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.
