Impact of a functional polymorphism in the PAR-1 gene promoter in COPD and COPD exacerbations

Proteinase-activated receptor-1 (PAR-1) plays a key role in mediating the interplay between coagulation and inflammation in response to injury. The aim of this study was to investigate the role of the promoter single-nucleotide polymorphism (SNP) rs2227744G>A in modulating PAR-1/ F2R gene expression in the context of chronic obstructive pulmonary disease (COPD) and COPD exacerbations. The function of the rs2227744G>A SNP was investigated by using reporter gene assays. The frequency of the polymorphism in the UK population was assessed by genotyping 8,579 healthy individuals from the Whitehall II and English Longitudinal Study of Ageing cohorts. The rs2227744G>A SNP was genotyped in a carefully phenotyped cohort of 203 COPD cases and matched controls. The results were further replicated in two different COPD cohorts. The minor allele of the rs2227744G>A polymorphism was found to increase F2R expression by 2.6-fold ( P < 0.001). The rs2227744G>A SNP was not significantly associated with COPD, or with lung function, in all cohorts. The minor allele of the SNP was found to be associated with protection from frequent exacerbations ( P = 0.04) in the cohort of COPD patients for which exacerbation frequency was available. Considering exacerbations as a continuous variable, the presence of the minor allele was associated with a significantly lower COPD exacerbation rate (3.03 vs. 1.98 exacerbations/year, Mann-Whitney U-test P = 0.04). Taken together, these data do not support a role for the rs2227744G>A F2R polymorphism in the development of COPD but suggest a protective role for this polymorphism from frequent exacerbations. Studies in separate cohorts to replicate these findings are warranted.

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Methylation of SERPINA1 gene promoter may predict chronic obstructive pulmonary disease in patients affected by acute coronary syndrome

Clinical Epigenetics ◽

10.1186/s13148-021-01066-w ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

John Charles Rotondo ◽

Giorgio Aquila ◽

Lucia Oton-Gonzalez ◽

Rita Selvatici ◽

Paola Rizzo ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Acute Coronary Syndrome ◽

Pulmonary Disease ◽

Blood Cells ◽

Gene Promoter ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Coronary Syndrome ◽

Copd Patients ◽

Potential Biomarker

Abstract Background Diagnostic biomarkers for detecting chronic obstructive pulmonary disease (COPD) in acute coronary syndrome (ACS) patients are not available. SERPINA1, coding for the most potent circulating anti-inflammatory protein in the lung, has been found to be differentially methylated in blood cells from COPD patients. This study aimed to investigate the methylation profile of SERPINA1 in blood cells from ACS patients, with (COPD+) or without COPD (COPD−). Methods Blood samples were from 115 ACS patients, including 30 COPD+ and 85 COPD− according to lung function phenotype, obtained with spirometry. DNA treated with sodium bisulfite was PCR-amplified at SERPINA1 promoter region. Methylation analysis was carried out by sequencing the PCR products. Lymphocytes count in ACS patients was recorded at hospital admission and discharge. Results SERPINA1 was hypermethylated in 24/30 (80%) COPD+ and 48/85 (56.5%) COPD− (p < 0.05). Interestingly, at hospital discharge, lymphocytes count was higher in COPD− patients carrying SERPINA1 hypermethylated (1.98 × 103 ± 0.6 cell/µl) than in COPD− carrying SERPINA1 hypomethylated (1.7 × 103 ± 0.48 cell/µl) (p < 0.05). Conclusions SERPINA1 is hypermethylated in blood cells from COPD+ patients. COPD− carrying SERPINA1 hypermethylated and high lymphocytes count may be at risk of COPD development. Therefore, SERPINA1 hypermethylation may represent a potential biomarker for predicting COPD development in ACS patients.

