Nrf2: A transcription factor that modifies susceptibility to cigarette smoke-induced pulmonary oxidative stress and emphysema

Pulmonary emphysema is a major manifestation of chronic obstructive pulmonary disease (COPD), which affects more than 16 million Americans (Blanchard 2003). COPD, which is caused primarily by cigarette smoking, is likely to become the third largest cause of death worldwide by 2020 (Viegi et al. 2001). Oxidative stress caused by chronic exposure of lungs to cigarette smoke contributes to the pathogenesis of emphysema and COPD. The capacity of the lungs to respond to this stress is an important determinant of their relative resistance or susceptibility to COPD. A battery of protective genes can be induced in a rapid and highly coordinated response to oxidants through activation of redox-sensitive transcription factors. The coordinated induction of these genes is fundamental to maintaining antioxidant and other cytoprotective functions against free radicals and electrophiles that arise from exposure to cigarette smoke. Multiple redoxsensitive transcription factors, such as activator protein 1, activator protein 2, nuclear factor kappa B (NF-?B), redox factor 1, signal transducer and activator of transcription, peroxisome proliferation activator receptor, p53, and aryl hydrocarbon receptor, are activated in lungs in response to oxidative stress. This chapter focuses on a relatively newly described basic leucine zipper transcription factor named nuclear factor erythroid 2-related factor 2 (Nrf2). Studies in knockout mice in particular are establishing Nrf2 as an important modifier of pulmonary oxidative stress, inflammation and emphysema.