The lung is constantly exposed to inhaled toxicants that damage the epithelial cells of the conducting airway. Acute injuries involving depletion of progenitor cells are repaired through activation of latent tissue stem cells. However, most environmental injuries are repetitive and result in continual cycles of injury and repair. It is unknown how airway stem cells contribute to repairing repetitive injuries. The hypothesis of this project is that airway stem cells respond to multiple cycles of injury by both proliferating and self-renewing. In injuries accompanied by inflammation, the response of the stem cell hierarchy is dysregulated. To test this hypothesis, nuclear label retention will be used to follow the behavior of airway stem cells in a model of repetitive injury (progenitor cell depletion) that occurs with little inflammation (Aim i). The second and third aims will investigate the hypothesis that injury associated with sustained inflammation impacts the reparative capacity of cells within the bronchiolar stem cell hierarchy. To study the effects of inflammation on lung progenitor cells, a mouse model of silicosis will be used. Silicosis is a fibrotic lung disease caused by long-term inhalation of crystalline silica. Silica exposure rapidly causes inflammatory cell recruitment to the terminal bronchioles and alveolar ducts, regions where stem cells are thought to reside. Impairment of the proliferate responses of the stem cells and transit amplifying cells in the presence of silica will be examined in Aim 2. Finally, TNFa receptor knockout mice will be used to dissect the contribution of inflammation to the impaired regenerative ability of the bronchiolar epithelium in silicosis (Aim 3). The eventual goals of these studies are to determine how silicosis impairs the stem cell hierarchy and to identify therapeutic targets that may halt disease progression. Inhaling silica dust causes scarring in the lung that eventually makes it difficult to breathe. This proposal studies how silica dust impairs the ability of stem cells in the lung to heal lung injuries without scarring. The information learned from this research may help identify new treatments for chronic lung disease. Number pages consecutively at the bottom throughout Form Page 2 the application. Do not use suffixes such as 2a, 2b. [unreadable] [unreadable] [unreadable]