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Domiciliary Cough Monitoring for the Prediction of COPD Exacerbations

Lung ◽

10.1007/s00408-021-00435-9 ◽

2021 ◽

Vol 199 (2) ◽

pp. 131-137

Author(s):

Michael G. Crooks ◽

Albertus C. den Brinker ◽

Susannah Thackray-Nocera ◽

Ralph van Dinther ◽

Caroline E. Wright ◽

...

Keyword(s):

Automated System ◽

Chronic Obstructive ◽

Service Utilisation ◽

Alert System ◽

Obstructive Pulmonary Disease ◽

Prospective Longitudinal Study ◽

Copd Exacerbations ◽

Cough Frequency ◽

Copd Patients ◽

Prospective Longitudinal

Abstract Introduction Acute exacerbations of COPD (AE-COPD) are a leading cause of health service utilisation and are associated with morbidity and mortality. Identifying the prodrome of AE-COPD by monitoring symptoms and physiological parameters (telemonitoring) has proven disappointing and false alerts limit clinical utility. We report objective monitoring of cough counts around AE-COPD and the performance of a novel alert system identifying meaningful change in cough frequency. Methods This prospective longitudinal study of cough monitoring included chronic obstructive pulmonary disease (COPD) patients experienced in telemonitoring that had two or more AE-COPD in the past year. Participants underwent cough monitoring and completed a daily questionnaire for 90 days. The automated system identified deteriorating trends in cough and this was compared with alerts generated by an established telemonitoring questionnaire. Results 28 patients [median age 66 (range 46–86), mean FEV-1% predicted 36% (SD 18%)] completed the study and had a total of 58 exacerbations (43 moderate and 15 severe). Alerts based on cough monitoring were generated mean 3.4 days before 45% of AE-COPD with one false alert every 100 days. In contrast, questionnaire-based alerts occurred in the prodrome of 88% of AE-COPD with one false alert every 10 days. Conclusion An alert system based on cough frequency alone predicted 45% AE-COPD; the low false alert rate with cough monitoring suggests it is a practical and clinically relevant tool. In contrast, the utility of questionnaire-based symptom monitoring is limited by frequent false alerts.

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Influence of N-acetylcysteine on chronic bronchitis or COPD exacerbations: a meta-analysis

European Respiratory Review ◽

10.1183/16000617.00002215 ◽

2015 ◽

Vol 24 (137) ◽

pp. 451-461 ◽

Cited By ~ 81

Author(s):

Mario Cazzola ◽

Luigino Calzetta ◽

Clive Page ◽

Josè Jardim ◽

Alexander G. Chuchalin ◽

...

Keyword(s):

Relative Risk ◽

Airway Obstruction ◽

Chronic Bronchitis ◽

Meta Analysis ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Regular Treatment ◽

Copd Exacerbations ◽

Copd Patients ◽

High Doses

In order to clarify the possible role of N-acetylcysteine (NAC) in the treatment of patients with chronic bronchitis and chronic obstructive pulmonary disease (COPD), we have carried out a meta-analysis testing the available evidence that NAC treatment may be effective in preventing exacerbations of chronic bronchitis or COPD and evaluating whether there is a substantial difference between the responses induced by low (≤600 mg per day) and high (>600 mg per day) doses of NAC.The results of the present meta-analysis (13 studies, 4155 COPD patients, NAC n=1933; placebo or controls n=2222) showed that patients treated with NAC had significantly and consistently fewer exacerbations of chronic bronchitis or COPD (relative risk 0.75, 95% CI 0.66–0.84; p<0.01), although this protective effect was more apparent in patients without evidence of airway obstruction. However, high doses of NAC were also effective in patients suffering from COPD diagnosed using spirometric criteria (relative risk 0.75, 95% CI 0.68–0.82; p=0.04). NAC was well tolerated and the risk of adverse reactions was not dose-dependent (low doses relative risk 0.93, 95% CI 0.89–0.97; p=0.40; high doses relative risk 1.11, 95% CI 0.89–1.39; p=0.58).The strong signal that comes from this meta-analysis leads us to state that if a patient suffering from chronic bronchitis presents a documented airway obstruction, NAC should be administered at a dose of ≥1200 mg per day to prevent exacerbations, while if a patient suffers from chronic bronchitis, but is without airway obstruction, a regular treatment of 600 mg per day seems to be sufficient.

