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.
Highlights
(BPD) [5, 25, 41]
Our past research has consistently demonstrated that Thioredoxin reductase-1 (TXNRD1) inhibition results in a disproportional increase in Hmox1 expression when compared with other nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-regulated genes, namely Nqo1 [25, 28]
The remainder of our studies focused on defining the role of Nrf2 on heme oxygenase-1 (HO-1) induction in airway epithelial cells following TXNRD1 inhibition
Summary
Our collective data suggest that the protective effects of TXNRD1 inhibition are mediated, at least in part, through the activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent responses [28]. These findings are consistent with other studies in which inhibition or genetic deletion of TXNRD1 enhances Nrf2-dependent responses, including increased heme oxygenase-1 (HO-1) expression [3, 6, 8, 15, 18, 29, 38]. Our group is actively pursuing TXNRD1 inhibition as a strategy to prevent ARDS and BPD; the contribution of Nrf toward disproportionate increases in HO-1 following TXNRD1 in lung epithelial cells has not been defined. Our group has previously shown that TXNRD1 inhibition attenuates lung injury in newborn and adult murine models of acute respiratory distress syndrome (ARDS) and bronchopulmonary dysplasia
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