Changes within the small airways of the lungs represent the key element in the mechanism of COPD, as they precede the development of emphysema and contribute to the progressive decline in expiratory airflow. One of the key features of COPD is the remodeling of the small airway epithelium (SAE), and COPD SAE phenotypes are often induced by smoking and broad gene expression changes in the SAE. Many of the specific mechanisms for maintenance and regeneration of small airways and differentiated SAE in adult human lungs are largely unknown, but smoking associated defects in the maintenance of the SAE may be an early event of COPD. Preliminary data from murine studies have indicated that fibroblast growth factor receptor 2 (FGFR2) signaling is critical for lung architecture and development, and preliminary evidence has shown the FGFR2 pathway is down regulated within the small airway epithelium (SAE) of smokers and smokers with COPD. We hypothesize that the suppression of FGFR2 signaling in SAE BC stem cells by cigarette smoking causes these cells to become less potent, shifting the expression of normally differentiated SAE towards the COPD-associated small airway phenotype and therefore affecting the generation and maintenance of these cells. Using technologies established in our laboratories, pure populations of BC will be isolated from the SAE of healthy nonsmokers, healthy smokers, and COPD smokers. The stem/progenitor cell capacities of the SAE BC of each group will then be analyzed through the use of 3D modeling. The basic mechanisms of COPD will be tested by focusing on the phenotypes present in the lungs of COPD patients and comparison to their nonsmoker and healthy smoker counterparts. The 3 aims will be assessed in parallel, with all aims sharing in the biologic samples: