Publications
2499 results found
Bewley M, Budd R, Ryan E, et al., 2018, Opsonic phagocytosis in chronic obstructive pulmonary disease is enhanced by Nrf2 agonists, American Journal of Respiratory and Critical Care Medicine, Vol: 198, Pages: 739-750, ISSN: 1073-449X
Rationale: Previous studies have identified defects in bacterial phagocytosis by alveolar macrophages (AM) in patients with chronic obstructive pulmonary disease (COPD) but the mechanisms and clinical consequences remain incompletely defined.Objectives: To examine the effect of COPD on AM phagocytic responses and identify the mechanisms, clinical consequences and potential for therapeutic manipulation of these defects.Methods: We isolated alveolar macrophages (AM) and monocyte-derived macrophages (MDM) from a cohort of COPD patients and controls within the MRC COPD-MAP consortium and measured phagocytosis of bacteria in relation to opsonic conditions and clinical features.Measurements and Main Results: COPD AM and MDM have impaired phagocytosis of S. pneumoniae. COPD AM have a selective defect in uptake of opsonized bacteria, despite the presence of anti-pneumococcal antibodies in bronchoalveolar lavage, not observed in MDM or healthy donor’s AM. AM defects in phagocytosis in COPD are significantly associated with exacerbation frequency, isolation of pathogenic bacteria and health related quality of life scores. Bacterial binding and initial intracellular killing of opsonized bacteria in COPD AM was not reduced. COPD AM have reduced transcriptional responses to opsonized bacteria, including cellular stress responses that include transcriptional modules involving antioxidant defenses and Nrf2-regualted genes. Agonists of the cytoprotective transcription factor Nrf2 (sulforaphane and Compound 7) reverse defects in phagocytosis of S. pneumoniae and non-type able Haemophilus influenzae by COPD AM. Conclusions: Patients with COPD have clinically relevant defects in opsonic phagocytosis by AM, associated with impaired transcriptional responses to cellular stress, which are reversed by therapeutic targeting with Nrf2 agonists.
Tregoning JS, Mallia P, Webber J, et al., 2018, Role of airway glucose in bacterial infections in chronic obstructive pulmonary disease, Journal of Allergy and Clinical Immunology, Vol: 142, Pages: 815-823.e6, ISSN: 0091-6749
BackgroundPatients with chronic obstructive pulmonary disease (COPD) have increased susceptibility to respiratory tract infection, which contributes to disease progression and mortality, but mechanisms of increased susceptibility to infection remain unclear.ObjectivesThe aim of this study was to determine whether glucose concentrations were increased in airway samples (nasal lavage fluid, sputum, and bronchoalveolar lavage fluid) from patients with stable COPD and to determine the effects of viral infection on sputum glucose concentrations and how airway glucose concentrations relate to bacterial infection.MethodsWe measured glucose concentrations in airway samples collected from patients with stable COPD and smokers and nonsmokers with normal lung function. Glucose concentrations were measured in patients with experimentally induced COPD exacerbations, and these results were validated in patients with naturally acquired COPD exacerbations. Relationships between sputum glucose concentrations, inflammatory markers, and bacterial load were examined.ResultsSputum glucose concentrations were significantly higher in patients with stable COPD compared with those in control subjects without COPD. In both experimental virus-induced and naturally acquired COPD exacerbations, sputum and nasal lavage fluid glucose concentrations were increased over baseline values. There were significant correlations between sputum glucose concentrations and sputum inflammatory markers, viral load, and bacterial load. Airway samples with higher glucose concentrations supported more Pseudomonas aeruginosa growth in vitro.ConclusionsAirway glucose concentrations are increased in patients with stable COPD and further increased during COPD exacerbations. Increased airway glucose concentrations might contribute to bacterial infections in both patients with stable and those with exacerbated COPD. This has important implications for the development of nonantibiotic therapeutic strategies for the prev
Maneechotesuwan K, Yao X, Ito K, et al., 2018, Correction: Suppression of GATA-3 nuclear import and phosphorylation: a novel mechanism of corticosteroid action in allergic disease, PLoS Medicine, Vol: 15, ISSN: 1549-1277
[This corrects the article DOI: 10.1371/journal.pmed.1000076.].