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Periodontal Health and Chronic Obstructive Pulmonary Disease (COPD) Exacerbations: A Systematic Review

10.21203/rs.3.rs-138210/v1 ◽

2021 ◽

Author(s):

Niamh Kelly ◽

Lewis Winning ◽

Christopher Irwin ◽

Fionnuala Lundy ◽

Dermot Linden ◽

...

Keyword(s):

Quality Of Life ◽

Systematic Review ◽

Chronic Obstructive Pulmonary Disease ◽

Risk Of Bias ◽

Chronic Obstructive ◽

Periodontal Health ◽

Obstructive Pulmonary Disease ◽

Copd Exacerbations ◽

Copd Patients

Abstract BackgroundA growing body of evidence suggests a role for oral bacteria in lung infections. This systematic review aimed to analyse the association between poor periodontal health and the frequency of chronic obstructive pulmonary disease (COPD) exacerbations. MethodsPubMed, Embase, Web of Science, CINAHL and Medline were searched for studies published until May 2020, with no language restriction. Studies reporting periodontal condition, or periodontal treatment outcomes, with data on the frequency of exacerbations of COPD, were identified. The primary outcome was the frequency of exacerbations and secondary outcomes included quality of life and hospitalisation. Studies were assessed for eligibility and quality by two assessors independently.Results Searches identified 532 records and 8 met the inclusion criteria. The data from intervention studies showed reduction in the frequency of exacerbations following periodontal treatment. Data from observational studies suggest association of worse plaque scores with exacerbation but not pocket depth or clinical attachment loss. Better periodontal health was also associated with reduced frequency of COPD exacerbations, hospitalisations and improved quality of life in COPD patients. Due to the high heterogeneity no meta-analysis was performed. The quality of some of the included studies was low and there was evidence of high risk of bias.ConclusionThe data supports possible association between poor periodontal health, the frequency of exacerbations and quality of life in COPD patients. The evidence is limited by high risk of bias suggesting need for well-designed and adequately powered randomised control trials.The PROSPERO registration number CRD42020180328

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LABA/LAMA fixed-dose combinations versus LAMA monotherapy in the prevention of COPD exacerbations: a systematic review and meta-analysis

Therapeutic Advances in Respiratory Disease ◽

10.1177/1753466620937194 ◽

2020 ◽

Vol 14 ◽

pp. 175346662093719

Author(s):

Ching-Yi Chen ◽

Wang-Chun Chen ◽

Chi-Hsien Huang ◽

Yi-Ping Hsiang ◽

Chau-Chyun Sheu ◽

...

Keyword(s):

Randomized Clinical Trials ◽

Meta Analysis ◽

Similar Efficacy ◽

Fixed Dose ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Copd Exacerbations ◽

Copd Patients ◽

History Of ◽

Long Acting

Background: Long-acting muscarinic antagonist (LAMA) monotherapy is recommended for chronic obstructive pulmonary disease (COPD) patients with high risk of exacerbations. It is unclear whether long-acting β2-agonist (LABA)/LAMA fixed-dose combinations (FDCs) are more effective than LAMAs alone in preventing exacerbations. The aim of this study was to systematically review the literature to investigate whether LABA/LAMA FDCs are more effective than LAMA monotherapy in preventing exacerbations. Methods: We searched several databases and manufacturers’ websites to identify relevant randomized clinical trials comparing LABA/LAMA FDC treatment with LAMAs alone ⩾24 weeks. Outcomes of interest were time to first exacerbation and rates of moderate to severe, severe and all exacerbations. Results: We included 10 trials in 9 articles from 2013 to 2018 with a total of 19,369 patients for analysis in this study. Compared with LAMA monotherapy, LABA/LAMA FDCs demonstrated similar efficacy in terms of time to first exacerbation [hazard ratio, 0.96; 95% confidence interval (CI) 0.79–1.18; p = 0.71], moderate to severe exacerbations [risk ratio (RR), 0.96; 95% CI 0.90–1.03; p = 0.28], severe exacerbations (RR, 0.92; 95% CI 0.81–1.03; p = 0.15), and a marginal superiority in terms of all exacerbations (RR, 0.92; 95% CI 0.86–1.00; p = 0.04). The incidence of all exacerbation events was lower in the LABA/LAMA FDC group for the COPD patients with a history of previous exacerbations and those with a longer treatment period (52–64 weeks). Conclusion: This study provides evidence that LABA/LAMA FDCs are marginally superior in the prevention of all exacerbations compared with LAMA monotherapy in patients with COPD. The reviews of this paper are available via the supplemental material section.

