COPD is characterized by limitation of expiratory airflow that is not reversible. The primary site of the airflow limitation is the small airways. Smoking cessation and/or corticosteroid therapy only partially improves the airflow limitation in COPD. It is not known whether these therapies fail because of irreversible structural changes or because they have limited effect on the abnormal biologic processes in the small airways. This project focuses on the biologic changes in the small airway epithelium in COPD, and the reversibility of these changes with therapeutic intervention. We hypothesize that smoking cessation and/or anti-inflammatory therapies do normalize some of the altered patterns of gene expression in the small airway epithelium in COPD, and that the identification of the alterations in small airway epithelial gene expression that are, andare not, reversed by these interventions will provide targets for the future development of therapies for COPD. Using newly developed technology with fiberoptic bronchoscopy with brushings of the small airways to obtain pure small airway epithelium, microarray assessment in COPD vs normal smokers and non-smokers allowed us to identify genes in different categories relevant to the pathogenesis of COPD. This "molecular signature" of the small airway epithelium is the focus of the 3 aims of this proposal. Aim 1 - to assess the hypothesis that the alterations in gene expression in the small airway epithelium associated with COPD are at least partially reversible with smoking cessation. We propose to study healthy smokers and nonsmokers, individuals with COPD (GOLD 0,1,and III), and individuals with early emphysema who do not meet the GOLD criteria. Gene expression will be evaluated at baseline and after smoking cessation. Aim 2 - To assess the hypothesis that the alterations in gene expression in the small airway epithelium associated with COPD are at least partially reversible with treatment with corticosteroid. Aim 3 - To assess the hypothesis that the alterations in gene expression in the small airway epithelium associated with COPD are at least partially reversible with treatment with an inhibitor of leukotriene synthesis.