Rationale: Chronic obstructive lung disease (COPD) is a common and disabling lung disease for which there are few therapeutic options.
Objectives: We reasoned that gene expression profiling of COPD lungs could reveal previously unidentified disease pathways.
Methods: Forty-eight human lung samples were obtained from tissue resected from five nonsmokers, 21 GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage 0, 9 GOLD stage 1, 10 GOLD stage 2, and 3 GOLD stage 3 patients. mRNA from the specimens was profiled using Agilent's Functional ID v2.0 array (Agilent, Santa Clara, CA) containing 23,720 sequences.
Measurements and main results: 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%) % predicted) 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 that participate in antiinflammatory responses were down-regulated. Immunohistochemistry confirmed expression of urokinase plasminogen activator (PLAU), urokinase plasminogen activator 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 (TGF)-beta1 and matrix metalloproteinases and are subject to inhibition by SERPINE2. Interestingly, both TGF-beta1 and SERPINE2 have been identified as candidate genes in COPD genetic linkage and association studies.
Conclusions: 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. Data deposited in GEO at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE8500.