Baker J, Vuppusetty C, Colley T, et al., 2018, MicroRNA-570 is a novel regulator of cellular senescence and inflammaging, FASEB Journal, ISSN: 0892-6638
Diseases of accelerated aging often occur together (multimorbidity), and their prevalence is increasing, with high societal and health care costs. Chronic obstructive pulmonary disease (COPD) is one such condition, in which one half of patients exhibit ≥4 age-related diseases. Diseases of accelerated aging share common molecular pathways, which lead to the detrimental accumulation of senescent cells. These senescent cells no longer divide but release multiple inflammatory proteins, known as the senescence-associated secretory phenotype, which may perpetuate and speed disease. Here, we show that inhibiting miR-570-3p, which is increased in COPD cells, reverses cellular senescence by restoring the antiaging molecule sirtuin-1. MiR-570-3p is induced by oxidative stress in airway epithelial cells through p38 MAP kinase-c-Jun signaling and drives senescence by inhibiting sirtuin-1. Inhibition of elevated miR-570-3p in COPD small airway epithelial cells, using an antagomir, restores sirtuin-1 and suppresses markers of cellular senescence (p16INK4a, p21Waf1, and p27Kip1), thereby restoring cellular growth by allowing progression through the cell cycle. MiR-570-3p inhibition also suppresses the senescence-associated secretory phenotype (matrix metalloproteinases-2/9, C-X-C motif chemokine ligand 8, IL-1β, and IL-6). Collectively, these data suggest that inhibiting miR-570-3p rejuvenates cells via restoration of sirtuin-1, reducing many of the abnormalities associated with cellular senescence.—Baker, J. R., Vuppusetty, C., Colley, T., Hassibi, S., Fenwick, P. S., Donnelly, L. E., Ito, K., Barnes, P. J. MicroRNA-570 is a novel regulator of cellular senescence and inflammaging.
Pelleg A, Schulman ES, Barnes PJ, 2018, Adenosine 5 '-triphosphate's role in bradycardia and syncope associated with pulmonary embolism, RESPIRATORY RESEARCH, Vol: 19, ISSN: 1465-993X
Adenosine 5′-triphiosphate (ATP) is released from cells under physiologic and pathophysiologic conditions. Extracellular ATP acts as an autocrine and paracrine agent affecting various cell types by activating cell surface P2 receptors (P2R), which include trans-cell membrane cationic channels, P2XR, and G protein coupled receptors, P2YR. We have previously shown that ATP stimulates vagal afferent nerve terminals in the lungs by activating P2X2/3R. This action could lead to bronchoconstriction, cough and the local release of pro-inflammatory neuropeptides. In addition, ATP markedly enhances the IgE-dependent histamine release from human lung mast cells. Thus, we have proposed for the first time that extracellular ATP plays a mechanistic role in pulmonary pathophysiology in general and chronic obstructive pulmonary disease (COPD), and acute bronchoconstriction in asthma in particular. The present review examines whether ATP could also play a role in bradycardia and syncope in a subset of patients with pulmonary embolism.
Dai Y, Yeo SCM, Barnes P, et al., 2018, Pre-clinical pharmacokinetic and metabolomic analyses of isorhapontigenin, a dietary resveratrol derivative, Frontiers in Pharmacology, Vol: 9, ISSN: 1663-9812
Background: Isorhapontigenin (trans–3,5,4′-trihydroxy–3′–methoxystilbene, ISO), a dietary resveratrol (trans–3,5,4′–trihydroxystilbene) derivative, possesses various health-promoting activities. To further evaluate its medicinal potentials, the pharmacokinetic and metabolomic profiles of ISO were examined in Sprague-Dawley rats.Methods: The plasma pharmacokinetics and metabolomics were monitored by liquid chromatography–tandem mass spectrometry (LC–MS/MS) and gas chromatography–tandem mass spectrometry (GC–MS/MS), respectively.Results: Upon intravenous injection (90 μmol/kg), ISO exhibited a fairly rapid clearance (CL) and short mean residence time (MRT). After a single oral administration (100 μmol/kg), ISO was rapidly absorbed and showed a long residence in the systemic circulation. Dose escalation to 200 μmol/kg resulted in higher dose-normalized maximal plasma concentrations (Cmax/Dose), dose-normalized plasma exposures (AUC/Dose), and oral bioavailability (F). One-week repeated daily dosing of ISO did not alter its major oral pharmacokinetic parameters. Pharmacokinetic comparisons clearly indicated that ISO displayed pharmacokinetic profiles superior to resveratrol as its Cmax/Dose, AUC/Dose, and F were approximately two to three folds greater than resveratrol. Metabolomic investigation revealed that 1-week ISO administration significantly reduced plasma concentrations of arachidonic acid, cholesterol, fructose, allantoin, and cadaverine but increased tryptamine levels, indicating its impact on metabolic pathways related to health-promoting effects.Conclusion: ISO displayed favorable pharmacokinetic profiles and may be a promising nutraceutical in view of its health-promoting properties.
