scholarly journals Identification of biomarkers associated with clinical severity of chronic obstructive pulmonary disease

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10513
Author(s):  
Jie Zhang ◽  
Changli Zhu ◽  
Hong Gao ◽  
Xun Liang ◽  
Xiaoqian Fan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Responses ◽  
Inflammatory Responses ◽  
Lymphocyte Activation ◽  
Stage I ◽  
Clinical Severity ◽  
Chronic Obstructive ◽  
Clinical Classification ◽  
Obstructive Pulmonary Disease ◽  
Blood Samples

We sought to identify the biomarkers related to the clinical severity of stage I to stage IV chronic obstructive pulmonary disease (COPD). Gene expression profiles from the blood samples of COPD patients at each of the four stages were acquired from the Gene Expression Omnibus Database (GEO, accession number: GSE54837). Genes showing expression changes among the different stages were sorted by soft clustering. We performed functional enrichment, protein–protein interaction (PPI), and miRNA regulatory network analyses for the differentially expressed genes. The biomarkers associated with the clinical classification of COPD were selected from logistic regression models and the relationships between TLR2 and inflammatory factors were verified in clinical blood samples by qPCR and ELISA. Gene clusters demonstrating continuously rising or falling changes in expression (clusters 1, 2, and 7 and clusters 5, 6, and 8, respectively) from stage I to IV were defined as upregulated and downregulated genes, respectively, and further analyzed. The upregulated genes were enriched in functions associated with defense, inflammatory, or immune responses. The downregulated genes were associated with lymphocyte activation and cell activation. TLR2, HMOX1, and CD79A were hub proteins in the integrated network of PPI and miRNA regulatory networks. TLR2 and CD79A were significantly correlated with clinical classifications. TLR2 was closely associated with inflammatory responses during COPD progression. Functions associated with inflammatory and immune responses as well as lymphocyte activation may play important roles in the progression of COPD from stage I to IV. TLR2 and CD79A may serve as potential biomarkers for the clinical severity of COPD. TLR2 and CD79A may also serve as independent biomarkers in the clinical classification in COPD. TLR2 may play an important role in the inflammatory responses of COPD.

scholarly journals Th17/Treg-Related Intracellular Signaling in Patients with Chronic Obstructive Pulmonary Disease: Comparison between Local and Systemic Responses

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1569
Author(s):  
Juliana D. Lourenço ◽  
Walcy R. Teodoro ◽  
Denise F. Barbeiro ◽  
Ana Paula P. Velosa ◽  
Larissa E. F. Silva ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Obstructive Pulmonary Disease ◽  
Peripheral Blood ◽  
Intracellular Signaling ◽  
Foxp3 Expression ◽  
Chronic Obstructive ◽  
Systemic Response ◽  
Obstructive Pulmonary Disease ◽  
Blood Samples ◽  
Systemic Responses

Th17/Treg imbalance plays a pivotal role in COPD development and progression. We aimed to assess Th17/Treg-related intracellular signaling at different COPD stages in local and systemic responses. Lung tissue and/or peripheral blood samples were collected and divided into non-obstructed (NOS), COPD stages I and II, and COPD stages III and IV groups. Gene expression of STAT3 and -5, RORγt, Foxp3, interleukin (IL)-6, -17, -10, and TGF-β was assessed by RT-qPCR. IL-6, -17, -10, and TGF-β levels were determined by ELISA. We observed increased STAT3, RORγt, Foxp3, IL-6, and TGF-β gene expression and IL-6 levels in the lungs of COPD I and II patients compared to those of NOS patients. Regarding the systemic response, we observed increased STAT3, RORγt, IL-6, and TGF-β gene expression in the COPD III and IV group and increased IL-6 levels in the COPD I and II group. STAT5 was increased in COPD III and IV patients, although there was a decrease in Foxp3 expression and IL-10 levels in the COPD I and II and COPD III and IV groups, respectively. We demonstrated that an increase in Th17 intracellular signaling in the lungs precedes this increase in the systemic response, whereas Treg intracellular signaling varies between the compartments analyzed in different COPD stages.

scholarly journals Newborn DNA-methylation, childhood lung function, and the risks of asthma and COPD across the life course

2019 ◽  
Vol 53 (4) ◽  
pp. 1801795 ◽  
Author(s):  
Herman T. den Dekker ◽  
Kimberley Burrows ◽  
Janine F. Felix ◽  
Lucas A. Salas ◽  
Ivana Nedeljkovic ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Function ◽  
Life Course ◽  
Cord Blood ◽  
Childhood Asthma ◽  
Respiratory Health ◽  
Forced Expiratory Volume ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
The Life Course

