Gene expression profiling in patients with chronic obstructive pulmonary disease and lung cancer.
BACKGROUND
Chronic obstructive lung disease (COPD) is a common and disabling lung disease for which there are few therapeutic options.


OBJECTIVE
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.


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.
Wang
I-Ming
IM
McDonald Research Wing, Room 166, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, Canada.
Stepaniants
Sergey
S
Boie
Yves
Y
Mortimer
James R
JR
Kennedy
Brian
B
Elliott
Mark
M
Hayashi
Shizu
S
Loy
Leanna
L
Coulter
Silvija
S
Cervino
Sandra
S
Harris
Jennifer
J
Thornton
Michele
M
Raubertas
Richard
R
Roberts
Chris
C
Hogg
Jim C
JC
Crackower
Michael
M
O'Neill
Gary
G
Paré
Peter D
PD
D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D007150:Immunohistochemistry; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011237:Predictive Value of Tests; D011336:Probability; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D012907:Smoking / Q000235:genetics / Q000473:pathology; D046509:Tissue Culture Techniques
D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D012333:RNA, Messenger