Senani N . H . Rathnayake (original) (raw)

Papers by Senani N . H . Rathnayake

Research paper thumbnail of Longitudinal Effects of 1-Year Smoking Cessation on Human Bronchial Epithelial Transcriptome

CHEST

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Research paper thumbnail of The Y-chromosome regulates hallmark features of asthma and COPD

03.01 - Molecular pathology and functional genomics

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Research paper thumbnail of Influence of smoking on bronchial epithelial cell composition by cellular deconvolution and IHC

03.01 - Molecular pathology and functional genomics

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Research paper thumbnail of Early transcriptional responses of bronchial epithelial cells to whole cigarette smoke mirror those of in-vivo exposed human bronchial mucosa

Respiratory Research

Background Despite the well-known detrimental effects of cigarette smoke (CS), little is known ab... more Background Despite the well-known detrimental effects of cigarette smoke (CS), little is known about the complex gene expression dynamics in the early stages after exposure. This study aims to investigate early transcriptomic responses following CS exposure of airway epithelial cells in culture and compare these to those found in human CS exposure studies. Methods Primary bronchial epithelial cells (PBEC) were differentiated at the air–liquid interface (ALI) and exposed to whole CS. Bulk RNA-sequencing was performed at 1 h, 4 h, and 24 h hereafter, followed by differential gene expression analysis. Results were additionally compared to data retrieved from human CS studies. Results ALI-PBEC gene expression in response to CS was most significantly changed at 4 h after exposure. Early transcriptomic changes (1 h, 4 h post CS exposure) were related to oxidative stress, xenobiotic metabolism, higher expression of immediate early genes and pro-inflammatory pathways (i.e., Nrf2, AP-1, AhR)...

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Research paper thumbnail of Transcriptome Dynamics in Bronchial Epithelial Cells Following to Cigarette Exposure

Respirology, Apr 1, 2021

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Research paper thumbnail of Single-nucleotide polymorphism rs2070600 regulates AGER splicing and the sputum levels of the COPD biomarker soluble receptor for advanced glycation end-products

ERJ Open Research, 2021

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Research paper thumbnail of Gene expression and methylation are altered by smoke cessationin the airway wall

European Respiratory Journal, 2020

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Research paper thumbnail of Longitudinal effects of 12 months smoking cessation on dna methylation and gene expression in bronchial biopsies

Respirology, 2020

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Research paper thumbnail of Smoking alters gene expression and methylation patterns in asthma patient nasal epithelium

06.04 - Genes and environment, 2021

Current-smoking significantly contributes to worse asthma prognosis and more severe disease sympt... more Current-smoking significantly contributes to worse asthma prognosis and more severe disease symptoms. Smoking limits the beneficial effects of corticosteroids by altering the physiological response in the airways. The nasal epithelium is a relevant site to investigate smoking-related molecular changes as it can reflect the lower airways. As such, we explore the relationship between nasal gene expression and methylation in current and ex-smoker asthma patients. We also investigate how these patterns are altered upon smoking cessation. The analysis was conducted on matched gene expression, and methylation samples collected from nasal brushings of 55 asthma-diagnosed patients. Differential gene expression and methylation analysis compared current vs ex-smokers. Expression quantitative trait methylation analysis was then conducted to explore smoking relevant genes by CpG sites that differ between current and ex-smokers. These sites were compared to a bronchial biopsy smoking-cessation dataset. The analysis was conducted using R software with a false discovery rate (FDR) determined with the Benjamini-Hochberg method. Current smoking in the nose differentially altered 809 genes and 18,814 CpG sites. The cis-eQTM analysis uncovered 171 CpG sites whose methylation status related to the expression of smoking-related genes, including AHRR, ALDH3A1, CYP1A1 and CYP1B1. Methylation of CpG sites altered by current smoking reversed upon one-year of smoking cessation. This study identifies smoking-associated changes in methylation and gene expression are detectable in the nasal epithelium of asthma patients. Our results support the nasal epithelium as an alternate site to investigate changes in the airways due to smoking. We show these patterns are partially reversible after smoking cessation.

