Noblesse Oblige: NRF2 Functions in the Airways

Abstract

The transcription factor, nuclear factor (NF), erythroid-derived 2-related factor 2 (NRF2), was discovered nearly 2 decades ago. Since then, over 4,000 papers have been published on NRF2 function in diverse biological systems, and it has been found to be a critical regulator of antioxidant and defense genes with antioxidant response elements in their promoters. NRF2 is particularly important in protecting cells and tissues under highly oxidative microenvironments, including the airways that interface with the external environment and are exposed to pollutants and other oxidant stressors. Using mice with targeted deletion of Nrf2, a protective role for this transcription factor has been determined in many model diseases, including acute lung injury, emphysema, allergy and asthma, pulmonary fibrosis, and respiratory syncytial virus disease. Recent studies have also found that murine Nrf2 is important in lung development and protection against neonatal lung injury. Moreover, functional polymorphisms in human NRF2 have been known to associate with disease severity, indicating a potentially important protective function. However, there is also a "dark side" to NRF2 function, as it has been found to enhance advanced stages of carcinogenesis in the lung and some other tissues. NRF2 inducers such as phytochemical isothyocyanates and synthetic triterpenoids, have been discovered and used in model systems of oxidant-induced lung diseases, and data suggest a potential for clinical interventions. Future investigations of NRF2 should yield further insight into its contribution to normal and pathophysiological conditions in the airways, and alternative treatment strategies to protect against oxidative respiratory disease.

Nrf2 Regulates the Risk of a Diesel Exhaust Inhalation-Induced Immune Response during Bleomycin Lung Injury and Fibrosis in Mice

“…Nrf2 is particularly important for protecting cells and tissues in highly oxidative microenvironments, including the airway, which interfaces with the external environment and is exposed to pollutants and other oxidant stressors [18]. Our previous study suggested that oxidative stress is involved in DE-induced airway inflammation [11] and allergic asthma [19], as evidenced by experiments involving Nrf2 knockout mice.…”

Nasal protein profiles in work‐related asthma caused by different exposures

“…Our results indicate that the nasal epithelial proteome of the WRA patients is highly enriched in processes related to inflammatory and calcium signalling, free radical scavenging and oxidative stress response, and metabolism. The most relevant signalling networks were through the pathways associated with redox‐sensitive transcription factors, NFκB and Nrf2, and with MAPKs, which differentially regulate pro‐inflammatory cytokine genes and protective antioxidant genes . Nrf2‐deficient mice have a heightened susceptibility to asthma, including elevated oxidative stress, inflammation, mucus and airway hyper‐responsiveness .…”

Esculentoside A Attenuates Allergic Airway Inflammation via Activation of the Nrf-2 Pathway

“…Bronchial epithelial cells have been shown to possess robust antioxidant defenses against environmental insults via the activation of Nrf-2 [26]. Disruption of the Nrf-2 gene also leads to increased expression of the Th2 cytokines, IL-4 and IL-13, in both the BALF and splenocytes after allergen challenge, indicating the important protective role of the Nrf-2 pathway in allergic and asthmatic responses in vivo [12]. Indeed, recent studies employing dendritic cells in a mouse model demonstrated that Nrf-2 protects against allergic airway inflammation following exposure to different stimuli in vivo [27,28].…”

“…Disruption of the Nrf-2 gene leads to severe allergen-driven airway inflammation and hyperresponsiveness in mice and increased expression of the Th2 cytokines, IL-4 and IL-13, in the bronchoalveolar lavage fluid (BALF) and splenocytes after allergen challenge [11]. Nrf-2 also protects the lungs against the development of pulmonary fibrosis by regulating cellular redox levels and the Th1/Th2 balance in the lung [12,13,14]. …”