Association of Nrf2 with airway pathogenesis: lessons learned from genetic mouse models

Abstract

Nrf2 is a key transcription factor for antioxidant response element (ARE)-bearing genes involved in diverse host defense functions including redox balance, cell cycle, immunity, mitochondrial biogenesis, energy metabolism, and carcinogenesis. Nrf2 in the airways is particularly essential as the respiratory system continuously interfaces with environmental stress. Since Nrf2 was determined to be a susceptibility gene for a model of acute lung injury, its protective capacity in the airways has been demonstrated in experimental models of human disorders using Nrf2 mutant mice which were susceptible to supplemental respiratory therapy (e.g., hyperoxia, mechanical ventilation), cigarette smoke, allergens, virus, environmental pollutants, and fibrotic agents compared to wild-type littermates. Recent studies also determined that Nrf2 is indispensable in developmental lung injury. While association studies with genetic NRF2 polymorphisms supported a protective role for murine Nrf2 in oxidative airway diseases, somatic NRF2 mutations enhanced NRF2-ARE responses, and were favorable for lung carcinogenesis and chemoresistance. Bioinformatic tools have elucidated direct Nrf2 targets as well as Nrf2-interacting networks. Moreover, potent Nrf2-ARE agonists protected oxidant-induced lung phenotypes in model systems, suggesting a therapeutic or preventive intervention. Further investigations on Nrf2 should yield greater understanding of its contribution to normal and pathophysiological function in the airways.

Nrf2 Modulates Host Defense during Streptococcus pneumoniae Pneumonia in Mice

“…Numerous studies using Nrf2 deficient mice have demonstrated the role of Nrf2 in mouse models of lung carcinogenesis, viral infections, allergy and asthma, pulmonary fibrosis, COPD, and acute lung injury (3). Previous work has also shown that Nrf2 may play an important role in inflammation and the innate immune response to bacterial pathogens in the lungs.…”

A Polymorphic Antioxidant Response Element Links NRF2/sMAF Binding to Enhanced MAPT Expression and Reduced Risk of Parkinsonian Disorders

“…Numerous mouse model studies implicate Nrf2 as a susceptibility factor in a broad range of oxidative stress-related pathologies (Cho and Kleeberger, 2015; Hybertson and Gao, 2014; Johnson and Johnson, 2015), suggesting that SNPs affecting human functional NRF2 binding sites (e.g. AREs) could affect risk of many diseases.…”

Potential therapeutic targets in Nrf2-dependent protection against neonatal respiratory distress disease predicted by cDNA microarray analysis and bioinformatics tools

“…We also demonstrated Nrf2-dependent protection against ALI by 15d-PGJ2 in mice [35]. Sulforaphane is a powerful phytochemical Nrf2 agonist, and its role in anti-carcinogenesis and pulmonary protection against bacterial infection following emphysema, respiratory syncytial virus infection, and inhaled arsenic has been demonstrated in rodent studies (see review [13]). Moreover, controlled human studies recently reported the therapeutic potential of sulforaphane in reducing adverse effects of airway toxicants [38–40].…”

“…Nuclear factor, erythroid-derived 2, like 2 (Nfe2l2) or NF-E2-related factor 2 (Nrf2) is an indispensable transcriptional regulator for diverse antioxidant enzyme and host defense protein genes bearing antioxidant response elements (AREs) that bind Nrf2. Critical roles of Nrf2 function have been well defined in vivo using adult mice with genetically engineered Nrf2 and its cytoplasmic inhibitor Kelch-like ECH-associated protein ( Keap1 ) in acute lung injury (ALI), emphysema, allergy and asthma, pulmonary fibrosis, lung tumor, and respiratory syncytial virus disease [13]. Roles for Nrf2 in organ development and neonatal disease have also recently been identified in murine experimental BPD.…”