Barnes PJ, 2018, Targeting cytokines to treat asthma and chronic obstructive pulmonary disease, NATURE REVIEWS IMMUNOLOGY, Vol: 18, Pages: 454-466, ISSN: 1474-1733
Cazzola M, Calzetta L, Barnes PJ, et al., 2018, Efficacy and safety profile of xanthines in COPD: a network meta-analysis, European Respiratory Review, Vol: 27, ISSN: 0905-9180
Theophylline can still have a role in the management of stable chronic obstructive pulmonary disease (COPD), but its use remains controversial, mainly due to its narrow therapeutic window. Doxofylline, another xanthine, is an effective bronchodilator and displays a better safety profile than theophylline. Therefore, we performed a quantitative synthesis to compare the efficacy and safety profile of different xanthines in COPD.The primary end-point of this meta-analysis was the impact of xanthines on lung function. In addition, we assessed the risk of adverse events by normalising data on safety as a function of person-weeks. Data obtained from 998 COPD patients were selected from 14 studies and meta-analysed using a network approach.The combined surface under the cumulative ranking curve (SUCRA) analysis of efficacy (change from baseline in forced expiratory volume in 1 s) and safety (risk of adverse events) showed that doxofylline was superior to aminophylline (comparable efficacy and significantly better safety), bamiphylline (significantly better efficacy and comparable safety), and theophylline (comparable efficacy and significantly better safety).Considering the overall efficacy/safety profile of the investigated agents, the results of this quantitative synthesis suggest that doxofylline seems to be the best xanthine for the treatment of COPD.
O'Byrne PM, FitzGerald JM, Bateman ED, et al., 2018, Inhaled Combined Budesonide-Formoterol as Needed in Mild Asthma, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 378, Pages: 1865-1876, ISSN: 0028-4793
Bateman ED, Reddel HK, O'Byrne PM, et al., 2018, As-needed budesonide-formoterol versus maintenance budesonide in mild asthma, New England Journal of Medicine, Vol: 378, Pages: 1877-1887, ISSN: 0028-4793
BackgroundPatients with mild asthma often rely on inhaled short-acting β2-agonists for symptom relief and have poor adherence to maintenance therapy. Another approach might be for patients to receive a fast-acting reliever plus an inhaled glucocorticoid component on an as-needed basis to address symptoms and exacerbation risk.MethodsWe conducted a 52-week, double-blind, multicenter trial involving patients 12 years of age or older who had mild asthma and were eligible for treatment with regular inhaled glucocorticoids. Patients were randomly assigned to receive twice-daily placebo plus budesonide–formoterol (200 μg of budesonide and 6 μg of formoterol) used as needed or budesonide maintenance therapy with twice-daily budesonide (200 μg) plus terbutaline (0.5 mg) used as needed. The primary analysis compared budesonide–formoterol used as needed with budesonide maintenance therapy with regard to the annualized rate of severe exacerbations, with a prespecified noninferiority limit of 1.2. Symptoms were assessed according to scores on the Asthma Control Questionnaire–5 (ACQ-5) on a scale from 0 (no impairment) to 6 (maximum impairment).ResultsA total of 4215 patients underwent randomization, and 4176 (2089 in the budesonide–formoterol group and 2087 in the budesonide maintenance group) were included in the full analysis set. Budesonide–formoterol used as needed was noninferior to budesonide maintenance therapy for severe exacerbations; the annualized rate of severe exacerbations was 0.11 (95% confidence interval [CI], 0.10 to 0.13) and 0.12 (95% CI, 0.10 to 0.14), respectively (rate ratio, 0.97; upper one-sided 95% confidence limit, 1.16). The median daily metered dose of inhaled glucocorticoid was lower in the budesonide–formoterol group (66 μg) than in the budesonide maintenance group (267 μg). The time to the first exacerbation was similar in the two groups (hazard ratio, 0.96; 95% CI, 0.78 to 1.17). The change
