A Dynamic Bronchial Airway Gene Expression Signature of Chronic Obstructive Pulmonary Disease and Lung Function Impairment

Steiling, Katrina; Berge, Maarten van den; Hijazi, Kahkeshan; Florido, Roberta; Campbell, Joshua D.; Lv, Gang; Xiao, Jianru; Zhang, Xiaohui; Duclos, Grant; Drizik, Eduard; Si, Huiqing; Perdomo, Catalina; Dumont, Charles; Coxson, Harvey O.; Alekseyev, Yuriy O.; Sin, Don D.; Paré, Peter D.; Hogg, James C.; McWilliams, Annette; Hiemstra, Pieter S.; Sterk, Peter J.; Timens, Wim; Chang, Jeffrey T.; Sebastiani, Paola; O’Connor, George T.; Bild, Andrea; Postma, Dirkje S.; Lam, Stephen; Spira, Avrum; Lenburg, Marc E.

doi:10.1164/rccm.201208-1449oc

Cited by 143 publications

(163 citation statements)

References 33 publications

(43 reference statements)

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“…Evidence has implicated these pathways in the responses to oxidative stress imposed by cigarette smoke, but this requires further exploration [25][26][27][28]. Although ATF4 signalling is activated in the airways of many patients with chronic obstructive pulmonary disease [44], a direct mechanistic link with disease pathogenesis remains elusive.…”

Section: Upr Sensorsmentioning

confidence: 99%

Endoplasmic reticulum stress in lung disease

Marciniak

2017

Eur Respir Rev

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Exposure to inhaled pollutants, including fine particulates and cigarette smoke is a major cause of lung disease in Europe. While it is established that inhaled pollutants have devastating effects on the genome, it is now recognised that additional effects on protein folding also drive the development of lung disease. Protein misfolding in the endoplasmic reticulum affects the pathogenesis of many diseases, ranging from pulmonary fibrosis to cancer. It is therefore important to understand how cells respond to endoplasmic reticulum stress and how this affects pulmonary tissues in disease. These insights may offer opportunities to manipulate such endoplasmic reticulum stress pathways and thereby cure lung disease.

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Section: Upr Sensorsmentioning

confidence: 99%

Endoplasmic reticulum stress in lung disease

Marciniak

2017

Eur Respir Rev

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“…Validation of human gene expression was performed in patient samples derived from the GLUCOLD study cohort measured by Affymetrix Human Gene ST array and Affymetrix miRNA 2.0 array (GSE36221) [12][13][14].…”

Section: Human Patient Samplesmentioning

confidence: 99%

MicroRNA-223 controls the expression of histone deacetylase 2: a novel axis in COPD

et al. 2016

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Reduced activity of histone deacetylase 2 (HDAC2) has been described in patients with chronic obstructive pulmonary disease (COPD), but the mechanisms resulting in decreased expression of this important epigenetic modifier remain unknown. Here, we employed several in vitro experiments to address the role of microRNAs (miRNAs) on the regulation of HDAC2 in endothelial cells. Manipulation of miRNA levels in human pulmonary artery endothelial cells (HPAEC) was achieved by using electroporation with anti-miRNAs and miRNA mimics. Target prediction software identified miR-223 as a potential repressor of HDAC2. In subsequent stimulation experiments using inflammatory cytokines known to be increased in patients with COPD, miR-223 was found to be significantly induced. Functional analysis demonstrated that overexpression of miR-223 decreased HDAC2 expression and activity in HPAEC. Conversely, HDAC2 expression and activity was preserved in anti-miR-223-treated cells. Direct miRNAtarget interaction was confirmed by reporter gene assay. In a next step, reduced expression of HDAC2 was found to increase the levels of the chemokine fractalkine (CX3CL1). In vivo studies confirmed elevated expression levels of miR-223 in mice exposed to cigarette smoke and in emphysematous lung tissue from LPS-treated mice. Moreover, a significant inverse correlation of miR-223 and HDAC2 expression was found in two independent cohorts of COPD patients. These data emphasize that miR-223, the most prevalent miRNA in COPD, controls expression and activity of HDAC2 in pulmonary cells, which, in turn, might alter the expression profile of chemokines. This pathway provides a novel pathogenic link between dysregulated miRNA expression and epigenetic activity in COPD. KEY MESSAGES: Histone deacetylase 2 is directly targeted by miR-223. Levels of miR-223 are induced by interleukin-1 and tumor necrosis factor-. miR-223 controls the expression of fractalkine by targeting histone deacetylase 2. miR-223 levels are increased in COPD mouse models. miR-223 levels inversely correlate with HDAC2 expression in COPD patients. AbstractReduced activity of Histone Deacetylase 2 (HDAC2) has been described in patients with chronic obstructive pulmonary disease (COPD) but the mechanisms resulting in decreased expression of this important epigenetic modifier remain unknown. Here we employed several in vitro experiments to address the role of microRNAs (miRNAs) on the regulation of HDAC2 in endothelial cells. Manipulation of miRNA levels in human pulmonary artery endothelial cells (HPAEC) was achieved by using electroporation with anti-miRNAs and miRNA mimics.Target prediction software identified miR-223 as a potential repressor of HDAC2. In subsequent stimulation experiments using inflammatory cytokines known to be increased in patients with COPD miR-223 was found to be significantly induced. Functional analysis demonstrated that overexpression of miR-223 decreased HDAC2 expression and activity in HPAEC. Conversely, HDAC2 expression and activity was preserved i...

