Lung tissue gene-expression signature for the ageing lung in COPD

Vries, Maaike de; Faiz, Alen; Woldhuis, Roy R; Postma, Dirkje S.; Jong, Tristan de; Sin, Don D.; Bossé, Yohan; Nickle, David C.; Guryev, Victor; Timens, Wim; Berge, Maarten van den; Brandsma, Corry‐Anke

doi:10.1136/thoraxjnl-2017-210074

Cited by 38 publications

(37 citation statements)

References 29 publications

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“…To evaluate whether aging signatures derived from GTEx were reproducible, we compared our results with aging gene lists from five independent studies covering multiple tissue types: brain (Berchtold et al, ), skin (Glass et al, ), adipose (Glass et al, ), blood (Lu et al, ), and lung (de Vries et al, ). We found that aging genes identified from GTEx showed a significant overlap with aging genes from these independent studies.…”

Section: Resultsmentioning

confidence: 99%

Transcriptome analysis reveals the difference between “healthy” and “common” aging and their connection with age‐related diseases

et al. 2020

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A key goal of aging research was to understand mechanisms underlying healthy aging and develop methods to promote the human healthspan. One approach is to identify gene regulations unique to healthy aging compared with aging in the general population (i.e., “common” aging). Here, we leveraged Genotype‐Tissue Expression (GTEx) project data to investigate “healthy” and “common” aging gene expression regulations at a tissue level in humans and their interconnection with diseases. Using GTEx donors' disease annotations, we defined a “healthy” aging cohort for each tissue. We then compared the age‐associated genes derived from this cohort with age‐associated genes from the “common” aging cohort which included all GTEx donors; we also compared the “healthy” and “common” aging gene expressions with various disease‐associated gene expressions to elucidate the relationships among “healthy,” “common” aging and disease. Our analyses showed that 1. GTEx “healthy” and “common” aging shared a large number of gene regulations; 2. Despite the substantial commonality, “healthy” and “common” aging genes also showed distinct function enrichment, and “common” aging genes had a higher enrichment for disease genes; 3. Disease‐associated gene regulations were overall different from aging gene regulations. However, for genes regulated by both, their regulation directions were largely consistent, implying some aging processes could increase the susceptibility to disease development; and 4. Possible protective mechanisms were associated with some “healthy” aging gene regulations. In summary, our work highlights several unique features of GTEx “healthy” aging program. This new knowledge could potentially be used to develop interventions to promote the human healthspan.

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Section: Resultsmentioning

confidence: 99%

Transcriptome analysis reveals the difference between “healthy” and “common” aging and their connection with age‐related diseases

et al. 2020

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“…mTORC1 is activated in COPD peripheral lung and peripheral blood mononuclear cells (PBMC), demonstrated by increased phosphorylated S6 kinase, and is effectively inhibited by rapamycin (44,45). Gene expression profiling also reveals increased mTOR pathway activation in aged COPD lungs compared to age-matched controls (46). mTOR is also activated in IPF (47,48).…”

Section: Pi3k-mtor Signalingmentioning

confidence: 99%

Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases

Barnes

Baker

Donnelly

2019

Am J Respir Crit Care Med

298

199

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Cellular senescence is now considered an important driving mechanism for chronic lung diseases, particularly COPD and idiopathic pulmonary fibrosis. Cellular senescence is due to replicative and stress-related senescence with activation of p53 and p16 INK4a respectively, leading to activation of p21 CIP1 and cell cycle arrest. Senescent cells secrete multiple inflammatory proteins known as the senescence-associated secretory phenotype (SASP), leading to low grade chronic inflammation, which further drives senescence. Loss of key anti-aging molecules sirtuin-1 and sirtuin-6 may be important in acceleration of aging and arises from oxidative stress reducing phosphatase PTEN, thereby activating PI3K (phosphoinositide-3-kinase) and mTOR (mammalian target of rapamycin). MicroRNA-34a, which is regulated by PI3K-mTOR signaling, plays a pivotal role in reducing sirtuin-1/6 and its inhibition with an antagomir results in their restoration, reducing markers of senescence, reducing SASP and reversing cell cycle arrest in epithelial cells from peripheral airways of COPD patients. MiR-570 is also involved in reduction of sirtuin-1 and cellular senescence and is activated by p38 MAP kinase. These miRNAs may be released from cells in extracellular vesicles that are taken up by other cells, thereby spreading senescence locally within the lung but outside the lung through the circulation; this may account for comorbidities of COPD and other lung diseases. Understanding the mechanisms of cellular senescence may result in new treatments for chronic lung disease, either by inhibiting PI3K-mTOR signaling, by inhibiting specific miRNAs or by deletion of senescent cells with senolytic therapies, already shown to be effective in experimental lung fibrosis.

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“…This suggests that the bronchiolitis and emphysema phenotypes of COPD occur via different mechanisms, leading to different treatment response and clinical outcome. We know from gene expression and polymorphism studies that COPD is a polygenic disease involving multiple pathogenic signalling pathways . Whether and how the disease processes differ between the emphysema and bronchiolitis phenotypes of COPD remains to be investigated.…”

Section: Introductionmentioning

confidence: 99%

“…We know from gene expression and polymorphism studies that COPD is a polygenic disease involving multiple pathogenic signalling pathways. [10][11][12] Whether and how the disease processes differ between the emphysema and bronchiolitis phenotypes of COPD remains to be investigated.…”

mentioning

confidence: 99%

Differential coexpression networks in bronchiolitis and emphysema phenotypes reveal heterogeneous mechanisms of chronic obstructive pulmonary disease

Qin

Yang

Zeng

et al. 2019

J Cellular Molecular Medi

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Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with multiple molecular mechanisms. To investigate and contrast the molecular processes differing between bronchiolitis and emphysema phenotypes of COPD, we downloaded the GSE69818 microarray data set from the Gene Expression Omnibus (GEO), which based on lung tissues from 38 patients with emphysema and 32 patients with bronchiolitis. Then, weighted gene coexpression network analysis (WGCNA) and differential coexpression (DiffCoEx) analysis were performed, followed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes enrichment analysis (KEGG) analysis. Modules and hub genes for bronchiolitis and emphysema were identified, and we found that genes in modules linked to neutrophil degranulation, Rho protein signal transduction and B cell receptor signalling were coexpressed in emphysema. DiffCoEx analysis showed that four hub genes (IFT88, CCDC103, MMP10 and Bik) were consistently expressed in emphysema patients; these hub genes were enriched, respectively, for functions of cilium assembly and movement, proteolysis and apoptotic mitochondrial changes. In our re‐analysis of GSE69818, gene expression networks in relation to emphysema deepen insights into the molecular mechanism of COPD and also identify some promising therapeutic targets.

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Lung tissue gene-expression signature for the ageing lung in COPD

Cited by 38 publications

References 29 publications

Transcriptome analysis reveals the difference between “healthy” and “common” aging and their connection with age‐related diseases

Transcriptome analysis reveals the difference between “healthy” and “common” aging and their connection with age‐related diseases

Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases

Differential coexpression networks in bronchiolitis and emphysema phenotypes reveal heterogeneous mechanisms of chronic obstructive pulmonary disease

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