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Use of Oligonucleotide Microarrays to Analyze Gene Expression Patterns in Pulmonary Fibrosis Reveals Distinct Patterns of Gene Expression in Mice and Humans*

Naftali Kaminski, MD; Fengrong Zuo, MD; Gady Cojocaro, MSC; Zohar Yakhini, PhD; Amir Ben-Dor, PhD; David Morris, MD; Dean Sheppard, MD; Annie Pardo, PhD; Moises Selman, MD; Renu A. Heller, PhD
Author and Funding Information

*From Functional Genomics (Dr. Kaminski and Mr. Cojocaro), Respiratory Medicine (Dr. Kaminski), Sheba Medical Center, Tel Hashomer, Israel; Roche Bioscience (Drs. Zuo and Heller), Palo Alto, CA; Agilent Laboratories (Drs. Yakhini and Ben-Dor), Palo Alto, CA; Lung Biology Center (Dr. Morris), San Francisco, CA; Faculty of Sciences, Universidad Autonoma de Mexico (Dr. Pardo), Mexico City; and National Institute of Respiratory Diseases (Dr. Selman), Mexico City, Mexico.

Correspondence to: Naftali Kaminski, MD, Director, Functional Genomics, Molecular Hemato-oncology and Respiratory Medicine, Sheba Medical Center, Tel Hashomer, Israel



Chest. 2002;121(3_suppl):31S-32S. doi:10.1378/chest.121.3_suppl.31S
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In order to determine transcriptional programs that are active in human pulmonary fibrosis, we analyzed gene expression patterns using GeneChip microarrays (Affymetrix; Santa Clara, CA) in samples from patients with histologic diagnoses of usual interstitial pneumonia (UIP), samples obtained from lung resections for cancer that were determined normal by histologic examination, and pooled normal-lung RNA obtained commercially. Surprisingly, gene expression patterns were quite homogenous among pulmonary fibrosis and control samples, despite the expected variability in genetic background and condition of subjects. Using the total number of misclassifications score, the information-content score, and Gaussian-error score, we determined that 100 genes were significantly differentially expressed between UIP and control lungs. Groups of genes that were significantly overexpressed included metalloproteases, extracellular matrix-related genes, markers of smooth-muscle differentiation, and antioxidants. Interestingly, we observed little evidence for overexpression of inflammatory-related genes (mainly immunoglobulins and complement components). To assess whether similar gene programs were activated in mice and humans, we compared gene expression patterns in the lungs of patients with pulmonary fibrosis with gene expression patterns observed in lungs of C57BL6 mice after bleomycin. Notably, most genes that were over expressed in human UIP were also induced by bleomycin in our mice, suggesting that the proteins encoded by these genes play an important role in the continuous destruction/remodeling process typical of pulmonary fibrosis. The global transcriptional patterns as well as the information about individual genes provided by our experiments should prove useful in the design of new interventions to halt disease progression.

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