Unknown,Transcriptomics,Genomics,Proteomics

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Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: A model for “active” disease.

ABSTRACT: Genomic profiling of bleomycin- and saline-treated mice across 7 timepoints (1, 2, 7, 14, 21, 28, 35 days post treatment) was carried out in C57BL6/J mice to determine the phases of response to bleomycin treatment which correspond to onset of active pulmonary fibrosis. Temporal genomic characterization of lung homogenate from male C57BL6/J mice treated intratracheally with bleomycin or saline was carried out at 7 timepoints post treatment (1, 2, 7, 14, 21, 28, 35 days). Bleomycin (2U/kg) in 50 μl was intratracheally sprayed once into mice lightly anaesthetized with isoflurane (5% in 100% O2). Control animals received 50 μl of saline. Total RNA was isolated from the mouse lung tissue of bleomycin- and saline-treated mice across the 7 time points (n=8 per group) and homogenized in QIAzol reagent. Purified total RNA was amplified and labeled using NuGen Ovation kits (NuGEN Technologies, Inc., San Carlos, CA), and RNA from samples was hybridized to Affymetrix Mouse 430 2.0 arrays. One sample (saline treated, d14) was flagged as an outlier in principal component analysis and removed from subsequent analysis.

ORGANISM(S): Mus musculus

SUBMITTER: Sriram Sridhar

PROVIDER: E-GEOD-40151 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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

Peng Ruoqi R Sridhar Sriram S Tyagi Gaurav G Phillips Jonathan E JE Garrido Rosario R Harris Paul P Burns Lisa L Renteria Lorena L Woods John J Chen Leena L Allard John J Ravindran Palanikumar P Bitter Hans H Liang Zhenmin Z Hogaboam Cory M CM Kitson Chris C Budd David C DC Fine Jay S JS Bauer Carla M T CM Stevenson Christopher S CS

PloS one 20130402 4

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 t ...[more]

PMID: 23565148

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Project description:Polyinosinic:polycytidylic acid (poly I:C) is a synthetic analogue of double-stranded (ds)RNA, a molecular pattern associated with viral infections, that is used to exacerbate inflammation in lung injury models. Despite its frequent use, there are no detailed studies of the responses elicited by a single topical administration of poly I:C to the lungs of mice. Our data provides the first demonstration that the molecular responses in the airways induced by poly I:C correlate to those observed in the lungs of COPD patients. These expression data also revealed three distinct phases of response to poly I:C, consistent with the changing inflammatory cell infiltrate in the airways. Poly I:C induced increased numbers of neutrophils and NK cells in the airways, which were blocked by CXCR2 and CCR5 antagonists, respectively. Using gene set variation analysis on representative data sets, gene sets defined by poly I:C-induced DEGs were enriched in the molecular profiles of chronic obstructive pulmonary disease (COPD), but not idiopathic pulmonary fibrosis patients. Collectively, these data represent a new approach for validating the clinical relevance of preclinical animal models and demonstrate that a dual CXCR2/CCR5 antagonist may be an effective treatment for COPD patients. Temporal genomic characterization of lung homogenate from male BALB/cJ mice treated intranasally with poly I:C or saline was carried out at 7 timepoints post poly I:C/saline adiministration (2, 6, 24, 48, 72, 96, 168 hours). Mice were anesthetized with isoflurane and intranasally (i.n.) administered saline or poly I:C (InvivoGen, San Diego, CA) at a sub-maximal dose of 30 µg in 50 µl sterile saline. For time course studies, the 30 µg was administered i.n. once and assessed from 2 – 168 hours. Total RNA was isolated from the mouse lung tissue of poly I:C and saline treated mice across 7 time points (2, 6, 24, 48, 72, 96, and 168 hours, n=6 per group) and homogenized in QIAzol reagent. Purified total RNA was amplified and labeled using NuGen Ovation kits (NuGEN Technologies, Inc., San Carlos, CA) and RNA from samples was hybridized to Affymetrix Mouse 430 2.0 arrays.

Dataset Information

Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: A model for “active” disease.

Publications

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

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