Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for "active" disease

PLoS One. 2013;8(4):e59348. doi: 10.1371/journal.pone.0059348. Epub 2013 Apr 2.

Abstract

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.

MeSH terms

  • Airway Remodeling / drug effects
  • Animals
  • Antibiotics, Antineoplastic / administration & dosage
  • Antibiotics, Antineoplastic / adverse effects*
  • Bleomycin / administration & dosage
  • Bleomycin / adverse effects*
  • Cluster Analysis
  • Disease Models, Animal
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects
  • Humans
  • Idiopathic Pulmonary Fibrosis / chemically induced*
  • Idiopathic Pulmonary Fibrosis / genetics*
  • Idiopathic Pulmonary Fibrosis / metabolism
  • Idiopathic Pulmonary Fibrosis / pathology
  • Imidazoles / pharmacology
  • Inflammation / chemically induced
  • Lung / drug effects
  • Lung / pathology
  • Lung / physiopathology
  • Male
  • Mice
  • Mitosis / genetics
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Quinoxalines / pharmacology
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors
  • Signal Transduction / drug effects

Substances

  • 6-(2-tert-butyl-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline
  • Antibiotics, Antineoplastic
  • Imidazoles
  • Quinoxalines
  • Receptors, Transforming Growth Factor beta
  • Bleomycin
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human
  • Tgfbr1 protein, mouse

Associated data

  • GEO/GSE44723