Publications
2499 results found
Dunne A, Kawamatawong T, Fenwick P, et al., 2019, Direct inhibitory rffect of the phosphodiesterase-4 inhibitor, roflumilast, on neutrophil migration in COPD, American Journal of Respiratory Cell and Molecular Biology, Vol: 60, Pages: 445-453, ISSN: 1044-1549
Neutrophilic inflammation is characteristic of COPD, yet there are no effective anti-inflammatory therapies. The phosphodiesterase (PDE)4 inhibitor, roflumilast is approved for use in COPD and suppresses sputum neutrophilia. The mechanism underlying this observation is unclear and therefore this study addressed whether roflumilast directly affected neutrophil migration. Blood-derived neutrophils were isolated from non-smokers, smokers and COPD patients and chemotaxis measured using Boyden chambers. Intracellular calcium ion concentration ([Ca2+]i) was measured by fluorimetry and shape change and CD11b expression by flow cytometry. Neutrophils from COPD patients showed enhanced chemotactic responses towards both CXCL1 and LTB4 compared with control cells. Chemotaxis was inhibited by both the active metabolite, roflumilast-N-oxide, and rolipram in a concentration-dependent manner with no difference in responsiveness between subjects. Roflumilast-N-oxide and rolipram were less efficacious against CXCL1 and LTB4-mediated [Ca2+]i suggesting that inhibition was not via this pathway. Both PDE4 inhibitors attenuated chemoattractant-mediated shape change and CD11b up-regulation suggesting common mechanisms. The stable cAMP analogue, 8-Br-cAMP, inhibited chemotaxis, as did the direct Epac1 activator 8-pCPT-2’-O-Me-cAMP but not the direct PKA activator, 6-Bnz-cAMP. These data suggest that roflumilast inhibits neutrophil chemotaxis directly via a cAMP-mediated mechanism requiring activation of Epac1, and that Epac1 activators could reduce COPD neutrophilic inflammation.
Barnes PJ, 2019, Pulmonary Diseases and Ageing., Subcell Biochem, Vol: 91, Pages: 45-74, ISSN: 0306-0225
Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis are regarded as a diseases of accelerated lung ageing and show all of the hallmarks of ageing, including telomere shortening, cellular senescence, activation of PI3 kinase-mTOR signaling, impaired autophagy, mitochondrial dysfunction, stem cell exhaustion, epigenetic changes, abnormal microRNA profiles, immunosenescence and a low grade chronic inflammation due to senescence-associated secretory phenotype (SASP). Many of these ageing mechanisms are driven by exogenous and endogenous oxidative stress. There is also a reduction in anti-ageing molecules, such as sirtuins and Klotho, which further accelerate the ageing process. Understanding these molecular mechanisms has identified several novel therapeutic targets and several drugs and dietary interventions are now in development to treat chronic lung disease.
Barnes PJ, 2019, Inflammatory Endotypes in COPD., Allergy
Chronic obstructive pulmonary disease (COPD) is a major global health problem that is poorly treated by current therapies as it has proved difficult to treat the underlying inflammation, which is largely corticosteroid-resistant in most patients. Although rare genetic endotypes of COPD have been recognised, despite the clinical heterogeneity of COPD it has proved difficult to identify distinct inflammatory endotypes. Most patients have increased neutrophils and macrophages in sputum, reflecting the increased secretion of neutrophil and monocyte chemotactic mediators in the lungs. However, some patients also have increased eosinophils in sputum and this may be reflected by increased blood eosinophils. Increased blood and sputum eosinophils are associated with more frequent exacerbations and predict a good response to corticosteroids in reducing and treating acute exacerbations. Eosinophilic COPD may represent an overlap with asthma but the mechanism of eosinophilia are uncertain as, although an increase in sputum IL-5 has been detected, anti-IL-5 therapies are not effective in preventing exacerbations. More research is needed to link inflammatory endotypes to clinical manifestations and outcomes in COPD and in particular to predict response to precision medicines. This article is protected by copyright. All rights reserved.
