Severity of lung function impairment drives transcriptional phenotypes of COPD and relates to immune and metabolic processes
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE212331 | GEO | 2023/08/31
REPOSITORIES: GEO
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Project description:PurposeThis study sought to characterize transcriptional phenotypes of COPD through unsupervised clustering of sputum gene expression profiles, and further investigate mechanisms underlying the characteristics of these clusters.Patients and methodsInduced sputum samples were collected from patients with stable COPD (n = 72) and healthy controls (n = 15). Induced sputum was collected for inflammatory cell counts, and RNA extracted. Transcriptional profiles were generated (Illumina Humanref-8 V2) and analyzed by GeneSpring GX14.9.1. Unsupervised hierarchical clustering and differential gene expression analysis were performed, and gene alterations validated in the ECLIPSE dataset (GSE22148).ResultsWe identified 2 main clusters (Cluster 1 [n = 35] and Cluster 2 [n = 37]), which further divided into 4 sub-clusters (Sub-clusters 1.1 [n = 14], 1.2 [n = 21], 2.1 [n = 20] and 2.2 [n = 17]). Compared with Cluster 1, Cluster 2 was associated with significantly lower lung function (p = 0.014), more severe disease (p = 0.009) and breathlessness (p = 0.035), and increased sputum neutrophils (p = 0.031). Sub-cluster 1.1 had significantly higher proportion of people with comorbid cardiovascular disease compared to the other 3 sub-clusters (92.5% vs 57.1%, 50% and 52.9%, p < 0.013). Through supervised analysis we determined that degree of airflow limitation (GOLD stage) was the predominant factor driving gene expression differences in our transcriptional clusters. There were 452 genes (adjusted p < 0.05 and ≥2 fold) altered in GOLD stage 3 and 4 versus 1 and 2, of which 281 (62%) were also found to be significantly expressed between these GOLD stages in the ECLIPSE data set (GSE22148). Differentially expressed genes were largely downregulated in GOLD stages 3 and 4 and connected in 5 networks relating to lipoprotein and cholesterol metabolism; metabolic processes in oxidation/reduction and mitochondrial function; antigen processing and presentation; regulation of complement activation and innate immune responses; and immune and metabolic processes.ConclusionSeverity of lung function drives 2 distinct transcriptional phenotypes of COPD and relates to immune and metabolic processes.
| S-EPMC10024507 | biostudies-literature
Project description:Severity of lung function impairment drives transcriptional phenotypes of COPD and relates to immune and metabolic processes
| PRJNA875062 | ENA
Project description:Induced sputum is used to sample inflammatory cells, predominantly neutrophils and macrophages, from the airways of COPD patients. Our aim was to identify candidate genes associated with the degree of airflow obstruction and the extent of emphysema by expression profiling, and then to confirm these findings for selected candidates using specific PCR and protein analysis. Two sputum studies were performed in GOLD stage 2 -4 COPD ex-smokers from the ECLIPSE cohort. First, gene array profiling at baseline in 1480 patients was performed. At year 1, samples from a separate population of 176 patients were used for real-time PCR. The gene expression findings for IL-18R were further analysed using immunohistochemistry in lung tissue and induced sputum samples from patients outside the ECLIPSE cohort.
2010-06-16 | E-GEOD-22148 | biostudies-arrayexpress
Project description:Induced sputum is used to sample inflammatory cells, predominantly neutrophils and macrophages, from the airways of COPD patients. Our aim was to identify candidate genes associated with the degree of airflow obstruction and the extent of emphysema by expression profiling, and then to confirm these findings for selected candidates using specific PCR and protein analysis.
2010-06-08 | GSE22148 | GEO
Project description:Long-term, low dose azithromycin reduces exacerbation frequency in COPD yet the mechanism remains unclear. This study characterises changes to gene expression in patients with neutrophilic COPD in response to long term low dose azithromycin therapy. Patients with neutrophilic COPD (>61% or >162x10^4/mL sputum neutrophils) were randomised to 12 weeks of either azithromycin or placebo treatment. RNA was extracted from sputum and blood collected before (pre) and after (post) treatment.
2018-11-14 | GSE119314 | GEO
Project description:We evaluated the applicability and usability of whole-genome methylomics of sputum samples in molecular profiling of chronic inflammatory lung diseases. Genomic DNA was purified from sputum samples of subjects with Asthma, COPD as well as healthy controls and analyzed on the Illumina Infinium HumanMethylation 450k platform.
2020-10-25 | GSE148000 | GEO
Project description:In addition to analyzing whole-genome methylation, we concomitantly evaluated sputum cell gene expression in the context of chronic inflammatory lung disease. Nucleic acids were purified from sputum samples of subjects with Asthma, COPD as well as healthy controls. Gene expression was analyzed on the Agilent Human GE 4x44k v2 platform.
