NRF2 Protects Mice From Cigarette Smoke‐Induced Emphysema

Abstract

Rationale: NRF2, a redox‐sensitive transcription factor, protects the lungs against cigarette smoke (CS)‐induced oxidative stress and emphysema by up‐regulating antioxidant and cytoprotective pathways. We hypothesize that activation of NRF2 by a small molecule activator will attenuate CS‐induced oxidative stress and emphysema. Methods: Wild‐type (WT) and NRF2−/− mice were fed a diet containing 90mg/kg CDDO‐Im, and exposed to CS for 5.5 months. Lungs were examined for emphysema, oxidative stress, inflammation, and NRF2‐pathway expression. Results: Chronic CS‐exposure induced oxidative stress and pulmonary emphysema in both WT and NRF2−/− mice with dramatically increased oxidative stress and alveolar destruction in NRF2−/− mice. WT mice treated with CDDO‐Im had significant reductions in both oxidative stress and alveolar destruction with increased transcriptional induction of multiple NRF2‐regulated antioxidant genes. Furthermore, NRF2−/− mice had no significant reduction in alveolar destruction following treatment with CDDO‐Im. Conclusion: This data suggests that activation of the NRF2‐pathway in emphysema may represent a novel therapy for oxidative stress related lung disease, such as COPD.