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Gene Expression Profiling in Patients with Chronic Obstructive Pulmonary Disease and Lung Cancer

¹ Rosetta Inpharmatics, Seattle, Washington; ² Merck Frosst Canada, Montreal, Quebec, Canada; ³ UBC James Hogg iCAPTURE Centre, St. Paul's Hospital, Vancouver, British Columbia, Canada; ⁴ Merck Frosst Rahway, Rahway, New Jersey; and ⁵ Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada

Correspondence and requests for reprints should be addressed to Peter D. Paré, M.D., McDonald Research Wing, Room 166, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6. E-mail: ppare{at}mrl.ubc.ca

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)-β1 and matrix metalloproteinases and are subject to inhibition by SERPINE2. Interestingly, both TGF-β1 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

Key Words: pulmonary emphysema • phenotype • transcriptional analysis • cigarette smoking

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject There have been few genomewide interrogations of gene expression in the lungs of smokers with and without chronic obstructive pulmonary disease. The separation of genes that are induced by smoking versus those that are induced in smokers who develop airflow obstruction is unclear. What This Study Adds to the Field The genes involved in tissue remodeling and repair are differentially regulated in the lungs of obstructed smokers and suggest that they are potential therapeutic targets.

 

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