Hakim A, Khan Y, Esteban I, et al., 2019, Low-dose budesonide/formoterol counteracts airway inflammation and improves lung function in COPD, American Journal of Respiratory and Critical Care Medicine, Vol: 199, Pages: 662-664, ISSN: 1073-449X
The latest Global Initiative for Chronic Obstructive Lung Disease (GOLD) document recommends new treatment algorithms, with inhaled corticosteroids (ICS) use only in moderate-to-severely symptomatic COPD patients with repeated exacerbations, where the emphasis is to review ICS use and to reduce ICS dosing (1). Indeed, safety concerns of pneumonia (2) with high-dose ICS has further concerted focus upon using appropriate doses of ICS. It is well-established that ICS in combination with long-acting β2-adrenoceptor agonist (LABA) can decrease exacerbations, improve symptomsand increase quality of life in patients with COPD (3-4), but nonetheless, the rationale to consider step-down of ICS is supported by several clinical studies (5). The Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management (WISDOM) trial studied severe COPD patients on therapy with ICS, LAMA and LABA, where stepwise withdrawal of ICS did not lead to an increase in exacerbations compared to continued ICS use (6). Determining the optimal dose of ICS and LABA combination therapy is of great biological and clinical importance in order to address safety concerns associated with high-dose ICS use. There is in vitro evidence to support the clinical practice of using low-dose ICS. Low-dose ICS in combination with LABA enhances corticosteroid function by enhancing glucocorticoid receptor (GR) activity (7) and suppresses the release of inflammatory mediators (8). However, it is unknown whether this observation of enhanced corticosteroid function with low-dose ICS/LABA has a direct effect on airways inflammation and lung function. Our study investigated the cellular function that may be relevant and underpin the clinical approach to lowering the dose of ICS therapy in COPD patients. We compared the single administra
Ghosh B, Gaike AH, Pyasi K, et al., 2019, Bacterial load and defective monocyte-derived macrophage bacterial phagocytosis in biomass-smoke COPD, European Respiratory Journal, Vol: 53, Pages: 1-14, ISSN: 0903-1936
Lower airway colonisation with potentially pathogenic bacterial species (PPBs) is associated with defective bacterial phagocytosis, in monocyte-derived macrophages (MDMs) and alveolar macrophages, from tobacco-smoke associated COPD (S-COPD) subjects. In developing world, COPD among non-smokers is largely due to biomass-smoke (BMS) exposure. Yet, little is known about PPBs colonisation and its association with impaired innate immunity in these subjects.We investigated the PPBs load (Streptococcus pneumoniae, SP; Haemophilus influenzae, HI; Moraxella catarrhalis, MC; and Pseudomonas aeruginosa, PA) in BMS-exposed COPD (BMS-COPD) compared with S-COPD and spirometrically normal subjects. We also examined the association between load of PPBs with phagocytic activity of MDMs and lung function.Induced sputum and peripheral venous blood samples were collected from 18 healthy non-smokers, 15 smokers without COPD, 16 BMS-exposed healthy, 19 S-COPD and 23 BMS-COPD subjects. PPBs load in induced sputum and MDMs phagocytic activity were determined using qPCR and fluorimetry respectively.Higher bacterial load of SP, HI, and PA were observed in BMS-COPD. Increased PPBs load in BMS-exposed subjects was significantly negatively associated with defective phagocytosis in MDMs, and spirometric lung function indices (p<0.05).Increased load of PPBs in airways of BMS-COPD subjects is inversely associated with defective bacterial phagocytosis and lung function.
Jia M, Yan X, Jiang X, et al., 2019, Ezrin, a membrane cytoskeleton cross-linker protein, as a marker of epithelial damage in asthma, American Journal of Respiratory and Critical Care Medicine, Vol: 199, Pages: 496-507, ISSN: 1073-449X
RATIONALE: Bronchial epithelial cell damage occurs in patients with bronchial asthma. Ezrin, a membrane-cytoskeleton protein, maintains cellular morphology and intercellular adhesion and protects the barrier function of epithelial cells. OBJECTIVES: To study the role of ezrin in bronchial epithelial cells injury and correlate its expression with asthma severity. METHODS: Levels of ezrin were measured in exhaled breath condensate (EBC) and serum in asthma patients and bronchoalveolar lavage fluid (BALF) from a mouse model of asthma by ELISA. The regulation of IL-13 on ezrin protein levels was studied in primary bronchial epithelial cells (PBECs). Ezrin knockdown using shRNA was studied in human bronchial epithelial 16HBE cells. RESULTS: Ezrin levels were decreased in asthmatic EBC (392.7±34.99 vs 150.5±10.22 pg/ml, p<0.0001) and serum (700.7±55.59 vs 279.2±25.83pg/ml, p<0.0001) compared to normal subjects. Levels were much lower in uncontrolled (p<0.001) and partly-controlled patients (p<0.01) compared to well-controlled subjects. EBC and serum ezrin levels correlated with lung function in asthma patients and serum ezrin levels were negatively correlated with serum IL-13 and periostin. IL-13-induced down-regulation of ezrin expression in PBECs was significantly attenuated by the JAK2 (Janus tyrosine kinase 2) inhibitor TG101348. Ezrin knockdown changed 16HBE cell morphology, enlarged intercellular spaces and increased their permeability. Ezrin expression was decreased in the lung tissue and BALF of 'asthmatic' mice and negatively correlated with BALF IL-13 level. CONCLUSIONS: Ezrin down-regulation is associated with IL-13-induced epithelial damage and might be a potential biomarker of asthma control.
Criner GJ, Martinez FJ, Aaron S, et al., 2019, Current Controversies in Chronic Obstructive Pulmonary Disease A Report from the Global Initiative for Chronic Obstructive Lung Disease Scientific Committee, ANNALS OF THE AMERICAN THORACIC SOCIETY, Vol: 16, Pages: 29-39, ISSN: 1546-3222
Caramori G, Adcock IM, Barnes PJ, et al., 2019, Drugs for the Treatment of Airway Disease, Nijkamp and Parnham’s Principles of Immunopharmacology: Fourth revised and extended edition, Pages: 425-474, ISBN: 9783030108090
Both ASTHMA and CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) are characterized by airflow obstruction and chronic inflammation of the lower airways, but there are important differences in inflammatory mechanisms and response to therapy between these diseases [1, 2]. This chapter discusses the pharmacology of the drugs used in the treatment of these obstructive airway diseases. These drugs include bronchodilators, which act mainly by reversing AIRWAY SMOOTH MUSCLE (ASM) contraction, and anti-inflammatory drugs, which in asthma suppress the inflammatory response in the airways. The most effective anti-inflammatory treatment for asthma is corticosteroids, which are covered in a separate chapter (C13). In COPD, no effective anti-inflammatory drugs are available, but several new classes of drug are now in development. We will not discuss the drug treatment of airway disease in the paediatric population for which we refer the interested readers to specific excellent textbooks (please see below the selected readings).
Baker J, Fenwick PS, Tilman J, et al., 2019, IL-36 gamma is Released from Small Airway Epithelial Cells and Drives Macrophage Inflammation in COPD, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Izuhara K, Barnes PJ, 2019, Can We Define Asthma-COPD Overlap (ACO) by Biomarkers?, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE, Vol: 7, Pages: 146-147, ISSN: 2213-2198
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Irwin RS, Heffner JE, Maxwell L, et al., 2019, Spread the Word About <i>CHEST</i> in 2019 Innovations, Introductions, and Farewells, CHEST, Vol: 155, Pages: 1-4, ISSN: 0012-3692
Jenkins CR, Wen F, Barnes PJ, et al., 2019, Theophylline and Systemic Corticosteroids in COPD: The TASCS Trial, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Anders KL, Belchamber KBR, Gaboriau DCA, et al., 2019, Dynein Has Defective Activity in COPD Macrophage Phagocytosis, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Wrench CL, Baker JR, Fenwick PS, et al., 2019, Senescence and Fibrotic Markers Are Induced by Oxidative Stress in Small Airway Fibroblasts from COPD Patients, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
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Bateman E, O'Byrne PM, FitzGerald JM, et al., 2019, Influence of Prior Treatment Upon the Efficacy of As-Needed Budesonide/Formoterol in Mild Asthma in the SYGMA 1 and 2 Studies, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Barnes PJ, 2019, Pharmacology of asthma and COPD, RESPIRATORY MEDICINE, 3RD EDITION, Editors: Palange, Rohde, Publisher: EUROPEAN RESPIRATORY SOCIETY, Pages: 344-352, ISBN: 978-1-84984-079-8
Gorlitz F, Lightley J, Kumar S, et al., 2019, Automated multiwell plate STORM: towards open source super-resolved high content analysis, Conference on Advances in Microscopic Imaging II, Publisher: SPIE-INT SOC OPTICAL ENGINEERING, ISSN: 0277-786X
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- Citations: 1
Barnes PJ, Vestbo J, Calverley PM, 2019, The Pressing Need to Redefine "COPD", CHRONIC OBSTRUCTIVE PULMONARY DISEASES-JOURNAL OF THE COPD FOUNDATION, Vol: 6, Pages: 380-383, ISSN: 2372-952X
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- Citations: 8
Singh DN, Arnepalli DN, 2019, Centrifuge Modeling of Contaminant Transport in Geomaterials, Environmental Science and Engineering, Publisher: Springer Singapore, Pages: 164-171, ISBN: 9789811322204
