Senani N . H . Rathnayake - Profile on Academia.edu (original) (raw)
Papers by Senani N . H . Rathnayake
Longitudinal Effects of 1-Year Smoking Cessation on Human Bronchial Epithelial Transcriptome
CHEST
The Y-chromosome regulates hallmark features of asthma and COPD
03.01 - Molecular pathology and functional genomics
Influence of smoking on bronchial epithelial cell composition by cellular deconvolution and IHC
03.01 - Molecular pathology and functional genomics
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)...
Transcriptome Dynamics in Bronchial Epithelial Cells Following to Cigarette Exposure
Respirology, Apr 1, 2021
ERJ Open Research, 2021
The COPD susceptibility SNP rs2070600 affects the levels of the COPD biomarker sRAGE in sputum as... more The COPD susceptibility SNP rs2070600 affects the levels of the COPD biomarker sRAGE in sputum as well as splicing of AGER. Moreover, we demonstrate large differences in sRAGE levels between serum and sputum.
Gene expression and methylation are altered by smoke cessationin the airway wall
European Respiratory Journal, 2020
Longitudinal effects of 12 months smoking cessation on dna methylation and gene expression in bronchial biopsies
Respirology, 2020
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.
Current Smoking Affects Gene Expression and Methylation Patterns in Asthma Patient Nasal Epithelium
TP112. TP112 PROTEOMICS/GENOMICS/METABOLOMICS IN LUNG DISEASE, 2021
American Journal of Respiratory Cell and Molecular Biology, 2021
Current smoking contributes to worsened asthma prognosis and more severe symptoms and limits the ... more Current smoking contributes to worsened asthma prognosis and more severe symptoms and limits the beneficial effects of corticosteroids. As the nasal epithelium can reflect smokinginduced changes in the lower airways, it is a relevant source to investigate changes in gene expression and DNA methylation. This study explores gene expression and DNA methylation changes in current and ex-smokers with asthma. Matched gene expression and epigenome-wide DNA methylation samples collected from nasal brushings of 55 patients enrolled in a clinical trial investigation of current and ex-smoker patients with asthma were analyzed. Differential gene expression and DNA methylation analyses were conducted comparing current smokers with ex-smokers. Expression quantitative trait methylation (eQTM) analysis was completed to explore smoking-relevant genes by CpG sites that differ between current and ex-smokers. To investigate the relevance of the smoking-associated DNA methylation changes for the lower airways, significant CpG sites were explored in bronchial biopsies from patients who had stopped smoking. A total of 809 genes and 18,814 CpG sites were differentially associated with current smoking in the nose. The cis-eQTM analysis uncovered 171 CpG sites with a methylation status associated with smoking-related gene expression, including AHRR, ALDH3A1, CYP1A1, and CYP1B1. The methylation status of CpG sites altered by current smoking reversed with 1 year of smoking cessation. We confirm that current smoking alters epigenetic patterns and affects gene expression in the nasal epithelium of patients with asthma, which is partially reversible in bronchial biopsies after smoking cessation. We demonstrate the ability to discern molecular changes in the nasal epithelium, presenting this as a tool in future investigations into disease-relevant effects of tobacco smoke.
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...
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....
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.
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.
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,...
European Respiratory Journal, 2019
Several studies have shown that sexual dimorphisms exist with respect to the susceptibility to sm... more Several studies have shown that sexual dimorphisms exist with respect to the susceptibility to smoking and the clinical presentation of chronic obstructive pulmonary disease (COPD) [1, 2]. Females with COPD have a faster annual decline in their forced expiratory volume in 1 s (FEV1) than males, even with a similar number of pack-years smoking [3, 4]. In addition, females develop a different type of COPD to males with less severe emphysematous destruction, but thicker small airway walls [5]. Several factors may contribute to the observed sex differences, e.g. smoking behaviour or exposures to other environmental agents [6, 7].
Current Opinion in Pulmonary Medicine, 2019
Take-down policy If you believe that this document breaches copyright please contact us providing... more Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
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...