Montuschi P, Santini G, Mores N, et al., 2018, Breathomics for assessing the effects of treatment and withdrawal with inhaled Beclomethasone/Formoterol in patients with COPD, Frontiers in Pharmacology, Vol: 9, ISSN: 1663-9812
Background: Prospective pharmacological studies on breathomics profiles in COPD patients have not been previously reported. We assessed the effects of treatment and withdrawal of an extrafine inhaled corticosteroid (ICS)-long-acting β2-agonist (LABA) fixed dose combination (FDC) using a multidimensional classification model including breathomics.Methods: A pilot, proof-of-concept, pharmacological study was undertaken in 14 COPD patients on maintenance treatment with inhaled fluticasone propionate/salmeterol (500/50 μg b.i.d.) for at least 8 weeks (visit 1). Patients received 2-week treatment with inhaled beclomethasone dipropionate/formoterol (100/6 μg b.i.d.) (visit 2), 4-week treatment with formoterol alone (6 μg b.i.d.) (visit 3), and 4-week treatment with beclomethasone/formoterol (100/6 μg b.i.d.) (visit 4). Exhaled breath analysis with two e-noses, based on different technologies, and exhaled breath condensate (EBC) NMR-based metabolomics were performed. Sputum cell counts, sputum supernatant and EBC prostaglandin E2 (PGE2) and 15-F2t-isoprostane, fraction of exhaled nitric oxide, and spirometry were measured.Results: Compared with formoterol alone, EBC acetate and sputum PGE2, reflecting airway inflammation, were reduced after 4-week beclomethasone/formoterol. Three independent breathomics techniques showed that extrafine beclomethasone/formoterol short-term treatment was associated with different breathprints compared with regular fluticasone propionate/salmeterol. Either ICS/LABA FDC vs. formoterol alone was associated with increased pre-bronchodilator FEF25−75% and FEV1/FVC (P = 0.008–0.029). The multidimensional model distinguished fluticasone propionate/salmeterol vs. beclomethasone/formoterol, fluticasone propionate/salmeterol vs. formoterol, and formoterol vs. beclomethasone/formoterol (accuracy > 70%, P < 0.01).Conclusions: Breathomics could be used for assessing ICS treatment and withdrawal in COPD patients. Large
Hashemian SM, Mortaz E, Jamaati H, et al., 2018, Budesonide facilitates weaning from mechanical ventilation in difficult-to-wean very severe COPD patients: association with inflammatory mediators and cells, Journal of Critical Care, Vol: 44, Pages: 161-167, ISSN: 0883-9441
INTRODUCTION: Mechanical ventilatory support is life-saving therapy for patients with respiratory failure in intensive care units (ICU) but is linked to ventilator-associated pneumonia and other nosocomial infections. Interventions that improve the efficiency of weaning from mechanical ventilation may improve patient outcomes. OBJECTIVE: To determine whether inhaled budesonide decreases time-to-weaning in COPD stage 4 difficult-to-wean patients and reduces the release of pro-inflammatory cytokines in ICU patients. MATERIALS AND METHODS: We recruited 55 difficult-to-wean COPD patients (Stage 4) within the ICU of the Masih Daneshvari Hospital. Subjects were randomly assigned to receive inhaled budesonide (0.5mg/day) or placebo (normal saline). Dynamic compliance and BAL cytokines were measured. RESULTS: Budesonide significantly reduced the number of days on MV (days-to-weaning=4.6±1.6days) compared to that seen in the control group (7.2±2.7days, p=0.014). Dynamic compliance was significantly improved in the budesonide group on days 3 (p=0.018) and 5 (p=0.011) The levels of CXCL-8 and IL-6 diminished on days 3-5 after start of budesonide (p<0.05). CONCLUSION: In COPD patients on MV, nebulized budesonide was associated with reduced BAL CXCL8 and IL-6 levels and neutrophil numbers as well as an improvement in ventilatory mechanics and facilitated weaning.
