The study investigates the role of nuclear factor, erythroid-derived 2, like 2 (Nrf2) in cigarette smoke (CS)-induced emphysema. Nrf2 is a transcription factor that regulates antioxidant and cytoprotective genes, which are crucial for protecting the lungs from oxidative stress. The researchers found that deleting the Nrf2 gene in mice led to earlier and more severe CS-induced emphysema compared to wild-type mice. This was accompanied by increased bronchoalveolar inflammation, enhanced oxidative stress, and increased apoptosis of alveolar septal cells, particularly endothelial and type II epithelial cells. Microarray analysis identified nearly 50 Nrf2-dependent genes that may contribute to the emphysema phenotype. Validation of these findings through Northern blot and enzyme assays confirmed the upregulation of genes involved in glutathione synthesis, NADPH regeneration, and detoxification of CS components. The results suggest that the responsiveness of the Nrf2 pathway plays a critical role in mitigating the development of CS-induced emphysema by upregulating antioxidant defenses and reducing lung inflammation and cell apoptosis.The study investigates the role of nuclear factor, erythroid-derived 2, like 2 (Nrf2) in cigarette smoke (CS)-induced emphysema. Nrf2 is a transcription factor that regulates antioxidant and cytoprotective genes, which are crucial for protecting the lungs from oxidative stress. The researchers found that deleting the Nrf2 gene in mice led to earlier and more severe CS-induced emphysema compared to wild-type mice. This was accompanied by increased bronchoalveolar inflammation, enhanced oxidative stress, and increased apoptosis of alveolar septal cells, particularly endothelial and type II epithelial cells. Microarray analysis identified nearly 50 Nrf2-dependent genes that may contribute to the emphysema phenotype. Validation of these findings through Northern blot and enzyme assays confirmed the upregulation of genes involved in glutathione synthesis, NADPH regeneration, and detoxification of CS components. The results suggest that the responsiveness of the Nrf2 pathway plays a critical role in mitigating the development of CS-induced emphysema by upregulating antioxidant defenses and reducing lung inflammation and cell apoptosis.