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Am J Respir Crit Care Med. 2009 Jul 15;180(2):167-75. doi: 10.1164/rccm.200810-1596OC. Epub 2009 Apr 10.

Gene expression profiles of acute exacerbations of idiopathic pulmonary fibrosis.

Author information

1
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.

Erratum in

  • Am J Respir Crit Care Med. 2009 Aug 15;180(4):380.

Abstract

RATIONALE:

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.

OBJECTIVES:

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.

MEASUREMENTS AND MAIN 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.

PMID:
19363140
PMCID:
PMC2714820
DOI:
10.1164/rccm.200810-1596OC
[Indexed for MEDLINE]
Free PMC Article

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