Smokers—Keap Quitting!

Nrf2—a transcription factor that turns on numerous genes encoding antioxidant and detoxifying enzymes—protects cells against environmental stressors, such as cigarette smoke. Under normal conditions, Nrf2 is bound to a cytosolic inhibitor, Keap1, but when challenged with stressors Nrf2 dissociates and translocates to the nucleus. Airways of patients with chronic obstructive pulmonary disease (COPD) already have decreased expression of Nrf2 target genes; cigarette smoke exposure further promotes inflammation and cell death, causing destruction of alveolar structure and reduced airflow. Indeed, cigarette smoke is the major risk factor in the development of COPD. Blake et al . investigated whether sustained activation of Nrf2, obtained by attenuating Keap1 expression, reduces cigarette smoke–induced oxidative stress. They used a conditional knockout mouse model in which the Keap1 gene was deleted from Clara cells, which are a common type of upper-airway epithelial cell in mice. Microarray and quantitative polymerase chain reaction analysis of the airways in this model showed increased expression of Nrf2 target genes; the airways also showed reduced oxidative stress and cigarette smoke–induced inflammation. Clara cells isolated from these mice were protected against oxidative stress, as were human airway epithelial cells in which KEAP1 expression was reduced by using small interfering RNA. In both cell types, Nrf2-dependent antioxidant genes were up-regulated. In this study, effects of acute cigarette smoke exposures were observed; studies with chronic cigarette smoke–induced oxidative stress are also needed. The same group previously reported that Keap1 dysfunction and sustained Nrf2 activation may cause lung cancer. However, the new study reveals lung cell–specific Nrf2 activation to be a promising intervention for COPD. D. J. Blake et al. , Deletion of Keap1 in the lung attenuates acute cigarette smoke–induced oxidative stress and inflammation. Am. J. Respir. Cell Mol. Biol. 42 , 524–536 (2010). [[Abstract]][1] [1]: http://ajrcmb.atsjournals.org/cgi/content/abstract/42/5/524