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Research paper thumbnail of Current Smoking Affects Gene Expression and Methylation Patterns in Asthma Patient Nasal Epithelium

TP112. TP112 PROTEOMICS/GENOMICS/METABOLOMICS IN LUNG DISEASE, 2021

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Research paper thumbnail of Current Smoking Alters Gene Expression and DNA Methylation in the Nasal Epithelium of Patients with Asthma

American Journal of Respiratory Cell and Molecular Biology, 2021

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Research paper thumbnail of Gene expression profiling of bronchial brushes is associated with the level of emphysema measured by computed tomography-based parametric response mapping

American Journal of Physiology-Lung Cellular and Molecular Physiology, 2020

Parametric response mapping (PRM) is a computed tomography (CT)-based method to phenotype patient... more Parametric response mapping (PRM) is a computed tomography (CT)-based method to phenotype patients with chronic obstructive pulmonary disease (COPD). It is capable of differentiating emphysema-related air trapping with nonemphysematous air trapping (small airway disease), which helps to identify the extent and localization of the disease. Most studies evaluating the gene expression in smokers and COPD patients related this to spirometric measurements, but none have investigated the relationship with CT-based measurements of lung structure. The current study aimed to examine gene expression profiles of brushed bronchial epithelial cells in association with the PRM-defined CT-based measurements of emphysema (PRMEmph) and small airway disease (PRMfSAD). Using the Top Institute Pharma (TIP) study cohort (COPD = 12 and asymptomatic smokers = 32), we identified a gene expression signature of bronchial brushings, which was associated with PRMEmph in the lungs. One hundred thirty-three gene...

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Research paper thumbnail of RAGE and TLR4 differentially regulate airway hyperresponsiveness: Implications for COPD

Allergy, 2020

BackgroundThe receptor for advanced glycation end products (RAGE) and Toll‐like receptor 4 (TLR4)... more BackgroundThe receptor for advanced glycation end products (RAGE) and Toll‐like receptor 4 (TLR4) is implicated in COPD. Although these receptors share common ligands and signalling pathways, it is not known whether they act in concert to drive pathological processes in COPD. We examined the impact of RAGE and/or TLR4 gene deficiency in a mouse model of COPD and also determined whether expression of these receptors correlates with airway neutrophilia and airway hyperresponsiveness (AHR) in COPD patients.MethodsWe measured airway inflammation and AHR in wild‐type, RAGE−/−, TLR4−/− and TLR4−/−RAGE−/− mice following acute exposure to cigarette smoke (CS). We also examined the impact of smoking status on AGER (encodes RAGE) and TLR4 bronchial gene expression in patients with and without COPD. Finally, we determined whether expression of these receptors correlates with airway neutrophilia and AHR in COPD patients.ResultsRAGE−/− mice were protected against CS‐induced neutrophilia and AHR....

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Research paper thumbnail of Longitudinal effect of smoking cessation on transcriptomics and epigenetics in the airways of COPD patients and asymptomatic controls

03.02 - Airway cell biology and immunopathology, 2020

Background: COPD is characterized by chronic inflammation of the lungs to noxious particles such ... more Background: COPD is characterized by chronic inflammation of the lungs to noxious particles such as cigarette smoke leading to accelerated decline in lung function. The inflammation associated with smoke exposure remains even after smoking stops. Aim a Objectives: This study aims to investigate the longitudinal effects of smoking cessation at transcriptomic and epigenetic levels. Methods: Bronchial biopsies were collected from 19 individuals (healthy= 7, COPD= 12) before and after 12 months smoking cessation followed by DNA/RNA extraction. DNA methylation was measured using Infinium-HumanMethylation850k and RNA-Seq using Illumina-NovaSeq6000 sequencing. A Benjamini–Hochberg corrected p |1.5| was considered significant. We used expression quantitative trait methylation (eQTM) analysis to correlate gene expression with DNA methylation. Results: Differential gene expression analysis before and after 12 months smoking cessation resulted in 613 differentially expressed genes, including a number of down-regulated oxidative stress genes (i.e. ALDH3A1, which oxidises toxic aldehydes and protects the airway epithelium from smoking-induced oxidative stress). Differential DNA methylation analysis before and after smoking cessation identified 261 hypomethylated, 289 hypermethylated significant CpG-sites, e.g. cg19171383. The CpG site cg19171383 was found to be differentially methylated and was negatively correlated with ALDH3A1 in the eQTM analysis. An interaction analysis of smoking cessation with disease found not differences at a transcriptomic and epigenetic levels. Conclusion: These findings indicate that smoking cessation increases the methylation of oxidative stress related genes, which may lead to their decrease in expression.

