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

The

thioredoxin reductase inhibitor auranofin induces heme oxygenase-1

in lung epithelial cells via Nrf2-dependent mechanisms. Am J Physiol

Lung Cell Mol Physiol 315: L545–L552, 2018. First published July

19, 2018; doi:10.1152/ajplung.00214.2018.—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 M) 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.