RationaleWe aimed to identify differentially methylated regions (DMRs) in cord blood DNA associated with childhood lung function, asthma and chronic obstructive pulmonary disease (COPD) across the life course.MethodsWe meta-analysed epigenome-wide data of 1688 children from five cohorts to identify cord blood DMRs and their annotated genes, in relation to forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC) ratio and forced expiratory flow at 75% of FVC at ages 7–13 years. Identified DMRs were explored for associations with childhood asthma, adult lung function and COPD, gene expression and involvement in biological processes.ResultsWe identified 59 DMRs associated with childhood lung function, of which 18 were associated with childhood asthma and nine with COPD in adulthood. Genes annotated to the top 10 identified DMRs were HOXA5, PAOX, LINC00602, ABCA7, PER3, CLCA1, VENTX, NUDT12, PTPRN2 and TCL1A. Differential gene expression in blood was observed for 32 DMRs in childhood and 18 in adulthood. Genes related with 16 identified DMRs were associated with respiratory developmental or pathogenic pathways.InterpretationOur findings suggest that the epigenetic status of the newborn affects respiratory health and disease across the life course.

scholarly journals Bioinformatic Analysis of ABCA1 Gene Expression in Smoking and Chronic Obstructive Pulmonary Disease

Membranes ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 674
Author(s):  
Stanislav Kotlyarov ◽  
Anna Kotlyarova
Keyword(s):  
Gene Expression ◽  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Alveolar Macrophages ◽  
Plasma Membranes ◽  
Bioinformatic Analysis ◽  
Transport Processes ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Abca1 Gene

Smoking is a key modifiable risk factor for developing the chronic obstructive pulmonary disease (COPD). When smoking, many processes, including the reverse transport of cholesterol mediated by the ATP binding cassette transporter A1 (ABCA1) protein are disrupted in the lungs. Changes in the cholesterol content in the lipid rafts of plasma membranes can modulate the function of transmembrane proteins localized in them. It is believed that this mechanism participates in increasing the inflammation in COPD. Methods: Bioinformatic analysis of datasets from Gene Expression Omnibus (GEO) was carried out. Gene expression data from datasets of alveolar macrophages and the epithelium of the respiratory tract in smokers and COPD patients compared with non-smokers were used for the analysis. To evaluate differentially expressed genes, bioinformatic analysis was performed in comparison groups using the limma package in R (v. 4.0.2), and the GEO2R and Phantasus tools (v. 1.11.0). Results: The conducted bioinformatic analysis showed changes in the expression of the ABCA1 gene associated with smoking. In the alveolar macrophages of smokers, the expression levels of ABCA1 were lower than in non-smokers. At the same time, in most of the airway epithelial datasets, gene expression did not show any difference between the groups of smokers and non-smokers. In addition, it was shown that the expression of ABCA1 in the epithelial cells of the trachea and large bronchi is higher than in small bronchi. Conclusions: The conducted bioinformatic analysis showed that smoking can influence the expression of the ABCA1 gene, thereby modulating lipid transport processes in macrophages, which are part of the mechanisms of inflammation development.

Research Advances in COPD Drugs and Novel Targets

Nano LIFE ◽  
2021 ◽  
Vol 11 (03) ◽  
pp. 2140008
Author(s):  
Lveli Wang ◽  
Chuang Xiao ◽  
Yaping Liang ◽  
Zhiying Weng ◽  
Weimin Yang
Keyword(s):  
Inflammatory Responses ◽  
Treatment Strategies ◽  
New Drugs ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Phosphodiesterase 4 Inhibitors ◽  
Novel Targets ◽  
Anti Inflammatory ◽  
To Come ◽  
Exacerbation Of Copd

Chronic obstructive pulmonary disease (COPD) is the third-most deadly disease in the world and will be a major healthcare problem for decades to come. Its etiology is mainly related to the exposure to cigarette smoke and poisonous gases, and the infections of viruses including COVID-19 induce acute exacerbation of COPD, which may cause death in patients. Few advances have been made in COPD pathological mechanism, and the current clinical treatment strategies focus on both bronchodilator and anti-inflammatory interventions; but with limited clinical therapeutic agents, COPD therapies still lack more drugs especially those that antagonize COPD-specific inflammatory responses. We review the COPD clinically applied drugs, and the progress of research on new drugs and related novel targets, including [Formula: see text] agonists and anti-muscarinic drugs for airway diastole, glucocorticoids and phosphodiesterase-4 inhibitors for anti-inflammatory, protease inhibitors, emerging antioxidants, adhesion factor inhibitors, growth factor antagonists, adenylate cyclase agonists, chemokine antagonists, etc. We thus provide insights on the COPD new drugs research and development.