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“…A similar field of injury has recently been demonstrated for COPD (34), suggesting a potential method by which it may be possible to readily characterize the molecular heterogeneity of COPD in patients with impaired lung function. Early studies of airway gene expression in COPD focused specific pathways believed to be involved in COPD pathogenesis.…”

Section: Airway Gene Expression Reflects Genomic Alterations Within Tmentioning

confidence: 71%

“…Early studies of airway gene expression in COPD focused specific pathways believed to be involved in COPD pathogenesis. Tilley and colleagues (35) (Figure 1) that mirrors distal disease-associated changes in independent small airway and lung tissue datasets (34). Genes increased in this bronchial airway signature of COPD appear to be regulated in part by activating transcription factor 4 (ATF4), a key mediator of the unfolded protein response (34).…”

Section: Airway Gene Expression Reflects Genomic Alterations Within Tmentioning

confidence: 98%

“…One of the more compelling findings of the airway gene expression study described above was the dynamic nature of the transcriptomic alterations post treatment with inhaled corticosteroids (34). Using Gene Set Enrichment Analysis (37), the 98-gene signature was found to be inversely correlated with genes that changed 30 months post treatment with fluticasone with or without salmeterol therapy within the GLUCOLD study, a cohort in which these therapies reduced the decline in lung function (19,34 (38). Together, these studies emphasize the key components of deriving and validating disease and disease subtype signatures, including the critical step of validation in samples from independent cohorts.…”

Section: Airway Gene Expression As Therapeutic Biomarker In Copdmentioning

confidence: 99%

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Personalized Management of Chronic Obstructive Pulmonary Disease via Transcriptomic Profiling of the Airway and Lung

Steiling¹,

Lenburg²,

Spira³

2013

Annals ATS

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Chronic obstructive pulmonary disease (COPD) is a clinically heterogeneous disease composed of variable degrees of airflow obstruction, emphysematous destruction, and small airway wall thickening. The natural history of this disease, although generally characterized by continued decline in lung function, is also highly variable. Novel transcriptomic approaches to study the airway and lung tissue in COPD hold the potential to improve our understanding of the molecular mechanisms underlying this heterogeneity and identify molecular subtypes of disease that have similar clinical manifestations. This new understanding can be leveraged to develop targeted COPD therapies and ultimately personalize treatment of COPD based on each patient's specific molecular subphenotype.

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A Dynamic Bronchial Airway Gene Expression Signature of Chronic Obstructive Pulmonary Disease and Lung Function Impairment

Cited by 143 publications

References 33 publications

Endoplasmic reticulum stress in lung disease

Endoplasmic reticulum stress in lung disease

MicroRNA-223 controls the expression of histone deacetylase 2: a novel axis in COPD

Personalized Management of Chronic Obstructive Pulmonary Disease via Transcriptomic Profiling of the Airway and Lung

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