Cigarette-Smoke-Induced Phenotype in Nrf2 KO Mice

Here, we provide detailed information on an inhalation study performed with Nrf2-/- mice and their corresponding wild-type littermates exposed to mainstream smoke from the Kentucky reference cigarette 2R4F. The information is supplementary to that in Thomas Müller’s presentation “from cellular genotype to cigarette-smoke-induced phenotype: the case of Nrf2”. Mice were exposed to 750 µg total particulate matter/l for 2, 3, or 4 hours per day (low, medium, and high dose groups) for 5 days per week over 5 months, with a post-exposure period of 13 days for the medium dose group. As key endpoints (in addition to the transcriptomics data presented by Thomas Müller), we analyzed the histopathology; inflammatory cells in lung tissue; inflammatory cells, cytokines, and chemokines in bronchoalveolar lavage fluid; detection of lung tissue destruction using morphometry, and functional respiratory changes using forced pulmonary maneuvers. Additional exploratory endpoints were the determination of activation markers on alveolar macrophages, the sub-typing of lymphocytes in bronchoalveolar lavage fluid, and the alteration of gene expression in the lungs. The results underline the relevance of Nrf2 activation as a general defense mechanism against CS-induced cellular stress. Their quantitative dimension will be discussed in the context of published data.