scholarly journals Eosinophil-derived IL-13 promotes emphysema

2019 ◽  
Vol 53 (5) ◽  
pp. 1801291 ◽  
Author(s):  
Alfred D. Doyle ◽  
Manali Mukherjee ◽  
William E. LeSuer ◽  
Tyler B. Bittner ◽  
Saif M. Pasha ◽  
...  
Keyword(s):  
Mouse Model ◽  
Inflammatory Responses ◽  
Pulmonary Inflammation ◽  
Forced Expiratory Volume ◽  
Chronic Obstructive ◽  
Chronic Type ◽  
Obstructive Pulmonary Disease ◽  
Lung Eosinophilia

The inflammatory responses in chronic airway diseases leading to emphysema are not fully defined. We hypothesised that lung eosinophilia contributes to airspace enlargement in a mouse model and to emphysema in patients with chronic obstructive pulmonary disease (COPD).A transgenic mouse model of chronic type 2 pulmonary inflammation (I5/hE2) was used to examine eosinophil-dependent mechanisms leading to airspace enlargement. Human sputum samples were collected for translational studies examining eosinophilia and matrix metalloprotease (MMP)-12 levels in patients with chronic airways disease.Airspace enlargement was identified in I5/hE2 mice and was dependent on eosinophils. Examination of I5/hE2 bronchoalveolar lavage identified elevated MMP-12, a mediator of emphysema. We showed, in vitro, that eosinophil-derived interleukin (IL)-13 promoted alveolar macrophage MMP-12 production. Airspace enlargement in I5/hE2 mice was dependent on MMP-12 and eosinophil-derived IL-4/13. Consistent with this, MMP-12 was elevated in patients with sputum eosinophilia and computed tomography evidence of emphysema, and also negatively correlated with forced expiratory volume in 1 s.A mouse model of chronic type 2 pulmonary inflammation exhibited airspace enlargement dependent on MMP-12 and eosinophil-derived IL-4/13. In chronic airways disease patients, lung eosinophilia was associated with elevated MMP-12 levels, which was a predictor of emphysema. These findings suggest an underappreciated mechanism by which eosinophils contribute to the pathologies associated with asthma and COPD.

scholarly journals Integrative Analysis Reveals Common and Unique Roles of Tetraspanins in Fibrosis and Emphysema

2020 ◽  
Vol 11 ◽  
Author(s):  
Lokesh P. Tripathi ◽  
Mari N. Itoh ◽  
Yoshito Takeda ◽  
Kazuyuki Tsujino ◽  
Yasushi Kondo ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Functional Enrichment ◽  
Integrative Approach ◽  
Chronic Obstructive ◽  
Lung Pathology ◽  
Obstructive Pulmonary Disease

While both chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are multifactorial disorders characterized by distinct clinical and pathological features, their commonalities and differences have not been fully elucidated. We sought to investigate the preventive roles of tetraspanins Cd151 and Cd9 -that are involved in diverse cellular processes in lung pathophysiology- in pulmonary fibrosis and emphysema, respectively, and to obtain a deeper understanding of their underlying molecular mechanisms toward facilitating improved therapeutic outcomes. Using an integrative approach, we examined the transcriptomic changes in the lungs of Cd151- and Cd9-deficient mice using functional-enrichment-analysis, pathway-perturbation-analysis and protein-protein-interaction (PPI) network analysis. Circadian-rhythm, extracellular-matrix (ECM), cell-adhesion and inflammatory responses and associated factors were prominently influenced by Cd151-deletion. Conversely, cellular-junctions, focal-adhesion, vascular-remodeling, and TNF-signaling were deeply impacted by Cd9-deletion. We also highlighted a “common core” of factors and signaling cascades that underlie the functions of both Cd151 and Cd9 in lung pathology. Circadian dysregulation following Cd151-deletion seemingly facilitated progressive fibrotic lung phenotype. Conversely, TGF-β signaling attenuation and TNF-signaling activation emerged as potentially novel functionaries of Cd9-deletion-induced emphysema. Our findings offer promising avenues for developing novel therapeutic treatments for pulmonary fibrosis and emphysema.

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