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Bronchoalveolar Lavage Fluid from COPD Patients Reveals More Compounds Associated with Disease than Matched Plasma

Metabolites ◽

10.3390/metabo9080157 ◽

2019 ◽

Vol 9 (8) ◽

pp. 157 ◽

Cited By ~ 2

Author(s):

Eitan Halper-Stromberg ◽

Lucas Gillenwater ◽

Charmion Cruickshank-Quinn ◽

Wanda Kay O’Neal ◽

Nichole Reisdorph ◽

...

Keyword(s):

Bronchoalveolar Lavage ◽

Cell Metabolism ◽

Lavage Fluid ◽

Forced Expiratory Volume ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Copd Exacerbations ◽

False Discovery ◽

Copd Patients ◽

Clinical Covariates

Smoking causes chronic obstructive pulmonary disease (COPD). Though recent studies identified a COPD metabolomic signature in blood, no large studies examine the metabolome in bronchoalveolar lavage (BAL) fluid, a more direct representation of lung cell metabolism. We performed untargeted liquid chromatography–mass spectrometry (LC–MS) on BAL and matched plasma from 115 subjects from the SPIROMICS cohort. Regression was performed with COPD phenotypes as the outcome and metabolites as the predictor, adjusted for clinical covariates and false discovery rate. Weighted gene co-expression network analysis (WGCNA) grouped metabolites into modules which were then associated with phenotypes. K-means clustering grouped similar subjects. We detected 7939 and 10,561 compounds in BAL and paired plasma samples, respectively. FEV1/FVC (Forced Expiratory Volume in One Second/Forced Vital Capacity) ratio, emphysema, FEV1 % predicted, and COPD exacerbations associated with 1230, 792, eight, and one BAL compounds, respectively. Only two plasma compounds associated with a COPD phenotype (emphysema). Three BAL co-expression modules associated with FEV1/FVC and emphysema. K-means BAL metabolomic signature clustering identified two groups, one with more airway obstruction (34% of subjects, median FEV1/FVC 0.67), one with less (66% of subjects, median FEV1/FVC 0.77; p < 2 × 10−4). Associations between metabolites and COPD phenotypes are more robustly represented in BAL compared to plasma.

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Neutrophil proteases alter the interleukin-22-receptor-dependent lung antimicrobial defence

European Respiratory Journal ◽

10.1183/09031936.00215114 ◽

2015 ◽

Vol 46 (3) ◽

pp. 771-782 ◽

Cited By ~ 25

Author(s):

Antoine Guillon ◽

Youenn Jouan ◽

Deborah Brea ◽

Fabien Gueugnon ◽

Emilie Dalloneau ◽

...