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Research paper thumbnail of Longitudinal effects of smoking cessation on DNA methylation in bronchial biopsies of COPD and asymptomatic smokers

Molecular pathology and funct. genomics, 2019

Introduction: COPD is characterized by chronic inflammation in lungs in response to smoke exposur... more Introduction: COPD is characterized by chronic inflammation in lungs in response to smoke exposure leading to accelerated decline in lung function. Only a subset of smokers will develop COPD. Once developed inflammation remains present even after patients quit smoking, suggesting persistent epigenetic changes in lungs. Whereas previous studies have been based on cross-sectional cohorts, this study is the first using a longitudinal cohort pre and post smoking cessation. Aim: To investigate the longitudinal effects of smoking cessation on DNA methylation and the differences between patients with COPD and non-COPD controls. Methods: Bronchial biopsies were collected from 19 individuals (healthy=7, COPD=12) pre and post 12 months smoking cessation. DNA methylation was measured using Infinium HumanMethylation850k Bead Chip. A Bonferroni corrected p Results: We identified 7 CpG-sites genome-wide significantly changed after smoking cessation. An interaction analysis between between healthy and COPD groups identified 3 suggestive CpG-sites. Conclusion: Even though this is a small study group the results clearly indicate significant differences in DNA methylation following smoking cessation as well as suggestive evidence of differential effect of smoking cessation on DNA methylation between COPD and healthy controls.

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Research paper thumbnail of Cigarette smoke exposure alters phosphodiesterases in human structural lung cells

American Journal of Physiology-Lung Cellular and Molecular Physiology, 2019

Cigarette smoke (CS), a highly complex mixture containing more than 4,000 compounds, causes aberr... more Cigarette smoke (CS), a highly complex mixture containing more than 4,000 compounds, causes aberrant cell responses leading to tissue damage around the airways and alveoli, which underlies various lung diseases. Phosphodiesterases (PDEs) are a family of enzymes that hydrolyze cyclic nucleotides. PDE inhibition induces bronchodilation, reduces the activation and recruitment of inflammatory cells, and the release of various cytokines. Currently, the selective PDE4 inhibitor roflumilast is an approved add-on treatment for patients with severe chronic obstructive pulmonary disease with chronic bronchitis and a history of frequent exacerbations. Additional selective PDE inhibitors are being tested in preclinical and clinical studies. However, the effect of chronic CS exposure on the expression of PDEs is unknown. Using mRNA isolated from nasal and bronchial brushes and lung tissues of never smokers and current smokers, we compared the gene expression of 25 PDE coding genes. Additionally,...

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Research paper thumbnail of Differential lung tissue gene expression in males and females: implications for the susceptibility to develop COPD

European Respiratory Journal, 2019

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Research paper thumbnail of Genetic profiling for disease stratification in chronic obstructive pulmonary disease and asthma

Current Opinion in Pulmonary Medicine, 2019

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Research paper thumbnail of Smoking induces shifts in cellular composition and transcriptome within the bronchial mucus barrier

Respirology

Background and ObjectiveSmoking disturbs the bronchial‐mucus‐barrier. This study assesses the cel... more Background and ObjectiveSmoking disturbs the bronchial‐mucus‐barrier. This study assesses the cellular composition and gene expression shifts of the bronchial‐mucus‐barrier with smoking to understand the mechanism of mucosal damage by cigarette smoke exposure. We explore whether single‐cell‐RNA‐sequencing (scRNA‐seq) based cellular deconvolution (CD) can predict cell‐type composition in RNA‐seq data.MethodsRNA‐seq data of bronchial biopsies from three cohorts were analysed using CD. The cohorts included 56 participants with chronic obstructive pulmonary disease [COPD] (38 smokers; 18 ex‐smokers), 77 participants without COPD (40 never‐smokers; 37 smokers) and 16 participants who stopped smoking for 1 year (11 COPD and 5 non‐COPD‐smokers). Differential gene expression was used to investigate gene expression shifts. The CD‐derived goblet cell ratios were validated by correlating with staining‐derived goblet cell ratios from the COPD cohort. Statistics were done in the R software (fals...

