Dataset Information

Gene profile of fibroblasts identify relation of CCL8 with idiopathic pulmonary fibrosis.

ABSTRACT:

Background

Idiopathic pulmonary fibrosis (IPF) is characterized by the complex interaction of cells involved in chronic inflammation and fibrosis. Global gene expression of a homogenous cell population will identify novel candidate genes.

Methods

Gene expression of fibroblasts derived from lung tissues (8 IPF and 4 controls) was profiled, and ontology and functional pathway were analyzed in the genes exhibiting >2 absolute fold changes with p-values?ResultsOne hundred seventy eight genes differentially expressed and 15 genes exhibited >10-fold change. Among them, 13 were novel in relation with IPF. CCL8 expression was 22.8-fold higher in IPF fibroblasts. The levels of CCL8 mRNA and protein were 3 and 9-fold higher in 14 IPF fibroblasts than those in 10 control fibroblasts by real-time PCR and ELISA (p?=?0.022 and p?=?0.026, respectively). The CCL8 concentrations in BAL fluid was significantly higher in 86 patients with IPF than those in 41 controls, and other interstitial lung diseases including non-specific interstitial pneumonia (n?=?22), hypersensitivity pneumonitis (n?=?20) and sarcoidosis (n?=?19) (p?28.61 pg/mL showed shorter survival compared to those with lower levels (p?=?0.012). CCL8 was expressed by ?-SMA-positive cells in the interstitium of IPF.

Conclusions

Transcriptome analysis identified several novel IPF-related genes. Among them, CCL8 is a candidate molecule for the differential diagnosis and prediction of survival.

SUBMITTER: Lee JU

PROVIDER: S-EPMC5216573 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Publications

Gene profile of fibroblasts identify relation of CCL8 with idiopathic pulmonary fibrosis.

Lee Jong-Uk JU Cheong Hyun Sub HS Shim Eun-Young EY Bae Da-Jeong DJ Chang Hun Soo HS Uh Soo-Taek ST Kim Young Hoon YH Park Jong-Sook JS Lee Bora B Shin Hyoung Doo HD Park Choon-Sik CS

Respiratory research 20170105 1

<h4>Background</h4>Idiopathic pulmonary fibrosis (IPF) is characterized by the complex interaction of cells involved in chronic inflammation and fibrosis. Global gene expression of a homogenous cell population will identify novel candidate genes.<h4>Methods</h4>Gene expression of fibroblasts derived from lung tissues (8 IPF and 4 controls) was profiled, and ontology and functional pathway were analyzed in the genes exhibiting >2 absolute fold changes with p-values < 0.05. CCL8 mRNA and protein l ...[more]

PMID: 28057004

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Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a fatal heterogeneous disease with a varied clinical course that is difficult to predict. Accurate predictive models are urgently needed to identify individuals with poor survival for the optimal timing of referral for transplantation and provide some clues for mechanistic research on disease progression.MethodsWe obtained the gene expression profiles of bronchoalveolar lavage fluid (BALF) from the Gene Expression Omnibus. Individuals from the GPL14550 platform were assigned to the derivation cohort (n=112) and individuals from the GPL17077 platform to the validation cohort (n=64). Univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analyses were applied to select candidate genes for overall survival. A nomogram model was constructed based on Cox hazard regression analysis. The model was assessed by C-statistic, calibration curve, and decision curve analysis (DCA) and was externally validated.ResultsA nomogram model comprising seven genes was constructed. Excellent discrimination and calibration were observed in the derivation (C-index 0.815) and validation (C-index 0.812) cohorts. The AUCs for predicting 1-, 2- and 3-year survival were 0.857, 0.918, 0.930 in the derivation cohort and 0.850, 0.880, 0.925 in the validation cohort, respectively. DCA confirmed the clinical applicability of the model. A risk score based on the model was an independent prognostic predictor and could divide patients into high- and low-risk groups. The Kaplan-Meier analysis displayed that high-risk patients exhibited significantly poorer survival compared with low-risk patients. Gene Set Enrichment Analysis (GSEA) showed that high-risk patients were primarily enriched in inflammatory hallmarks, and single sample GSEA (ssGSEA) indicated that the high-risk group is closely correlated with the immune process. These lead to increased insight into mechanisms associated with IPF progression that inflammation mediated by immune response might be involved in the disease progression.ConclusionsThe novel BALF seven-gene model performed well in risk stratification and individualized survival prediction for patients with IPF, facilitating personalized management of IPF patients. It deepened the understanding of the role of inflammation in IPF progression, which needs to be further studied.

Project description:Idiopathic pulmonary fibrosis (IPF) is a lethal fibrotic lung disease with an increasing global burden. It is hypothesized that fibroblasts have a number of functions that may affect the development and progression of IPF. However, the present understanding of cellular and molecular mechanisms associated with fibroblasts in IPF remains limited. The present study aimed to identify the dysregulated genes in IPF fibroblasts, elucidate their functions and explore potential microRNA (miRNA)‑mRNA interactions. mRNA and miRNA expression profiles were obtained from IPF fibroblasts and normal lung fibroblasts using a next‑generation sequencing platform, and bioinformatic analyses were performed in a step‑wise manner. A total of 42 dysregulated genes (>2 fold‑change of expression) were identified, of which 5 were verified in the Gene Expression Omnibus (GEO) database analysis, including the upregulation of neurotrimin (NTM), paired box 8 (PAX8) and mesoderm development LRP chaperone, and the downregulation of ITPR interacting domain containing 2 and Inka box actin regulator 2 (INKA2). Previous data indicated that PAX8 and INKA2 serve roles in cell growth, proliferation and survival. Gene Ontology analysis indicated that the most significant function of these 42 dysregulated genes was associated with the composition and function of the extracellular matrix (ECM). A total of 60 dysregulated miRNAs were also identified, and 1,908 targets were predicted by the miRmap database. The integrated analysis of mRNA and miRNA expression data, combined with GEO verification, finally identified Homo sapiens (hsa)‑miR‑1254‑INKA2 and hsa‑miR‑766‑3p‑INKA2 as the potential miRNA‑mRNA interactions in IPF fibroblasts. In summary, the results of the present study suggest that dysregulation of PAX8, hsa‑miR‑1254‑INKA2 and hsa‑miR‑766‑3p‑INKA2 may promote the proliferation and survival of IPF fibroblasts. In the functional analysis of the dysregulated genes, a marked association between fibroblasts and the ECM was identified. These data improve the current understanding of fibroblasts as key cells in the pathogenesis of IPF. As a screening study using bioinformatics approaches, the results of the present study require additional validation.

Dataset Information

Gene profile of fibroblasts identify relation of CCL8 with idiopathic pulmonary fibrosis.

Background

Methods

Conclusions

Publications

Gene profile of fibroblasts identify relation of CCL8 with idiopathic pulmonary fibrosis.

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