Singh D, Barnes PJ, Stockley R, et al., 2018, Pharmacological treatment of COPD: the devil is always in the detail, EUROPEAN RESPIRATORY JOURNAL, Vol: 51, ISSN: 0903-1936
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Yanagisawa S, Baker JR, Vuppusetty C, et al., 2018, The dynamic shuttling of SIRT1 between cytoplasm and nuclei in bronchial epithelial cells by single and repeated cigarette smoke exposure, PLoS ONE, Vol: 13, ISSN: 1932-6203
SIRT1 (silent information regulator 2 homolog 1) is a crucial cellular survival protein especially in oxidative stress environments, and has been thought to locate within the nuclei, but also known to shuttle between cytoplasm and nuclei in some cell types. Here, we show for the first time the dynamics of SIRT1 in the presence of single or concurrent cigarette smoke extract (CSE) exposure in human bronchial epithelial cells (HBEC). In BEAS-2B HBEC or primary HBEC, SIRT1 was localized predominantly in cytoplasm, and the CSE (3%) induced nuclear translocation of SIRT1 from cytoplasm in the presence of L-buthionine sulfoximine (an irreversible inhibitor of γ-glutamylcystein synthetase), mainly through the activation of phosphatidylinositol 3-kinase (PI3K) α subunit. This SIRT1 nuclear shuttling was associated with FOXO3a nuclear translocation and the strong induction of several anti-oxidant genes including superoxide dismutase (SOD) 2 and 3; therefore seemed to be an adaptive response. When BEAS-2B cells were pretreated with repeated exposure to a lower concentration of CSE (0.3%), the CSE-induced SIRT1 shuttling and resultant SOD2/3 mRNA induction were significantly impaired. Thus, this result offers a useful cell model to mimic the impaired anti-oxidant capacity in cigarette smoking-associated lung disease such as chronic obstructive pulmonary disease.
Wrench C, Belchamber K, Bercusson A, et al., 2018, Reduced Clearance of Fungal Spores by Chronic Obstructive Pulmonary Disease GM-CSF- and M-CSF-derived Macrophages, Publisher: American Thoracic Society, Pages: 271-273, ISSN: 1044-1549
Sood A, Assad NA, Barnes PJ, et al., 2018, ERS/ATS workshop report on respiratory health effects of household air pollution, European Respiratory Journal, Vol: 51, ISSN: 0903-1936
Exposure to household air pollution (HAP) from solid fuel combustion affects almost half of the world population. Adverse respiratory outcomes such as respiratory infections, impaired lung growth and chronic obstructive pulmonary disease have been linked to HAP exposure. Solid fuel smoke is a heterogeneous mixture of various gases and particulates. Cell culture and animal studies with controlled exposure conditions and genetic homogeneity provide important insights into HAP mechanisms. Impaired bacterial phagocytosis in exposed human alveolar macrophages possibly mediates several HAP-related health effects. Lung pathological findings in HAP-exposed individuals demonstrate greater small airways fibrosis and less emphysema compared with cigarette smokers. Field studies using questionnaires, air pollution monitoring and/or biomarkers are needed to better establish human risks. Some, but not all, studies suggest that improving cookstove efficiency or venting emissions may be associated with reduced respiratory symptoms, lung function decline in women and severe pneumonia in children. Current studies focus on fuel switching, stove technology replacements or upgrades and air filter devices. Several governments have initiated major programmes to accelerate the upgrade from solid fuels to clean fuels, particularly liquid petroleum gas, which provides research opportunities for the respiratory health community.
Belchamber K, Barnes PJ, Donnelly L, 2018, Aberrant Scavenger Receptor Response to Bacterial Phagocytosis in COPD Macrophages, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Bateman E, Reddel HK, O'Byrne PM, et al., 2018, Severe Exacerbations and Inhaled Corticosteroid Load with As-Needed Budesonide/Formoterol vs Maintenance Budesonide in Mild Asthma, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Barnes PJ, 2018, Inflammatory Mechanisms in Chronic Obstructive Pulmonary Disease, INFLAMMATION: FROM MOLECULAR AND CELLULAR MECHANISMS TO THE CLINIC, VOLS 1-4, Editors: Cavaillon, Singer, Publisher: WILEY-V C H VERLAG GMBH, Pages: 1173-1197, ISBN: 978-3-527-33899-3
Di Stefano A, Sangiorgi C, Gnemmi I, et al., 2017, TGF-β signalling pathways in different compartments of the lower airways of stable COPD patients., Chest, Vol: 153, Pages: 851-862, ISSN: 0012-3692
BACKGROUND: The expression and localization of transforming growth factor-beta (TGF-β) pathway proteins in different compartments of the lower airways of stable COPD patients is unclear. OBJECTIVE: To determine TGF-β pathway protein expression in patients with stable COPD. METHODS: The expression and localization of TGF-β pathway components was measured in the bronchial mucosa and peripheral lung of patients with stable COPD (n=44), control smokers with normal lung function (n=24) and control non-smoking subjects (n=11) using immunohistochemistry. RESULTS: TGF-β1, TGF-β3 and CCN2 expression were significantly decreased in the bronchiolar epithelium, with TGF-β1 also decreased in alveolar macrophages, of stable COPD patients compared to control smokers with normal lung function. TGF-β3 expression was increased in the bronchial lamina propria of both control smokers with normal lung function and mild/moderate stable COPD compared to control non-smokers and correlated significantly with pack-years. However, TGF-β3+ cells decreased in severe/very severe COPD compared to control smokers. LTBP-1 expression was increased in the bronchial lamina propria in stable COPD of all severities compared with control smokers with normal lung function. BAMBI expression in the bronchial mucosa was significantly increased in stable COPD of all severities compared to control subjects. No other significant differences were observed between groups for all the other molecules studied either in the bronchial mucosa and peripheral lung. CONCLUSION: Expression of TGF-βs and their regulatory proteins is distinct within different lower airway compartments in stable COPD. Selective reduction in TGF-β1 and enhanced BAMBI expression may be associated with the increase in autoimmunity in COPD.