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Research paper thumbnail of Longitudinal Effects of 1-Year Smoking Cessation on Human Bronchial Epithelial Transcriptome

CHEST

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Research paper thumbnail of The Y-chromosome regulates hallmark features of asthma and COPD

03.01 - Molecular pathology and functional genomics

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Influence of smoking on bronchial epithelial cell composition by cellular deconvolution and IHC

03.01 - Molecular pathology and functional genomics

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Early transcriptional responses of bronchial epithelial cells to whole cigarette smoke mirror those of in-vivo exposed human bronchial mucosa

Respiratory Research

Background Despite the well-known detrimental effects of cigarette smoke (CS), little is known ab... more Background Despite the well-known detrimental effects of cigarette smoke (CS), little is known about the complex gene expression dynamics in the early stages after exposure. This study aims to investigate early transcriptomic responses following CS exposure of airway epithelial cells in culture and compare these to those found in human CS exposure studies. Methods Primary bronchial epithelial cells (PBEC) were differentiated at the air–liquid interface (ALI) and exposed to whole CS. Bulk RNA-sequencing was performed at 1 h, 4 h, and 24 h hereafter, followed by differential gene expression analysis. Results were additionally compared to data retrieved from human CS studies. Results ALI-PBEC gene expression in response to CS was most significantly changed at 4 h after exposure. Early transcriptomic changes (1 h, 4 h post CS exposure) were related to oxidative stress, xenobiotic metabolism, higher expression of immediate early genes and pro-inflammatory pathways (i.e., Nrf2, AP-1, AhR)...

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Research paper thumbnail of Transcriptome Dynamics in Bronchial Epithelial Cells Following to Cigarette Exposure

Respirology, Apr 1, 2021

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Research paper thumbnail of Single-nucleotide polymorphism rs2070600 regulates AGER splicing and the sputum levels of the COPD biomarker soluble receptor for advanced glycation end-products

ERJ Open Research, 2021

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Gene expression and methylation are altered by smoke cessationin the airway wall

European Respiratory Journal, 2020

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Longitudinal effects of 12 months smoking cessation on dna methylation and gene expression in bronchial biopsies

Respirology, 2020

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Smoking alters gene expression and methylation patterns in asthma patient nasal epithelium

06.04 - Genes and environment, 2021

Current-smoking significantly contributes to worse asthma prognosis and more severe disease sympt... more Current-smoking significantly contributes to worse asthma prognosis and more severe disease symptoms. Smoking limits the beneficial effects of corticosteroids by altering the physiological response in the airways. The nasal epithelium is a relevant site to investigate smoking-related molecular changes as it can reflect the lower airways. As such, we explore the relationship between nasal gene expression and methylation in current and ex-smoker asthma patients. We also investigate how these patterns are altered upon smoking cessation. The analysis was conducted on matched gene expression, and methylation samples collected from nasal brushings of 55 asthma-diagnosed patients. Differential gene expression and methylation analysis compared current vs ex-smokers. Expression quantitative trait methylation analysis was then conducted to explore smoking relevant genes by CpG sites that differ between current and ex-smokers. These sites were compared to a bronchial biopsy smoking-cessation dataset. The analysis was conducted using R software with a false discovery rate (FDR) determined with the Benjamini-Hochberg method. Current smoking in the nose differentially altered 809 genes and 18,814 CpG sites. The cis-eQTM analysis uncovered 171 CpG sites whose methylation status related to the expression of smoking-related genes, including AHRR, ALDH3A1, CYP1A1 and CYP1B1. Methylation of CpG sites altered by current smoking reversed upon one-year of smoking cessation. This study identifies smoking-associated changes in methylation and gene expression are detectable in the nasal epithelium of asthma patients. Our results support the nasal epithelium as an alternate site to investigate changes in the airways due to smoking. We show these patterns are partially reversible after smoking cessation.

