Comparative expression profiling in pulmonary fibrosis suggests a role of hypoxia-inducible factor-1alpha in disease pathogenesis.
BACKGROUND
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
We performed expression profiling of disease progression in a well-characterized animal model of the disease. Differentially expressed genes that were identified were compared with all publicly available expression profiles both from human patients and animal models. The role of hypoxia-inducible factor (HIF)-1alpha in disease pathogenesis was examined with a series of immunostainings, both in the animal model as well as in tissue microarrays containing tissue samples of human patients, followed by computerized image analysis.


RESULTS
Comparative expression profiling produced a prioritized gene list of high statistical significance, which consisted of the most likely disease modifiers identified so far in pulmonary fibrosis. Extending beyond target identification, a series of meta-analyses produced a number of biological hypotheses on disease pathogenesis. Among them, the role of HIF-1 signaling was further explored to reveal HIF-1alpha 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 histopathologic sections, adding substantial confidence in pathologic evaluations. More importantly, our results suggest an early primary role of HIF-1 in alveolar epithelial cell homeostasis and disease pathogenesis, provide insights on the pathophysiologic differences of different interstitial pneumonias, and indicate the importance of assessing the efficacy of pharmacologic inhibitors of HIF-1 activity in the treatment of pulmonary fibrosis.
Tzouvelekis
Argyris
A
Department of Pneumonology, Medical School, Democritus University of Thrace, and University Hospital of Alexandroupolis, Alexandroupolis, Greece.
Harokopos
Vaggelis
V
Paparountas
Triantafillos
T
Oikonomou
Nikos
N
Chatziioannou
Aristotelis
A
Vilaras
George
G
Tsiambas
Evangelos
E
Karameris
Andreas
A
Bouros
Demosthenes
D
Aidinis
Vassilis
V
D000818:Animals; D017209:Apoptosis; D018450:Disease Progression; D004848:Epithelium / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D007091:Image Processing, Computer-Assisted; D008168:Lung / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D011014:Pneumonia / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D015398:Signal Transduction; D014018:Tissue Distribution; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A