Longitudinal Effects of 1-Year Smoking Cessation on Human Bronchial Epithelial Transcriptome
CHEST
The Y-chromosome regulates hallmark features of asthma and COPD
03.01 - Molecular pathology and functional genomics
Influence of smoking on bronchial epithelial cell composition by cellular deconvolution and IHC
03.01 - Molecular pathology and functional genomics
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)...
Transcriptome Dynamics in Bronchial Epithelial Cells Following to Cigarette Exposure
Respirology, Apr 1, 2021
ERJ Open Research, 2021
The COPD susceptibility SNP rs2070600 affects the levels of the COPD biomarker sRAGE in sputum as... more The COPD susceptibility SNP rs2070600 affects the levels of the COPD biomarker sRAGE in sputum as well as splicing of AGER. Moreover, we demonstrate large differences in sRAGE levels between serum and sputum.
Gene expression and methylation are altered by smoke cessationin the airway wall
European Respiratory Journal, 2020
Longitudinal effects of 12 months smoking cessation on dna methylation and gene expression in bronchial biopsies
Respirology, 2020
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.
Current Smoking Affects Gene Expression and Methylation Patterns in Asthma Patient Nasal Epithelium
TP112. TP112 PROTEOMICS/GENOMICS/METABOLOMICS IN LUNG DISEASE, 2021
American Journal of Respiratory Cell and Molecular Biology, 2021
Current smoking contributes to worsened asthma prognosis and more severe symptoms and limits the ... more Current smoking contributes to worsened asthma prognosis and more severe symptoms and limits the beneficial effects of corticosteroids. As the nasal epithelium can reflect smokinginduced changes in the lower airways, it is a relevant source to investigate changes in gene expression and DNA methylation. This study explores gene expression and DNA methylation changes in current and ex-smokers with asthma. Matched gene expression and epigenome-wide DNA methylation samples collected from nasal brushings of 55 patients enrolled in a clinical trial investigation of current and ex-smoker patients with asthma were analyzed. Differential gene expression and DNA methylation analyses were conducted comparing current smokers with ex-smokers. Expression quantitative trait methylation (eQTM) analysis was completed to explore smoking-relevant genes by CpG sites that differ between current and ex-smokers. To investigate the relevance of the smoking-associated DNA methylation changes for the lower airways, significant CpG sites were explored in bronchial biopsies from patients who had stopped smoking. A total of 809 genes and 18,814 CpG sites were differentially associated with current smoking in the nose. The cis-eQTM analysis uncovered 171 CpG sites with a methylation status associated with smoking-related gene expression, including AHRR, ALDH3A1, CYP1A1, and CYP1B1. The methylation status of CpG sites altered by current smoking reversed with 1 year of smoking cessation. We confirm that current smoking alters epigenetic patterns and affects gene expression in the nasal epithelium of patients with asthma, which is partially reversible in bronchial biopsies after smoking cessation. We demonstrate the ability to discern molecular changes in the nasal epithelium, presenting this as a tool in future investigations into disease-relevant effects of tobacco smoke.
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...
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....
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.
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.
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,...
European Respiratory Journal, 2019
Several studies have shown that sexual dimorphisms exist with respect to the susceptibility to sm... more Several studies have shown that sexual dimorphisms exist with respect to the susceptibility to smoking and the clinical presentation of chronic obstructive pulmonary disease (COPD) [1, 2]. Females with COPD have a faster annual decline in their forced expiratory volume in 1 s (FEV1) than males, even with a similar number of pack-years smoking [3, 4]. In addition, females develop a different type of COPD to males with less severe emphysematous destruction, but thicker small airway walls [5]. Several factors may contribute to the observed sex differences, e.g. smoking behaviour or exposures to other environmental agents [6, 7].
Current Opinion in Pulmonary Medicine, 2019
Take-down policy If you believe that this document breaches copyright please contact us providing... more Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
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...