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Published ahead of print on August 29, 2007, doi:10.1164/rccm.200705-683OC

Am. J. Respir. Crit. Care Med., Volume 176, Number 11, December 2007, 1108-1119

A more recent version of this article appeared on December 1, 2007
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Submitted on May 8, 2007
Accepted on August 30, 2007

Pulmonary Fibrosis Comparative Expression Profiling Suggests Key Role of Hypoxia Inducible Factor 1a

Argyris Tzouvelekis1, Vaggelis Harokopos2, Triantafillos Paparountas2, Nikos Oikonomou2, Aristotelis Chatziioannou3, George Vilaras4, Evangelos Tsiambas4, Andreas Karameris4, Demosthenes Bouros1, and Vassilis Aidinis2*

1 Department of Pneumonology, Medical School, Democritus University of Thrace and University Hospital of Alexandroupolis, Alexandroupolis, Greece, 2 Institute of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Athens, Greece, 3 Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, Athens, Greece, 4 Department of Pathology, Veterans Administration Hospital (N.I.M.T.S), Athens, Greece

* To whom correspondence should be addressed. E-mail: v.aidinis{at}Fleming.gr.

Rationale: Despite intense research efforts, the etiology and pathogenesis of idiopathic pulmonary fibrosis remain poorly understood. Objective: To discover novel genes and/or cellular pathways involved in the pathogenesis of the disease. Methods/Measurements: Expression profiling of disease progression in an animal model of the disease was compared with all publicly available expression profiles both from human patients and animal models. Hypoxia inducible factor 1a expression was determined in tissue microarrays containing tissue samples of human patients, followed by computerized image analysis. Main results: A highly statistically significant, prioritized list of differentially expressed genes in idiopathic and/or modeled pulmonary fibrosis. Extending beyond target identification, a series of data meta- analyses produced a number of biological hypotheses on disease pathogenesis. From these, the role of hypoxia inducible factor 1a was further explored to reveal overexpression in the hyperplastic epithelium of fibrotic lungs, colocalized with its target genes p53 and VEGF. Conclusions Comparative expression profiling was shown to be a highly efficient method in identifying deregulated genes and pathways. Moreover, tissue microarrays and computerized image analysis allowed for the high throughput and unbiased assessment of histopathological sections, adding substantial confidence to pathological evaluations. More importantly, our results suggest an early primary role of hypoxia inducible factor 1 in alveolar epithelial cell homeostasis and disease pathogenesis, provide insights on the pathophysiological differences of different interstitial pneumonias, and indicate the importance of assessing the efficacy of pharmacological inhibitors of HIF-1 activity in the treatment of pulmonary fibrosis.
Key words: Pulmonary fibrosis, expression profiling, tissue microarrays, hypoxia inducing factor-1a




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