O'Byrne P, Bateman E, FitzGerald JM, et al., 2019, Efficacy of As-Needed Budesonide/Formoterol for Reducing Severe Exacerbations in Adolescents with Mild Asthma: Pooled Subgroup Analysis of the SYGMA 1 and 2 Trials, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Fenwick P, Taylor A, Ujetz J, et al., 2019, Antagonism of Sphingosine-1-Phosphate Receptors Improves Macrophage Phagocytosis of Bacteria in COPD Patients, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Barnes PJ, 2019, Chronic obstructive pulmonary disease, GENOMIC AND PRECISION MEDICINE: INFECTIOUS AND INFLAMMATORY DISEASE, 3RD EDITION, Editors: Tsalik, Woods, Publisher: ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD, Pages: 383-399, ISBN: 978-0-12-801496-7
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Barnes PJ, 2018, THERAPY FOR ASTHMA AND COPD, Publisher: BMJ PUBLISHING GROUP, Pages: A2-A3, ISSN: 0032-5473
Carpagnano GE, Scioscia G, Lacedonia D, et al., 2018, Looking for Airways Periostin in Severe Asthma Could It Be Useful for Clustering Type 2 Endotype?, CHEST, Vol: 154, Pages: 1083-1090, ISSN: 0012-3692
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- Citations: 22
Devereux G, Cotton S, Fielding S, et al., 2018, Effect of Theophylline as Adjunct to Inhaled Corticosteroids on Exacerbations in Patients With COPD A Randomized Clinical Trial, JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, Vol: 320, Pages: 1548-1559, ISSN: 0098-7484
Belchamber KBR, Thomas C, Dunne A, et al., 2018, Comparison of fluticasone propionate and budesonide on COPD macrophage and neutrophil function, International Journal of COPD, Vol: 2018, Pages: 2883-2897, ISSN: 1176-9106
Background: Inhaled corticosteroid (ICS) use is associated with increased rates of pneumonia in COPD patients. The underlying mechanism is unknown although recent data suggest that pneumonia is more frequent in patients treated with fluticasone propionate (FP) than budesonide. Macrophages and neutrophils from COPD patients are deficient in clearing bacteria and this might explain increased bacterial colonisation in COPD. ICS may further suppress this response; therefore, we examined the effect of FP and budesonide on phagocytosis of common respiratory pathogens by monocyte-derived macrophages (MDM) and neutrophils.Methods: MDM from COPD patients (n=20-24) were pre-incubated with FP or budesonide for 1 or 18 h after which phagocytosis of fluorescently labelled inert beads or heat-killed Haemophilus influenzae or Streptococcus pneumoniae were measured fluorimetrically after 1 or 4 h. Additionally, the following was measured: CXCL-8, IL-6 and TNFα concentrations in supernatants by ELISA, MDM scavenger receptor expression by flow cytometry, and the MDM ability to kill bacteria. Neutrophils from COPD patients (n=8) were pre-incubated with corticosteroids for 1 h, and phagocytosis of bacteria was measured by flow cytometry. Results: After 1 h pre-incubation, neither corticosteroid altered MDM phagocytosis of beads or H. influenzae; however, budesonide (10-7M) increased phagocytosis of S. pneumoniae by 23% (P<0.05). After 18 h pre-incubation, neither corticosteroid altered MDM phagocytosis of any prey, although phagocytosis of H. influenzae by budesonide was significantly greater compared to FP at 10-6 and 10-5M (P<0.05). The 1 h pre-incubation with either corticosteroid inhibited bacteria-induced CXCL-8 release (at 10-7 and 10-5M, P<0.05); however, this effect was lost at 18 h pre-incubation. There was no change in receptor expression, bacterial killing or neutrophil phagocytosis by either corticosteroid. Conclusions: These data suggest that dissolved FP an
Bhandari A, Baker J, Donnelly L, et al., 2018, Metformin regulates sirtuin expression in airway epithelial cells, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Cazzola M, Calzetta L, Barnes PJ, et al., 2018, Efficacy and safety profile of xanthines in COPD: a network meta-analysis, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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O'Byrne P, Fitzgerald JM, Bateman ED, et al., 2018, Late Breaking Abstract - Risk of a severe exacerbation following higher reliever use: post-hoc analysis of SYGMA 1 in mild asthma, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Wrench C, Baker J, Fenwick P, et al., 2018, Small airway fibroblasts from COPD patients are senescent and pro-fibrotic, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 4
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