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 RNA from cultured human fibroblasts of donor samples in the 10-14th passage was carried out to determine expression changes in the fibroblasts of individual with different degrees of pulmonary fibrosis. Donors consisted of individuals with rapid progressing pulmonary fibrosis, slow progressing pulmonary fibrosis, or no fibrosis. Genomic characterization of cultured human fibroblasts from donor samples was carried out in samples from donors with from 3 groups: rapid progressing pulmonary fibrosis, slow progressing pulmonary fibrosis, and non-fibrotic individuals. Large RNA (> ~ 200bp) was isolated from fibroblast cultures. 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 HG-U133 plus 2.0 arrays.

ORGANISM(S): Homo sapiens

SUBMITTER: Sriram Sridhar

PROVIDER: E-GEOD-44723 | 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:As a group, fibroproliferative disorders of the lung, liver, kidney, heart, vasculature and integument are common, progressive and refractory to therapy. They can emerge following toxic insults, but are frequently idiopathic. Their enigmatic propensity to resist therapy and progress to organ failure has focused attention on the myofibroblast – the primary effector of the fibroproliferative response. A central unanswered question is whether these myofibroblasts have acquired a distinct pathological phenotype - or whether they are normal myofibroblasts with a pathological phenotype that depends upon residing in a sea of pro-fibrotic cytokines and an abnormal extracellular matrix. Using a systems approach to study this question in a prototype fibrotic disease, Idiopathic Pulmonary Fibrosis (IPF); here we show organized changes in the gene expression pathway of primary lung myofibroblasts that persist for up to 9 sub-cultivations in vitro. When comparing IPF and control myofibroblasts in a 3-dimensional type I collagen matrix, more genes differed at the level of ribosome recruitment than at the level of transcript abundance, indicating pathological translational control as a major characteristic of IPF myofibroblasts. To determine the effect of matrix state on translational control, myofibroblasts were permitted to contract the matrix. Ribosome recruitment in control myofibroblasts was relatively stable. In contrast, IPF cells manifested large alterations in the ribosome recruitment pattern. Pathological studies suggest an epithelial origin for IPF myofibroblasts through the epithelial to mesenchymal transition (EMT). In accord with this, we found systems-level indications for TGF?b -driven EMT as one source of IPF myofibroblasts. Keywords: cell type comparison Comparison of lung myofibroblasts from patients with Idiopatic Pulmonary Fibrosis (IPF, 6 donors) to control (6 donors) in contractile and non-contractile matrices using both total and polyribosomal RNA

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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