Rationale: Chronic Obstructive Lung Disease (COPD) is a common and disabling lung disease for which there are few therapeutic options. We reasoned that gene expression profiling of COPD lungs could reveal previously unidentified disease pathways. Methods and Main Results: 48 human lung samples were obtained from tissue resected from 5 non-smokers, 21 GOLD 0, 9 GOLD 1, 10 GOLD 2 and 3 GOLD 3 patients. mRNA from the specimens was profiled using Agilent's Functional ID v2.0 array containing 23,720 sequences. The gene expression pattern was influenced by the percentage of the sample made up of parenchyma. Gene expression was related to Forced Expiratory Flow between 25 and 75% of forced expiratory volume (FEF 25-75% P) revealing a signature gene set of 203 transcripts. Genes involved in extracellular matrix synthesis/degradation and apoptosis were among the up-regulated genes whereas genes which participate in anti-inflammatory responses were down-regulated. Immunohistochemistry confirmed expression of urokinase (PLAU), urokinanse receptor (PLAUR) and thrombospondin (THBS1) by alveolar macrophages and airway epithelial cells. Genes in this pathway have been shown to be involved in the activation of transforming growth factor beta-1 (TGF [beta] 1) and matrix metalloproteinases (MMP) and are subject to inhibition by SERPINE 2. Interestingly, both TGF beta 1 and SERPINE 2 have been identified as candidate genes in COPD genetic linkage and association studies. Conclusion: The results provide evidence that genes involved in tissue remodeling and repair are differentially regulated in the lungs of obstructed smokers and suggest that they are potential therapeutic targets. Clinical Trial Registry Information: ID# GSE8500 registered at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=ldolzqeugcwegfs&acc=GSE8500