Genetic ablation of Nrf2 increases susceptibility to cigarette smoke-induced emphysema in mice. Nrf2 is a redox-sensitive transcription factor that regulates antioxidant and cytoprotective genes. In Nrf2-deficient mice, exposure to cigarette smoke (CS) led to earlier-onset and more severe emphysema compared to wild-type mice. These mice exhibited increased bronchoalveolar inflammation, higher levels of oxidative stress markers, and more apoptotic alveolar septal cells. Microarray analysis identified nearly 50 Nrf2-dependent antioxidant and cytoprotective genes in the lungs that may counteract CS-induced oxidative stress and inflammation. The Nrf2 pathway's responsiveness plays a critical role in reducing susceptibility to CS-induced emphysema by upregulating antioxidant defenses and decreasing lung inflammation and alveolar cell apoptosis. The study shows that Nrf2 is a critical determinant of susceptibility to CS-induced emphysema. Nrf2-deficient mice are more susceptible to CS-induced emphysema than wild-type mice, as the ICR strain is intrinsically resistant to CS-induced alveolar destruction. The increased susceptibility of Nrf2-deficient mice is likely due to reduced antioxidant defenses and increased oxidative stress. The study also found that Nrf2-deficient mice had increased apoptosis of alveolar septal cells, including endothelial and type II epithelial cells, and increased inflammatory cell infiltration. These findings suggest that Nrf2 plays a key role in protecting the lungs from oxidative stress and inflammation caused by CS exposure. Nrf2 is activated in response to CS in the lungs of wild-type mice, leading to the transcriptional induction of target genes that may provide resistance against the development of emphysema. Conversely, a lack of responsiveness of the Nrf2 pathway confers susceptibility to severe emphysema due to CS exposure in this model. The identification of Nrf2 as a determinant of susceptibility can have wide implications in the area of tobacco smoke-related lung diseases, where oxidative stress and inflammation play important roles. Nrf2 regulates genes involved in two major redox systems, the glutathione and thioredoxin systems, which are critical for protecting the lungs from oxidative stress and inflammation. The study also identified several Nrf2-regulated genes that may contribute to the protection against oxidative stress and inflammation in the lungs. These findings suggest that Nrf2 is a key player in the pathogenesis of CS-induced emphysema.Genetic ablation of Nrf2 increases susceptibility to cigarette smoke-induced emphysema in mice. Nrf2 is a redox-sensitive transcription factor that regulates antioxidant and cytoprotective genes. In Nrf2-deficient mice, exposure to cigarette smoke (CS) led to earlier-onset and more severe emphysema compared to wild-type mice. These mice exhibited increased bronchoalveolar inflammation, higher levels of oxidative stress markers, and more apoptotic alveolar septal cells. Microarray analysis identified nearly 50 Nrf2-dependent antioxidant and cytoprotective genes in the lungs that may counteract CS-induced oxidative stress and inflammation. The Nrf2 pathway's responsiveness plays a critical role in reducing susceptibility to CS-induced emphysema by upregulating antioxidant defenses and decreasing lung inflammation and alveolar cell apoptosis. The study shows that Nrf2 is a critical determinant of susceptibility to CS-induced emphysema. Nrf2-deficient mice are more susceptible to CS-induced emphysema than wild-type mice, as the ICR strain is intrinsically resistant to CS-induced alveolar destruction. The increased susceptibility of Nrf2-deficient mice is likely due to reduced antioxidant defenses and increased oxidative stress. The study also found that Nrf2-deficient mice had increased apoptosis of alveolar septal cells, including endothelial and type II epithelial cells, and increased inflammatory cell infiltration. These findings suggest that Nrf2 plays a key role in protecting the lungs from oxidative stress and inflammation caused by CS exposure. Nrf2 is activated in response to CS in the lungs of wild-type mice, leading to the transcriptional induction of target genes that may provide resistance against the development of emphysema. Conversely, a lack of responsiveness of the Nrf2 pathway confers susceptibility to severe emphysema due to CS exposure in this model. The identification of Nrf2 as a determinant of susceptibility can have wide implications in the area of tobacco smoke-related lung diseases, where oxidative stress and inflammation play important roles. Nrf2 regulates genes involved in two major redox systems, the glutathione and thioredoxin systems, which are critical for protecting the lungs from oxidative stress and inflammation. The study also identified several Nrf2-regulated genes that may contribute to the protection against oxidative stress and inflammation in the lungs. These findings suggest that Nrf2 is a key player in the pathogenesis of CS-induced emphysema.