2020-10-25 | GSE148004 | GEO
Project description:Chronic obstructive pulmonary disease (COPD) is one of the most prevalent lung diseases, and involves persistent airflow limitation and incorporates both emphysema and chronic bronchitis. Cigarette smoking has been identified as the main risk factor for disease development and progression. In a basic model of COPD, the disease is initiated when the physiologic response mechanisms to cigarette smoke exposure are overwhelmed; for example, because of long-term exposure effects or other aging-related changes. In this parallel-group case-controlled clinical study we asked to what extent the different transitions in a chronic-exposure-to-disease model are reflected in the proteome and cellular transcriptome of induced sputum samples from the lung. For this, we selected 60 age- and gender-matched individuals for each of four study groups: current healthy smokers, current-smoker COPD patients, former smokers, and never smokers (a total of 240 individuals). Induced sputum was collected, the cell-free supernatant was analyzed by quantitative proteomics (isobaric-tag based), and the cellular mRNA fraction was analyzed by microarray-based expression profiling. The sputum proteome of current smokers (healthy or COPD patients) clearly reflected the common physiological responses to smoke exposure, including alterations in mucin/trefoil proteins (e.g., MUC5AC and TFF1/3up-regulation), peptidase regulators (e.g., TIMP1 up-regulation), and a prominent xenobiotic/oxidative stress response (e.g., NQO1 and ALDH3A1 up-regulation). The latter response also was observed in the sputum transcriptome, which additionally demonstrated an immune-related polarization change (toward a M2 signature). The (long-term) former smoker group showed nearly complete reversal of the observable biological effects. Thirteen differentially abundant proteins between the COPD and healthy smoker groups were identified. These abundant proteins included previously reported COPD-associated proteins (e.g., TIMP1 (up-regulation) and APOA1 (down-regulation)) and novel proteins such as C6orf58 and BPIFB1 (LPLUNC1) (both up-regulated in the COPD group compared with the healthy smokers). In summary, our study demonstrates that sputum proteomics/transcriptomics can capture the complex and reversible physiological response to cigarette smoke exposure, which appears to be only slightly modulated in early-stage COPD patients. The study has been registered on ClinicalTrials.gov with identifier NCT01780298.
2016-10-21 | MSV000080275 | MassIVE
Project description:Chronic obstructive pulmonary disease (COPD) is one of the most prevalent lung diseases, and involves persistent airflow limitation and incorporates both emphysema and chronic bronchitis. Cigarette smoking has been identified as the main risk factor for disease development and progression. In a basic model of COPD, the disease is initiated when the physiologic response mechanisms to cigarette smoke exposure are overwhelmed; for example, because of long-term exposure effects or other aging-related changes. In this parallel-group case-controlled clinical study we asked to what extent the different transitions in a chronic-exposure-to-disease model are reflected in the proteome and cellular transcriptome of induced sputum samples from the lung. For this, we selected 60 age- and gender-matched individuals for each of four study groups: current healthy smokers, current-smoker COPD patients, former smokers, and never smokers (a total of 240 individuals). Induced sputum was collected, the cell-free supernatant was analyzed by quantitative proteomics (isobaric-tag based), and the cellular mRNA fraction was analyzed by microarray-based expression profiling. The sputum proteome of current smokers (healthy or COPD patients) clearly reflected the common physiological responses to smoke exposure, including alterations in mucin/trefoil proteins (e.g., MUC5AC and TFF1/3up-regulation), peptidase regulators (e.g., TIMP1 up-regulation), and a prominent xenobiotic/oxidative stress response (e.g., NQO1 and ALDH3A1 up-regulation). The latter response also was observed in the sputum transcriptome, which additionally demonstrated an immune-related polarization change (toward a M2 signature). The (long-term) former smoker group showed nearly complete reversal of the observable biological effects. Thirteen differentially abundant proteins between the COPD and healthy smoker groups were identified. These abundant proteins included previously reported COPD-associated proteins (e.g., TIMP1 (up-regulation) and APOA1 (down-regulation)) and novel proteins such as C6orf58 and BPIFB1 (LPLUNC1) (both up-regulated in the COPD group compared with the healthy smokers). In summary, our study demonstrates that sputum proteomics/transcriptomics can capture the complex and reversible physiological response to cigarette smoke exposure, which appears to be only slightly modulated in early-stage COPD patients. The study has been registered on ClinicalTrials.gov with identifier NCT01780298.
2015-08-28 | E-MTAB-3604 | biostudies-arrayexpress
Project description:Background: Macrophages are important cells in pathogenesis of obstructive lung diseases including asthma and chronic obstructive pulmonary disease (COPD). The aim of the study was a multivariate, genetic, comparative analysis of macrophages from patients with asthma and COPD. Methods: Macrophages were isolated from induced sputum (IS) by magnetic bead separation. Transcriptomic measurements were carried out using Affymetrix Human Gene 2.1 ST ArrayStrip in 17 samples: 8 asthma (4 ICS naive , 4 ICS treated), 4 COPD and 5 control samples. The expression of the most significantly differentiating genes was evaluated by real time PCR in 34 samples (15 patients with asthma, 11 patients with COPD and 17 controls). Results: USP53 was the only gene differentially expressed (p adjusted clue =0.09) in the comparison between ICS naïve and ICS treated asthma. The PCR verification showed increased expression of BTF3, CDS2, DNAJC13, DDX5, GNAI2, SCGB1A1, SIRPB1, TRAF3IP, USP53, WDR49 in the asthma compared to COPD group. The changed gene expression profile of macrophages were characterized mostly by gene ontology terms linked with cell motility, cilium function, cell junction and adhesion organization. Conclusions: Gene expression profiling of sputum macrophages revealed distinct molecular capacity in asthma and COPD. The role of sputum macrophages in the pathophysiology of obstructive lung diseases is probably connected with biological processes associated with their motility, cilium dysfunction and cell junction organization.
2018-08-09 | GSE112260 | GEO