Keyword(s):

Chronic Obstructive ◽

Dependent Lung ◽

Obstructive Pulmonary Disease ◽

Copd Exacerbations ◽

Interleukin 22 ◽

Copd Patients ◽

Acute Exacerbations ◽

Underlying Mechanisms

Chronic obstructive pulmonary disease (COPD) is punctuated by episodes of infection-driven acute exacerbations. Despite the life-threatening nature of these exacerbations, the underlying mechanisms remain unclear, although a high number of neutrophils in the lungs of COPD patients is known to correlate with poor prognosis. Interleukin (IL)-22 is a cytokine that plays a pivotal role in lung antimicrobial defence and tissue protection. We hypothesised that neutrophils secrete proteases that may have adverse effects in COPD, by altering the IL-22 receptor (IL-22R)-dependent signalling.Using in vitro and in vivo approaches as well as reverse transcriptase quantitative PCR, flow cytometry and/or Western blotting techniques, we first showed that pathogens such as the influenza virus promote IL-22R expression in human bronchial epithelial cells, whereas Pseudomonas aeruginosa, bacterial lipopolysaccharide or cigarette smoke do not. Most importantly, neutrophil proteases cleave IL-22R and impair IL-22-dependent immune signalling and expression of antimicrobial effectors such as β-defensin-2. This proteolysis resulted in the release of a soluble fragment of IL-22R, which was detectable both in cellular and animal models as well as in sputa from COPD patients with acute exacerbations.Hence, our study reveals an unsuspected regulation by the proteolytic action of neutrophil enzymes of IL-22-dependent lung host response. This process probably enhances pathogen replication, and ultimately COPD exacerbations.

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Upregulation of Leukocyte Immunoglobulin-Like Receptor B4 on Interstitial Macrophages in COPD; Their Possible Protective Role Against Emphysema Formation

10.21203/rs.3.rs-723302/v1 ◽

2021 ◽

Author(s):

Ayumi Mitsune ◽

Mitsuhiro Yamada ◽

Naoya Fujino ◽

Tadahisa Numakura ◽

Tomohiro Ichikawa ◽

...

Keyword(s):

Mouse Model ◽

Inflammatory Responses ◽

Feedback System ◽

Surface Expression ◽

Protective Role ◽

Chronic Obstructive ◽

Wild Type ◽

Obstructive Pulmonary Disease ◽

Copd Patients ◽

Deficient Mice

Abstract Background: Leukocyte immunoglobulin-like receptor B4 (LILRB4) is one of the inhibitory receptors in various types of immune cells including macrophages. Previous reports suggested that LILRB4 could be involved in a negative feedback system to prevent excessive inflammatory responses. However, its role has been unclear in chronic obstructive pulmonary disease (COPD), in which macrophages play a crucial role in the pathogenesis. In this study, we aimed to examine the changes of LILRB4 on macrophages both in the lung specimens of COPD patients and the lungs of a mouse emphysema model. We then tried to compare the differences in both inflammation and emphysematous changes of the model between wild-type and LILRB4-deficient mice in order to elucidate the role of LILRB4 in the pathogenesis of COPD.Methods: We prepared single-cell suspensions of resected lung specimens of never-smokers (n = 21), non-COPD smokers (n = 16), and COPD patients (n = 14). The identification of LILRB4-expressing cells and the level of LILRB4 expression were evaluated by flow cytometry. We analyzed the relationships between the LILRB4 expression and clinical characteristics including respiratory function. In the experiments using an elastase-induced mouse model of emphysema, we also analyzed the LILRB4 expression on lung macrophages. We compared inflammatory cell accumulation and emphysematous changes induced by elastase instillation between wild-type and LILRB4-deficient mice.Results: The levels of surface expression of LILRB4 are relatively high on monocyte linage cells including macrophages in the human lungs. The percentage of LILRB4+ cells in lung interstitial macrophages was increased in COPD patients compared to non-COPD smokers (p = 0.018) and correlated with the severity of emphysematous lesions detected by CT scan (rs = 0.559, p < 0.001), whereas the amount of smoking showed no correlation with LILRB4 expression. Increased LILRB4 on interstitial macrophages was also observed in elastase-treated mice (p = 0.008). LILRB4-deficient mice showed severer emphysematous lesions with increased MMP-12 expression in the model.Conclusions: LILRB4 on interstitial macrophages was upregulated both in human COPD lungs and in a mouse model of emphysema. This upregulated LILRB4 may have a protective effect against emphysema formation, possibly through decreasing MMP-12 expression in the lungs.

