United States
• PMID: 30024305 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antirheumatic Agents
• Membrane Proteins
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Auranofin
• Heme Oxygenase-1
• Hmox1 protein, mouse
• Thioredoxin Reductase 1
• Txnrd1 protein, mouse

Topics

• Animals
• Antirheumatic Agents (pharmacology)
• Auranofin (pharmacology)
• Cells, Cultured
• Epithelial Cells (drug effects, enzymology)
• Gene Expression Regulation, Enzymologic (drug effects)
• Heme Oxygenase-1 (genetics, metabolism)
• Lung (drug effects, enzymology)
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Inbred C3H
• Mice, Knockout
• NF-E2-Related Factor 2 (physiology)
• Thioredoxin Reductase 1 (antagonists & inhibitors, physiology)