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Research paper thumbnail of Current Smoking Affects Gene Expression and Methylation Patterns in Asthma Patient Nasal Epithelium

TP112. TP112 PROTEOMICS/GENOMICS/METABOLOMICS IN LUNG DISEASE, 2021

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Research paper thumbnail of Current Smoking Alters Gene Expression and DNA Methylation in the Nasal Epithelium of Patients with Asthma

American Journal of Respiratory Cell and Molecular Biology, 2021

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Research paper thumbnail of Gene expression profiling of bronchial brushes is associated with the level of emphysema measured by computed tomography-based parametric response mapping

American Journal of Physiology-Lung Cellular and Molecular Physiology, 2020

Parametric response mapping (PRM) is a computed tomography (CT)-based method to phenotype patient... more Parametric response mapping (PRM) is a computed tomography (CT)-based method to phenotype patients with chronic obstructive pulmonary disease (COPD). It is capable of differentiating emphysema-related air trapping with nonemphysematous air trapping (small airway disease), which helps to identify the extent and localization of the disease. Most studies evaluating the gene expression in smokers and COPD patients related this to spirometric measurements, but none have investigated the relationship with CT-based measurements of lung structure. The current study aimed to examine gene expression profiles of brushed bronchial epithelial cells in association with the PRM-defined CT-based measurements of emphysema (PRMEmph) and small airway disease (PRMfSAD). Using the Top Institute Pharma (TIP) study cohort (COPD = 12 and asymptomatic smokers = 32), we identified a gene expression signature of bronchial brushings, which was associated with PRMEmph in the lungs. One hundred thirty-three gene...

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Research paper thumbnail of RAGE and TLR4 differentially regulate airway hyperresponsiveness: Implications for COPD

Allergy, 2020

BackgroundThe receptor for advanced glycation end products (RAGE) and Toll‐like receptor 4 (TLR4)... more BackgroundThe receptor for advanced glycation end products (RAGE) and Toll‐like receptor 4 (TLR4) is implicated in COPD. Although these receptors share common ligands and signalling pathways, it is not known whether they act in concert to drive pathological processes in COPD. We examined the impact of RAGE and/or TLR4 gene deficiency in a mouse model of COPD and also determined whether expression of these receptors correlates with airway neutrophilia and airway hyperresponsiveness (AHR) in COPD patients.MethodsWe measured airway inflammation and AHR in wild‐type, RAGE−/−, TLR4−/− and TLR4−/−RAGE−/− mice following acute exposure to cigarette smoke (CS). We also examined the impact of smoking status on AGER (encodes RAGE) and TLR4 bronchial gene expression in patients with and without COPD. Finally, we determined whether expression of these receptors correlates with airway neutrophilia and AHR in COPD patients.ResultsRAGE−/− mice were protected against CS‐induced neutrophilia and AHR....

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Research paper thumbnail of Longitudinal effect of smoking cessation on transcriptomics and epigenetics in the airways of COPD patients and asymptomatic controls

03.02 - Airway cell biology and immunopathology, 2020

Background: COPD is characterized by chronic inflammation of the lungs to noxious particles such ... more Background: COPD is characterized by chronic inflammation of the lungs to noxious particles such as cigarette smoke leading to accelerated decline in lung function. The inflammation associated with smoke exposure remains even after smoking stops. Aim a Objectives: This study aims to investigate the longitudinal effects of smoking cessation at transcriptomic and epigenetic levels. Methods: Bronchial biopsies were collected from 19 individuals (healthy= 7, COPD= 12) before and after 12 months smoking cessation followed by DNA/RNA extraction. DNA methylation was measured using Infinium-HumanMethylation850k and RNA-Seq using Illumina-NovaSeq6000 sequencing. A Benjamini–Hochberg corrected p |1.5| was considered significant. We used expression quantitative trait methylation (eQTM) analysis to correlate gene expression with DNA methylation. Results: Differential gene expression analysis before and after 12 months smoking cessation resulted in 613 differentially expressed genes, including a number of down-regulated oxidative stress genes (i.e. ALDH3A1, which oxidises toxic aldehydes and protects the airway epithelium from smoking-induced oxidative stress). Differential DNA methylation analysis before and after smoking cessation identified 261 hypomethylated, 289 hypermethylated significant CpG-sites, e.g. cg19171383. The CpG site cg19171383 was found to be differentially methylated and was negatively correlated with ALDH3A1 in the eQTM analysis. An interaction analysis of smoking cessation with disease found not differences at a transcriptomic and epigenetic levels. Conclusion: These findings indicate that smoking cessation increases the methylation of oxidative stress related genes, which may lead to their decrease in expression.