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Real-Life Clinical and Functional Effects of Fluticasone Furoate/Umeclidinium/Vilanterol-Combined Triple Therapy in Patients with Chronic Obstructive Pulmonary Disease

Respiration ◽

10.1159/000512064 ◽

2020 ◽

pp. 1-8

Author(s):

Corrado Pelaia ◽

Giada Procopio ◽

Maria Rosaria Deodato ◽

Olivia Florio ◽

Angelantonio Maglio ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Triple Therapy ◽

Real Life ◽

Chronic Obstructive ◽

Fluticasone Furoate ◽

Obstructive Pulmonary Disease ◽

Copd Exacerbations ◽

Copd Patients ◽

Inhaled Therapy ◽

Long Acting

Background: Triple therapy consisting of a drug association including an inhaled corticosteroid, a long-acting muscarinic receptor antagonist and a long-acting β2-adrenergic agonist, delivered via a single device, can be a valuable treatment for chronic obstructive pulmonary disease (COPD) patients experiencing frequent disease exacerbations. Objectives: The aim of this real-life, single-center, observational study was to evaluate, in 44 COPD patients with recurrent exacerbations, the effects of the triple inhaled therapy combining fluticasone furoate, umeclidinium, and vilanterol (FF/UMEC/VI). Methods: Within such a therapeutic context, several clinical and lung functional parameters were considered at baseline and after 24 weeks of treatment with combined inhaled triple therapy. Results: With respect to baseline, after 24 weeks of treatment with FF/UMEC/VI, significant changes were recorded with regard to Modified British Medical Research Council (p < 0.0001) and COPD Assessment Test (p < 0.0001) scores, COPD exacerbations (p < 0.001), forced expiratory volume in the first second (p < 0.001), residual volume (p < 0.01), forced mid-expiratory flow between 25 and 75% of FVC (p < 0.0001), inspiratory capacity (p < 0.01), forced vital capacity (p < 0.05), and peak expiratory flow (p < 0.0001). Moreover, in a subgroup of 28 patients, a significant increase of diffusion lung capacity (p < 0.01) was also detected. Conclusions: In conclusion, our real-life results suggest that triple inhaled therapy with FF/UMEC/VI, when given to COPD patients with frequent exacerbations, is able to positively impact on dyspnea and global health status as well as to significantly decrease COPD exacerbations and improve airflow limitation and lung hyperinflation.

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Neutrophil to lymphocyte ratio and clinical outcomes in COPD: recent evidence and future perspectives

European Respiratory Review ◽

10.1183/16000617.0113-2017 ◽

2018 ◽

Vol 27 (147) ◽

pp. 170113 ◽

Cited By ~ 39

Author(s):

Panagiotis Paliogiannis ◽

Alessandro G. Fois ◽

Salvatore Sotgia ◽

Arduino A. Mangoni ◽

Elisabetta Zinellu ◽

...

Keyword(s):

Complete Blood Count ◽

Neutrophil To Lymphocyte Ratio ◽

Airflow Limitation ◽

Chronic Obstructive ◽

Future Perspectives ◽

Obstructive Pulmonary Disease ◽

Lymphocyte Ratio ◽

Copd Exacerbations ◽

Copd Patients ◽

Acute Exacerbations

Chronic obstructive pulmonary disease (COPD) is a disabling condition that is characterised by poorly reversible airflow limitation and inflammation. Acute exacerbations of COPD are a common cause of hospitalisation and death among COPD patients. Several biochemical markers have been studied as outcome predictors in COPD; however, their measurement often requires significant time and resources. Relatively simple biomarkers of inflammation calculated from routine complete blood count tests, such as the neutrophil to lymphocyte ratio (NLR), might also predict COPD progression and outcomes. This review discusses the available evidence from studies investigating the associations between the NLR, COPD exacerbations and death in this patient group.

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