Wang Z, Singh R, Miller BE, et al., 2017, Sputum microbiome temporal variability and dysbiosis in chronic obstructive pulmonary disease exacerbations: an analysis of the COPDMAP study, Thorax, Vol: 73, Pages: 331-338, ISSN: 1468-3296
BACKGROUND: Recent studies suggest that lung microbiome dysbiosis, the disease associated disruption of the lung microbial community, might play a key role in chronic obstructive pulmonary disease (COPD) exacerbations. However, characterising temporal variability of the microbiome from large longitudinal COPD cohorts is needed to better understand this phenomenon. METHODS: We performed a 16S ribosomal RNA survey of microbiome on 716 sputum samples collected longitudinally at baseline and exacerbations from 281 subjects with COPD at three UK clinical centres as part of the COPDMAP consortium. RESULTS: The microbiome composition was similar among centres and between stable and exacerbations except for a small significant decrease of Veillonella at exacerbations. The abundance of Moraxella was negatively associated with bacterial alpha diversity. Microbiomes were distinct between exacerbations associated with bacteria versus eosinophilic airway inflammation. Dysbiosis at exacerbations, measured as significant within subject deviation of microbial composition relative to baseline, was present in 41% of exacerbations. Dysbiosis was associated with increased exacerbation severity indicated by a greater fall in forced expiratory volume in one second, forced vital capacity and a greater increase in CAT score, particularly in exacerbations with concurrent eosinophilic inflammation. There was a significant difference of temporal variability of microbial alpha and beta diversity among centres. The variation of beta diversity significantly decreased in those subjects with frequent historical exacerbations. CONCLUSIONS: Microbial dysbiosis is a feature of some exacerbations and its presence, especially in concert with eosinophilic inflammation, is associated with more severe exacerbations indicated by a greater fall in lung function. TRIAL REGISTRATION NUMBER: Results, NCT01620645.
Mitani A, Azam A, Vuppusetty C, et al., 2017, Quercetin restores corticosteroid sensitivity in cells from patients with chronic obstructive pulmonary disease., Experimental Lung Research, Vol: 43, Pages: 417-425, ISSN: 1521-0499
Corticosteroid resistance is a major barrier to the effective treatment of chronic obstructive pulmonary disease (COPD). Oxidative stress from cigarette smoke and chronic inflammation is likely to induce this corticosteroid insensitivity. Quercetin is a polyphenol that has been reported to be an active oxygen scavenger as well as a functional adenosine monophosphate-activated protein kinase (AMPK) activator. The aim of this study was to investigate the effect of quercetin on corticosteroid responsiveness in COPD cells. Corticosteroid sensitivity was examined in human monocytic U937 cells exposed to cigarette smoke extract (CSE) and peripheral blood mononuclear cells (PBMC) collected from patients with COPD. Corticosteroid sensitivity was determined as the dexamethasone concentration causing 40% inhibition of tumor necrosis factor alpha-induced CXCL8 production (Dex-IC40) in the presence or absence of quercetin. In U937 cells, treatment with quercetin activated AMPK and induced expression of nuclear factor erythroid 2-related factor 2, and consequently reversed CSE-induced corticosteroid insensitivity. PBMC from patients with COPD showed corticosteroid insensitivity compared with those from healthy volunteers, and treatment with quercetin restored corticosteroid sensitivity. In conclusion, quercetin restores corticosteroid sensitivity, and has the potential to be a novel treatment in combination with corticosteroids in COPD.
