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Gene expression signatures for Normal-looking, fibrotic foci and hyperplastic (adjacent to fibrotic foci) area in IPF lungs

ABSTRACT: To further understand the pathologic microenvironment in IPF, we have employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to distinguish normal and IPF lung in normal-looking, fibrotic foci and hyperplastic areas of IPF lung. Four IPF lungs were dissected into normal-looking, fibrotic foci and hyperplastic areas by Laser-Capture-Microdissection. Gene expression analysis showed that 638 significantly different genes were identified that clearly distinguished the different IPF microenvironments . Among them, MMP19 was revealed as one of the most significantly up-regulated genes that distinguished normal looking epithelial cells (N) to hyperplastic epithelial cells, MMP19 up-regulation in IPF lungs was verified by immunohistochemical (IHC), qRT-PCR and Western-blot.

ORGANISM(S): Homo sapiens

PROVIDER: GSE35309 | GEO | 2013/01/11

SECONDARY ACCESSION(S): PRJNA159577

REPOSITORIES: GEO

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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

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Gene expression signatures for Normal-looking, fibrotic foci and hyperplastic (adjacent to fibrotic foci) area in IPF lungs

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