Journal Article

Bleomycin Induces Molecular Changes Directly Relevant to Idiopathic Pulmonary Fibrosis: A Model for “Active” Disease

Chen, Leena, Liang, Zhenmin, Allard, John, Hogaboam, Cory M., Ravindran, Palanikumar, Burns, Lisa, Stevenson, Christopher S., Budd, David C., Garrido, Rosario, Harris, Paul, Tyagi, Gaurav, Sridhar, Sriram, Phillips, Jonathan E., Renteria, Lorena, Fine, Jay S., Peng, Ruoqi, Bitter, Hans, Kitson, Chris, Woods, John, Bauer, Carla MT

2013

Overview

The preclinical model of bleomycin-induced lung fibrosis, used to investigate mechanisms related to idiopathic pulmonary fibrosis (IPF), has incorrectly predicted efficacy for several candidate compounds suggesting that it may be of limited value. As an attempt to improve the predictive nature of this model, integrative bioinformatic approaches were used to compare molecular alterations in the lungs of bleomycin-treated mice and patients with IPF. Using gene set enrichment analysis we show for the first time that genes differentially expressed during the fibrotic phase of the single challenge bleomycin model were significantly enriched in the expression profiles of IPF patients. The genes that contributed most to the enrichment were largely involved in mitosis, growth factor, and matrix signaling. Interestingly, these same mitotic processes were increased in the expression profiles of fibroblasts isolated from rapidly progressing, but not slowly progressing, IPF patients relative to control subjects. The data also indicated that TGFβ was not the sole mediator responsible for the changes observed in this model since the ALK-5 inhibitor SB525334 effectively attenuated some but not all of the fibrosis associated with this model. Although some would suggest that repetitive bleomycin injuries may more effectively model IPF-like changes, our data do not support this conclusion. Together, these data highlight that a single bleomycin instillation effectively replicates several of the specific pathogenic molecular changes associated with IPF, and may be best used as a model for patients with active disease.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Airway Remodeling - drug effects / Animals / Antibiotics, Antineoplastic - administration & dosage / Antibiotics, Antineoplastic - adverse effects / Biology / Bleomycin / Bleomycin - administration & dosage / Bleomycin - adverse effects / Cluster Analysis / Complications and side effects / Disease Models, Animal / Enrichment / Extracellular matrix / Fibroblasts / Fibroblasts - drug effects / Fibroblasts - metabolism / Fibrosis / Gene expression / Gene Expression Profiling / Gene Expression Regulation - drug effects / Gene set enrichment analysis / Genes / Genetically modified mice / Growth factors / Health services utilization / Humans / Idiopathic Pulmonary Fibrosis - chemically induced / Idiopathic Pulmonary Fibrosis - genetics / Idiopathic Pulmonary Fibrosis - metabolism / Idiopathic Pulmonary Fibrosis - pathology / Imidazoles - pharmacology / Inflammation / Inflammation - chemically induced / Interferon / Lung - drug effects / Lung - pathology / Lung - physiopathology / Lung diseases / Lungs / Male / Mathematical models / Medicine / Mice / Mitosis / Mitosis - genetics / Pathology / Patients / Pharmacology / Physiology / Protein-Serine-Threonine Kinases - antagonists & inhibitors / Pulmonary fibrosis / Quinoxalines - pharmacology / Receptors, Transforming Growth Factor beta - antagonists & inhibitors / Risk factors / Rodents / Signal Transduction - drug effects / Signaling