Wang G, Zhang X, Zhang HP, et al., 2017, Corticosteroid plus β2-agonist in a single inhaler as reliever therapy in intermittent and mild asthma: a proof-of-concept systematic review and meta-analysis., Respiratory Research, Vol: 18, ISSN: 1465-9921
BACKGROUND: Current guidelines recommend a single inhaler maintenance and reliever therapy (SMART) regimen for moderate to severe asthma. However, evidence for the inhaled corticosteroid plus fast-onset-acting β2-agonist (ICS/FABA) as reliever therapy in management of intermittent and mild asthma patients is lacking. OBJECTIVE: To systematically explore efficacy and safety of the proof-of-concept of the ICS plus FABA regimen in a single inhaler as reliever therapy across children and adults with intermittent and mild persistent asthma. METHODS: We searched online bibliographic databases for randomized controlled trials (RCTs) involving the as-needed use of ICS/FABA as monotherapy in intermittent or mild asthma patients. The primary outcomes were exacerbations and the hazard ratio (HR) of the time to first exacerbation. RESULTS: Six RCTs (n = 1300) met the inclusion criteria. Compared with the as-needed FABA regimen, the as-needed use of ICS/FABA as monotherapy statistically reduced exacerbations (RR = 0.56, P = 0.001). Compared with regular ICS regimen, the as-needed ICS/FABA therapy had slightly higher risk of exacerbations (RR = 1.39, P = 0.011). The HR for time to first exacerbations in the ICS/FABA regimen was significant lower when compared with FABA regimen (HR = 0.52, P = 0.002) but had no difference when compared with ICS regimen (HR = 1.30, P = 0.286). The corticosteroid exposure in the daily ICS regimen was 2- to 5-fold compared with as-needed use of ICS/FABA regimen. CONCLUSIONS: Our analysis shows that the ICS/FABA as a symptom-driven therapy may be a promising alternative regimen for the patients with intermittent or mild asthma, but it needs further real-world RCTs to confirm these findings.
Duffett EC, Fenwick PS, Barnes PJ, et al., 2017, PHOSPHOINOSITIDE-3 KINASE AND MEK INHIBITION PREVENTS UPTAKE OF BACTERIA BY AIRWAY EPITHELIAL CELLS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A111-A111, ISSN: 0040-6376
Michaeloudes C, Kuo C-H, Haji G, et al., 2017, Metabolic re-patterning in COPD airway smooth muscle cells., European Respiratory Journal, Vol: 50, ISSN: 0903-1936
Chronic obstructive pulmonary disease (COPD) airways are characterised by thickening of airway smooth muscle, partly due to airway smooth muscle cell (ASMC) hyperplasia. Metabolic reprogramming involving increased glycolysis and glutamine catabolism supports the biosynthetic and redox balance required for cellular growth. We examined whether COPD ASMCs show a distinct metabolic phenotype that may contribute to increased growth.We performed an exploratory intracellular metabolic profile analysis of ASMCs from healthy nonsmokers, healthy smokers and COPD patients, under unstimulated or growth conditions of transforming growth factor (TGF)-β and fetal bovine serum (FBS).COPD ASMCs showed impaired energy balance and accumulation of the glycolytic product lactate, glutamine, fatty acids and amino acids compared to controls in unstimulated and growth conditions. Fatty acid oxidation capacity was reduced under unstimulated conditions. TGF-β/FBS-stimulated COPD ASMCs showed restoration of fatty acid oxidation capacity, upregulation of the pentose phosphate pathway product ribose-5-phosphate and of nucleotide biosynthesis intermediates, and increased levels of the glutamine catabolite glutamate. In addition, TGF-β/FBS-stimulated COPD ASMCs showed a higher reduced-to-oxidised glutathione ratio and lower mitochondrial oxidant levels. Inhibition of glycolysis and glutamine depletion attenuated TGF-β/FBS-stimulated growth of COPD ASMCs.Changes in glycolysis, glutamine and fatty acid metabolism may lead to increased biosynthesis and redox balance, supporting COPD ASMC growth.
