title: Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for "active" disease.
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.
authors.affiliation: DTA Inflammation, Hoffmann-La Roche Inc., pRED, Pharma Research and Early Development, Nutley, New Jersey, United States of America.
authors.forename: Ruoqi
authors.initials: R
authors.lastname: Peng
authors.forename: Sriram
authors.initials: S
authors.lastname: Sridhar
authors.forename: Gaurav
authors.initials: G
authors.lastname: Tyagi
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Phillips
authors.forename: Rosario
authors.initials: R
authors.lastname: Garrido
authors.forename: Paul
authors.initials: P
authors.lastname: Harris
authors.forename: Lisa
authors.initials: L
authors.lastname: Burns
authors.forename: Lorena
authors.initials: L
authors.lastname: Renteria
authors.forename: John
authors.initials: J
authors.lastname: Woods
authors.forename: Leena
authors.initials: L
authors.lastname: Chen
authors.forename: John
authors.initials: J
authors.lastname: Allard
authors.forename: Palanikumar
authors.initials: P
authors.lastname: Ravindran
authors.forename: Hans
authors.initials: H
authors.lastname: Bitter
authors.forename: Zhenmin
authors.initials: Z
authors.lastname: Liang
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
authors.forename: Chris
authors.initials: C
authors.lastname: Kitson
authors.forename: David C
authors.initials: DC
authors.lastname: Budd
authors.forename: Jay S
authors.initials: JS
authors.lastname: Fine
authors.forename: Carla M T
authors.initials: CM
authors.lastname: Bauer
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Stevenson
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D001761:Bleomycin / Q000008:administration & dosage / Q000009:adverse effects*; D016000:Cluster Analysis; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008938:Mitosis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011810:Quinoxalines / Q000494:pharmacology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C521813:6-(2-tert-butyl-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline; D000903:Antibiotics, Antineoplastic; D007093:Imidazoles; D011810:Quinoxalines; D018125:Receptors, Transforming Growth Factor beta; D001761:Bleomycin; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse
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