Assessment of Protection Offered By the NRF2 Pathway Against Hyperoxia-Induced Acute Lung Injury in NRF2 Knockout Rats

Authors

Said H. Audi, Marquette UniversityFollow
Elizabeth R. Jacobs, Marquette UniversityFollow
Taheri Pardis, Marquette UniversityFollow
Swetha Ganesh, Marquette University
Anne V. Clough, Marquette UniversityFollow

Document Type

Article

Publication Date

2-2022

Publisher

Lippincott Williams & Wilkins, Inc.

Source Publication

Shock

Source ISSN

1073-2322

Original Item ID

DOI: 10.1097/SHK.0000000000001882

Abstract

Nuclear factor erythroid 2-related factor (Nrf2) is a redox-sensitive transcription factor that responds to oxidative stress by activating expressions of key antioxidant and cytoprotective enzymes via the Nrf2-antioxidant response element (ARE) signaling pathway. Our objective was to characterize hyperoxia-induced acute lung injury (HALI) in Nrf2 knock-out (KO) rats to elucidate the role of this pathway in HALI. Adult Nrf2 wildtype (WT), and KO rats were exposed to room air (normoxia) or >95% O₂ (hyperoxia) for 48 h, after which selected injury and functional endpoints were measured in vivo and ex vivo. Results demonstrate that the Nrf2-ARE signaling pathway provides some protection against HALI, as reflected by greater hyperoxia-induced histological injury and higher pulmonary endothelial filtration coefficient in KO versus WT rats. We observed larger hyperoxia-induced increases in lung expression of glutathione (GSH) synthetase, 3-nitrotyrosine (index of oxidative stress), and interleukin-1β, and in vivo lung uptake of the GSH-sensitive SPECT biomarker ^99mTc-HMPAO in WT compared to KO rats. Hyperoxia also induced increases in lung expression of myeloperoxidase in both WT and KO rats, but with no difference between WT and KO. Hyperoxia had no effect on expression of Bcl-2 (anti-apoptotic protein) or peroxiredoxin-1. These results suggest that the protection offered by the Nrf2-ARE pathway against HALI is in part via its regulation of the GSH redox pathway. To the best of our knowledge, this is the first study to assess the role of the Nrf2-ARE signaling pathway in protection against HALI using a rat Nrf2 knockout model.

Comments

Accepted version. Shock, Vol. 57, No. 2 (February 2022): 274-280. DOI. © 2022 Lippincott Williams & Wilkins, Inc. Used with permission.

Recommended Citation

Audi, Said H.; Jacobs, Elizabeth R.; Pardis, Taheri; Ganesh, Swetha; and Clough, Anne V., "Assessment of Protection Offered By the NRF2 Pathway Against Hyperoxia-Induced Acute Lung Injury in NRF2 Knockout Rats" (2022). Biomedical Engineering Faculty Research and Publications. 660.
https://epublications.marquette.edu/bioengin_fac/660