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Research paper thumbnail of Longitudinal effects of smoking cessation on DNA methylation in bronchial biopsies of COPD and asymptomatic smokers

Molecular pathology and funct. genomics, 2019

Introduction: COPD is characterized by chronic inflammation in lungs in response to smoke exposur... more Introduction: COPD is characterized by chronic inflammation in lungs in response to smoke exposure leading to accelerated decline in lung function. Only a subset of smokers will develop COPD. Once developed inflammation remains present even after patients quit smoking, suggesting persistent epigenetic changes in lungs. Whereas previous studies have been based on cross-sectional cohorts, this study is the first using a longitudinal cohort pre and post smoking cessation. Aim: To investigate the longitudinal effects of smoking cessation on DNA methylation and the differences between patients with COPD and non-COPD controls. Methods: Bronchial biopsies were collected from 19 individuals (healthy=7, COPD=12) pre and post 12 months smoking cessation. DNA methylation was measured using Infinium HumanMethylation850k Bead Chip. A Bonferroni corrected p Results: We identified 7 CpG-sites genome-wide significantly changed after smoking cessation. An interaction analysis between between healthy and COPD groups identified 3 suggestive CpG-sites. Conclusion: Even though this is a small study group the results clearly indicate significant differences in DNA methylation following smoking cessation as well as suggestive evidence of differential effect of smoking cessation on DNA methylation between COPD and healthy controls.

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Research paper thumbnail of Cigarette smoke exposure alters phosphodiesterases in human structural lung cells

American Journal of Physiology-Lung Cellular and Molecular Physiology, 2019

Cigarette smoke (CS), a highly complex mixture containing more than 4,000 compounds, causes aberr... more Cigarette smoke (CS), a highly complex mixture containing more than 4,000 compounds, causes aberrant cell responses leading to tissue damage around the airways and alveoli, which underlies various lung diseases. Phosphodiesterases (PDEs) are a family of enzymes that hydrolyze cyclic nucleotides. PDE inhibition induces bronchodilation, reduces the activation and recruitment of inflammatory cells, and the release of various cytokines. Currently, the selective PDE4 inhibitor roflumilast is an approved add-on treatment for patients with severe chronic obstructive pulmonary disease with chronic bronchitis and a history of frequent exacerbations. Additional selective PDE inhibitors are being tested in preclinical and clinical studies. However, the effect of chronic CS exposure on the expression of PDEs is unknown. Using mRNA isolated from nasal and bronchial brushes and lung tissues of never smokers and current smokers, we compared the gene expression of 25 PDE coding genes. Additionally,...

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Research paper thumbnail of Differential lung tissue gene expression in males and females: implications for the susceptibility to develop COPD

European Respiratory Journal, 2019

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Genetic profiling for disease stratification in chronic obstructive pulmonary disease and asthma

Current Opinion in Pulmonary Medicine, 2019

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Smoking induces shifts in cellular composition and transcriptome within the bronchial mucus barrier

Respirology

Background and ObjectiveSmoking disturbs the bronchial‐mucus‐barrier. This study assesses the cel... more Background and ObjectiveSmoking disturbs the bronchial‐mucus‐barrier. This study assesses the cellular composition and gene expression shifts of the bronchial‐mucus‐barrier with smoking to understand the mechanism of mucosal damage by cigarette smoke exposure. We explore whether single‐cell‐RNA‐sequencing (scRNA‐seq) based cellular deconvolution (CD) can predict cell‐type composition in RNA‐seq data.MethodsRNA‐seq data of bronchial biopsies from three cohorts were analysed using CD. The cohorts included 56 participants with chronic obstructive pulmonary disease [COPD] (38 smokers; 18 ex‐smokers), 77 participants without COPD (40 never‐smokers; 37 smokers) and 16 participants who stopped smoking for 1 year (11 COPD and 5 non‐COPD‐smokers). Differential gene expression was used to investigate gene expression shifts. The CD‐derived goblet cell ratios were validated by correlating with staining‐derived goblet cell ratios from the COPD cohort. Statistics were done in the R software (fals...

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