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

<p>The</p> <p>thioredoxin reductase inhibitor auranofin induces heme oxygenase-1</p> <p>in lung epithelial cells via Nrf2-dependent mechanisms. Am J Physiol</p> <p>Lung Cell Mol Physiol 315: L545–L552, 2018. First published July</p> <p>19, 2018; doi:10.1152/ajplung.00214.2018.—Thioredoxin reductase-</p> <p>1 (TXNRD1) inhibition effectively activates nuclear factor (erythroid-</p> <p>derived 2)-like 2 (Nrf2) responses and attenuates lung injury in</p> <p>acute respiratory distress syndrome (ARDS) and bronchopulmonary</p> <p>dysplasia (BPD) models. Upon TXNRD1 inhibition, heme oxygenase-</p> <p>1 (HO-1) is disproportionally increased compared with Nrf2</p> <p>target NADPH quinone oxidoreductase-1 (Nqo1). HO-1 has been</p> <p>investigated as a potential therapeutic target in both ARDS and BPD.</p> <p>TXNRD1 is predominantly expressed in airway epithelial cells; however,</p> <p>the mechanism of HO-1 induction by TXNRD1 inhibitors is</p> <p>unknown. We tested the hypothesis that TXNRD1 inhibition induces</p> <p>HO-1 via Nrf2-dependent mechanisms. Wild-type (WT), Nrf2KO1.3,</p> <p>and Nrf2KO2.2 cells were morphologically indistinguishable, indicating</p> <p>that Nrf2 can be deleted from murine-transformed club cells</p> <p>(mtCCs) using CRISPR/Cas9 gene editing. Hemin, a Nrf2-independent</p> <p>HO-1-inducing agent, significantly increased HO-1 expression in</p> <p>WT, Nrf2KO1.3, and Nrf2KO2.2. Auranofin (AFN) (0.5 M) inhibited</p> <p>TXNRD1 activity by 50% and increased Nqo1 and Hmox1 mRNA</p> <p>levels by 6- and 24-fold, respectively, in WT cells. Despite similar</p> <p>levels of TXNRD1 inhibition, Nqo1 mRNA levels were not different</p> <p>between control and AFN-treated Nrf2KO1.3 and Nrf2KO2.2. AFN</p> <p>slightly increased Hmox1 mRNA levels in Nrf2KO1.3 and Nrf2KO2.2</p> <p>cells compared with controls. AFN failed to increase HO-1 protein in</p> <p>Nrf2KO1.3 and Nrf2KO2.2 compared with a 36-fold increase in WT</p> <p>mtCCs. Our data indicate that Nrf2 is the primary mechanism by</p> <p>which TXNRD1 inhibitors increase HO-1 in lung epithelia. Future</p> <p>studies will use ARDS and BPD models to define the role of HO-1 in</p> <p>attenuation of lung injury by TXNRD1 inhibitors.</p>