Page C, O'Shaughnessy B, Barnes P, 2017, Pathogenesis of COPD and Asthma., Pharmacology and Therapeutics of Asthma and COPD. Handbook of Experimental Pharmacology, Publisher: Springer, Pages: 1-21, ISBN: 978-3-319-52173-2
Asthma and COPD remain two diseases of the respiratory tract with unmet medical needs. This review considers the current state of play with respect to what is known about the underlying pathogenesis of these two chronic inflammatory diseases of the lung. The review highlights why they are different conditions requiring different approaches to treatment and provides a backdrop for the subsequent chapters in this volume discussing recent advances in the pharmacology and treatment of asthma and COPD.
Birch J, Barnes PJ, Passos JF, 2017, Mitochondria, telomeres and cell senescence: Implications for lung ageing and disease, Pharmacology and Therapeutics, Vol: 183, Pages: 34-49, ISSN: 0163-7258
Cellular senescence, the irreversible loss of replicative capacity in somatic cells, plays a causal role in the development of age-related pathology and in a number of age-related chronic inflammatory diseases. The ageing lung is marked by an increasing number of senescent cells, and evidence is mounting that senescence may directly contribute to a number of age-related respiratory diseases, including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Telomere dysfunction and alterations in mitochondrial homeostasis frequently occur in cellular senescence and are important to the development of the often detrimental senescence-associated secretory phenotype (SASP). The roles of telomeres, the mitochondria and cellular senescence in lung ageing and disease are discussed. Therapeutic interventions targeting cellular senescence are considered for delaying or potentially reversing age-related respiratory disease.
Bewley MA, Preston JA, Mohasin M, et al., 2017, Impaired Mitochondrial Microbicidal Responses in Chronic Obstructive Pulmonary Disease Macrophages, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 196, Pages: 845-855, ISSN: 1073-449X
Usmani OS, Kemppinen A, Gardener E, et al., 2017, A randomized pragmatic trial of changing to and stepping down Fluticasone/formoterol in asthma, Journal of Allergy and Clinical Immunology: In Practice, Vol: 5, Pages: 1378-1387.e5, ISSN: 2213-2198
BACKGROUND: Guidelines recommend reducing treatment in patients with well-controlled asthma after 3 months of stability. However, there is inadequate real-life data to guide physicians on therapy change in daily practice. OBJECTIVE: To assess asthma control after change to and step-down of fluticasone propionate/formoterol fumarate dihydrate (FP/FOR) in real-life patients. METHODS: In a randomized controlled, pragmatic, open-label trial, 225 well-controlled patients with asthma were randomized (1:2) to maintain high-dose fluticasone propionate/salmeterol xinafoate (FP/SAL, 1000/100 μg) or switch to FP/FOR (1000/40 μg) daily for 12 weeks (phase 1). One hundred sixteen patients stable on FP/FOR at week 12 were subsequently randomized (1:1) to maintain this therapy, or stepped down to FP/FOR (500/20 μg) daily for 12 weeks (phase 2). The primary end point was the 7-question Asthma Control Questionnaire (ACQ7) score. RESULTS: In phase 1, FP/FOR (1000/40 μg) (n = 126) was noninferior to FP/SAL (1000/100 μg) (n = 73) for ACQ7 (difference in means, -0.12; 95% CI, -0.32 to 0.09). In phase 2, FP/FOR (500/20 μg) (n = 52) was noninferior to FP/FOR (1000/40 μg) (n = 52) for ACQ7 (difference in means, 0.01; 95% CI, -0.20 to 0.22). There was no significant difference in exacerbation rate between the groups in either phase. However, 1 to 2 exacerbations in 12 months before phase 1 were associated with the occurrence of an exacerbation after step-down (P = .007). CONCLUSIONS: In patients with well-controlled asthma, a change from FP/SAL to FP/FOR did not compromise asthma control. Step-down of FP/FOR was well tolerated; however, in contrast to current guidelines, our data suggest caution in stepping down patients uncontrolled in the last 12 months. Larger step-down studies are required to confirm these findings.
Tambascio J, Dutra de Souza HC, Martinez R, et al., 2017, Effects of an Airway Clearance Device on Inflammation, Bacteriology, and Mucus Transport in Bronchiectasis, RESPIRATORY CARE, Vol: 62, Pages: 1067-1074, ISSN: 0020-1324
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