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Published ahead of print on September 16, 2004, doi:10.1165/rcmb.2004-0273OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 31, pp. 601-610, 2004
© 2004 American Thoracic Society
DOI: 10.1165/rcmb.2004-0273OC

Gene Expression Profiling of Human Lung Tissue from Smokers with Severe Emphysema

Avrum Spira, Jennifer Beane, Victor Pinto-Plata, Aran Kadar, Gang Liu, Vishal Shah, Bartolome Celli and Jerome S. Brody

The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston; Bioinformatics Program, College of Engineering, Boston University, Boston; and COPD Center at St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts

Address correspondence to: Avrum Spira, M.D., The Pulmonary Center, Boston Medical Center, 715 Albany Street, R304, Boston, MA 02118. E-mail: aspira{at}lung.bumc.bu.edu

The mechanism by which inhaled smoke causes the anatomic lesions and physiologic impairment of chronic obstructive pulmonary disease remains unknown. We used high-density microarrays to measure gene expression in severely emphysematous lung tissue removed from smokers at lung volume reduction surgery (LVRS) and normal or mildly emphysematous lung tissue from smokers undergoing resection of pulmonary nodules. Class prediction algorithms identified 102 genes that accurately distinguished severe emphysema from non-/mildly emphysematous lung tissue. We also defined a number of genes whose expression levels correlated strongly with lung diffusion capacity for carbon monoxide and/or forced expiratory volume at 1 s. Genes related to oxidative stress, extracellular matrix synthesis, and inflammation were increased in severe emphysema, whereas expression of endothelium-related genes was decreased. To identify candidate genes that might be causally involved in the pathogenesis of emphysema, we linked gene expression profiles to chromosomal regions previously associated with chronic obstructive pulmonary disease in genome-wide linkage analyses. Unsupervised hierarchical clustering of the LVRS samples revealed distinct molecular subclasses of severe emphysema, with body mass index as the only clinical variable that differed between the groups. Class prediction models established a set of genes that predicted functional outcome at 6 mo after LVRS. Our findings suggest that the gene expression profiles from human emphysematous lung tissue may provide insight into pathogenesis, uncover novel molecular subclasses of disease, predict response to LVRS, and identify targets for therapeutic intervention.

Abbreviations: body mass index, BMI • chronic obstructive pulmonary disease, COPD • diffusion capacity for carbon monoxide, DLCO • extracellular matrix, ECM • forced expiratory volume at 1 s, FEV1 • insulin-like growth factor binding protein, IGFBP • logarithm of the odds ratio, LOD • lung volume reduction surgery, LVRS • matrix {gamma}-carboxyglutamic acid protein, MGP • Overholt–Blue Cross Emphysema Surgery Trial, OBEST • real-time polymerase chain reaction, RT-PCR • short-tandem repeat, STR




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