Gene expression profiles of acute exacerbations of idiopathic pulmonary fibrosis.
BACKGROUND
The molecular mechanisms underlying acute exacerbations of idiopathic pulmonary fibrosis (IPF) are poorly understood. We studied the global gene expression signature of acute exacerbations of IPF.


OBJECTIVE
To understand the gene expression patterns of acute exacerbations of IPF.


METHODS
RNA was extracted from 23 stable IPF lungs, 8 IPF lungs with acute exacerbation (IPF-AEx), and 15 control lungs and used for hybridization on Agilent gene expression microarrays. Functional analysis of genes was performed with Spotfire and Genomica. Gene validations for MMP1, MMP7, AGER, DEFA1-3, COL1A2, and CCNA2 were performed by real-time quantitative reverse transcription-polymerase chain reaction. Immunohistochemistry and in situ terminal deoxynucleotidyltransferase dUTP nick end-labeling assays were performed on the same tissues used for the microarray. ELISA for alpha-defensins was performed on plasma from control subjects, patients with stable IPF, and patients with IPF-AEx.


RESULTS
Gene expression patterns in IPF-AEx and IPF samples were similar for the genes that distinguish IPF from control lungs. Five hundred and seventy-nine genes were differentially expressed (false discovery rate < 5%) between stable IPF and IPF-AEx. Functional analysis of these genes did not indicate any evidence of an infectious or overwhelming inflammatory etiology. CCNA2 and alpha-defensins were among the most up-regulated genes. CCNA2 and alpha-defensin protein levels were also higher and localized to the epithelium of IPF-AEx, where widespread apoptosis was also detected. alpha-Defensin protein levels were increased in the peripheral blood of patients with IPF-AEx.


CONCLUSIONS
Our results indicate that IPF-AEx is characterized by enhanced epithelial injury and proliferation, as reflected by increases in CCNA2 and alpha-defensins and apoptosis of epithelium. The concomitant increase in alpha-defensins in the peripheral blood and lungs may suggest their use as biomarkers for this disorder.
Division of Pulmonary, Allergy and Critical Care Medicine, Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Kazuhisa
K
Konishi
Kevin F
KF
Gibson
Kathleen O
KO
Lindell
Thomas J
TJ
Richards
Yingze
Y
Zhang
Rajiv
R
Dhir
Michelle
M
Bisceglia
Sebastien
S
Gilbert
Samuel A
SA
Yousem
Jin Woo
JW
Song
Dong Soon
DS
Kim
Naftali
N
Kaminski
D000208:Acute Disease; D000368:Aged; D016022:Case-Control Studies; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism*; D056751:Cyclin A2; D004417:Dyspnea / Q000209:etiology* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005819:Genetic Markers; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D023084:alpha-Defensins / Q000235:genetics / Q000378:metabolism*
C503721:CCNA2 protein, human; D019925:Cyclin A; D056751:Cyclin A2; D005819:Genetic Markers; D012333:RNA, Messenger; D023084:alpha-Defensins; C406427:human neutrophil peptide 3; C406428:human neutrophil peptide 4