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Gene Expression Profiles of Acute Exacerbations of Idiopathic Pulmonary Fibrosis

¹ Division of Pulmonary, Allergy and Critical Care Medicine, Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases; ² Department of Pathology; and ³ Department of Thoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and ⁴ Division of Pulmonary and Critical Care Medicine, Department of Medicine, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, South Korea

Correspondence and requests for reprints should be addressed to Naftali Kaminski, M.D., University of Pittsburgh Medical Center, NW 628 MUH, 3459 5th Avenue, Pittsburgh, PA 15261. E-mail: kaminskin{at}upmc.edu (Naftali Kaminski, M.D.); dskim{at}amc.seoul.kr (Dong Soon Kim, M.D.).

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 -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 -defensins were among the most up-regulated genes. CCNA2 and -defensin protein levels were also higher and localized to the epithelium of IPF-AEx, where widespread apoptosis was also detected. -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 -defensins and apoptosis of epithelium. The concomitant increase in -defensins in the peripheral blood and lungs may suggest their use as biomarkers for this disorder.

Key Words: CCNA2 • -defensins • microarray • apoptosis • viral infection

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The mechanisms of acute exacerbation of idiopathic pulmonary fibrosis (IPF-AEx), a syndrome characterized by new development of pulmonary infiltrates, deterioration of lung function and hypoxemia, are unknown. What This Study Adds to the Field This analysis of genome-scale gene expression patterns in lungs of patients with IPF-AEx identifies epithelial injury and proliferation as the key molecular genetic events in IPF-AEx, and suggests plasma defensins as new biomarkers. Therapeutic strategies that protect the epithelium should be evaluated in this syndrome.

 

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Erratum: Incorrect Cover Caption

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AJRCCM 2009 180: 380. [Full Text]  

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				E. Abraham Erratum: Incorrect Cover Caption Am. J. Respir. Crit. Care Med., August 15, 2009; 180(4): 380 - 380. [Full Text] [PDF]