Gene expression profiles of acute exacerbations of idiopathic pulmonary fibrosis

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Aged
  • Case-Control Studies
  • Cyclin A / genetics
  • Cyclin A / metabolism*
  • Cyclin A2
  • Dyspnea / etiology*
  • Dyspnea / metabolism
  • Female
  • Gene Expression Profiling
  • Genetic Markers
  • Humans
  • Idiopathic Pulmonary Fibrosis / complications
  • Idiopathic Pulmonary Fibrosis / genetics*
  • Idiopathic Pulmonary Fibrosis / metabolism*
  • Male
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis
  • RNA, Messenger / metabolism
  • alpha-Defensins / genetics
  • alpha-Defensins / metabolism*


  • CCNA2 protein, human
  • Cyclin A
  • Cyclin A2
  • Genetic Markers
  • RNA, Messenger
  • alpha-Defensins
  • human neutrophil peptide 3
  • human neutrophil peptide 4