Imperial College London

Professor Peter Barnes, FRS

Faculty of MedicineNational Heart & Lung Institute

Senior Research Investigator
 
 
 
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Contact

 

+44 (0)20 7594 7959p.j.barnes Website

 
 
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Assistant

 

Miss Carolyn Green +44 (0)20 7594 7959

 
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Location

 

227CGuy Scadding BuildingRoyal Brompton Campus

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Summary

 

Publications

Publication Type
Year
to

2235 results found

Barnes PJ, Szefler SJ, Reddel HK, Chipps BEet al., 2019, Symptoms and perception of airway obstruction in asthma: clinical implications for use of reliever medications., J Allergy Clin Immunol

BACKGROUND: Asthma causes the unpleasant sensation of breathlessness (dyspnea) due to airway obstruction. Patients with poor perception of airway obstruction are at risk of delay in seeking medical attention and under-treatment, which can lead to avoidable deaths. Conversely, those with heightened perception are at risk of over-treatment and iatrogenic adverse effects with reliever medications, anxiety, and unnecessary use of healthcare resources. OBJECTIVE: To review evidence about symptom misperception in asthma and how to identify and manage affected patients, particularly with regard to reliever medications. METHODS: We conducted a systematic literature search for studies of perception of airway function in asthma. We searched the OVID [Medline and Medline (R) in process (PubMed)], Embase, and Adisearch/Odyssey databases, restricting our search to human studies published in English from 1990-2018, with no restrictions on age, gender, or racial origins. RESULTS: We found that both under- and over-perception, assessed during induced bronchoconstriction or bronchodilation or during changes in airway resistance, were common across all age groups, and that aging, disease severity, smoking, gender, ethnicity, psychological factors, and medication are all associated with differences in perception. Importantly, airway inflammation was associated with impaired perception and with a history of severe or near-fatal asthma. We also identified knowledge gaps, such as whether an individual patient's perception varies over time, and the influence perception has on patients' use of reliever medication. CONCLUSION: We found that abnormal perception of airway obstruction has important clinical implications for the management of patients with asthma.

Journal article

Belchamber K, Singh R, Batista C, Moira W, Dockrell D, Kilty I, Matthew R, Wedzicha J, Barnes P, Donnelly Let al., Defective bacterial phagocytosis is associated with dysfunctional mitochondria in COPD macrophages, European Respiratory Journal, ISSN: 0903-1936

Background: Increased reactive oxygen species (ROS) have been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). Objective: This study examined the effect of exogenous and endogenous oxidative stress on macrophage phagocytosis in patients with COPD. Methods: Monocyte-derived macrophages (MDM) were generated from non-smoker, smoker and COPD subjects, differentiated in either GM-CSF (G-Mϕ) or M-CSF (M-Mϕ). Alveolar macrophages were isolated from lung tissue or bronchoalveolar lavage. Macrophages were incubated +/- 200M H2O2 for 24 hours, then exposed to fluorescently-labelled H. influenzae or S. pneumoniae for 4 hours, after which phagocytosis, mitochondrial ROS (mROS), and mitochondrial membrane potential (m) were measured. Results: Phagocytosis of bacteria was significantly decreased in both G-Mϕ and M-Mϕ from COPD patients, compared to non-smoker controls. In non-smokers and smokers, bacterial phagocytosis did not alter mROS or m, however in COPD, phagocytosis increased early mROS and decreased m in both G-Mϕ and M-Mϕ. Exogenous oxidative stress reduced phagocytosis in non-smoker and COPD alveolar macrophages, and non-smoker MDM, associated with reduced mROS production. Conclusion: COPD macrophages show defective phagocytosis, which is associated with altered mitochondrial function and an inability to regulate mROS production. Targeting mitochondrial dysfunction may restore the phagocytic defect in COPD.

Journal article

Devereux G, Cotton S, Fielding S, McMeekin N, Barnes PJ, Briggs A, Burns G, Chaudhuri R, Chrystyn H, Davies L, De Soyza A, Gompertz S, Haughney J, Innes K, Kaniewska J, Lee A, Morice A, Norrie J, Sullivan A, Wilson A, Price Det al., 2019, Introduction, HEALTH TECHNOLOGY ASSESSMENT, Vol: 23, Pages: 1-+, ISSN: 1366-5278

Journal article

Efthimiou J, Poll C, Barnes PJ, 2019, Dual mechanism of action of T2 inhibitor therapies in virally induced exacerbations of asthma: evidence for a beneficial counter-regulation., Eur Respir J, Vol: 54

Biological agents such as omalizumab and monoclonal antibodies (mAbs) that inhibit type 2 (T2) immunity significantly reduce exacerbations, which are mainly due to viral infections, when added to inhaled corticosteroids in patients with severe asthma. The mechanisms for the therapeutic benefit of T2 inhibitors in reducing virally induced exacerbations, however, remain to be fully elucidated. Pre-clinical and clinical evidence supports the existence of a close counter-regulation of the high-affinity IgE receptor and interferon (IFN) pathways, and a potential dual mechanism of action and therapeutic benefit for omalizumab and other T2 inhibitors that inhibit IgE activity, which may enhance the prevention and treatment of virally induced asthma exacerbations. Similar evidence regarding some novel T2 inhibitor therapies, including mAbs and small-molecule inhibitors, suggests that such a dual mechanism of action with enhancement of IFN production working through non-IgE pathways might also exist. The specific mechanisms for this dual effect could be related to the close counter-regulation between T2 and T1 immune pathways, and potential key underlying mechanisms are discussed. Further basic research and better understanding of these underlying counter-regulatory mechanisms could provide novel therapeutic targets for the prevention and treatment of virally induced asthma exacerbations, as well as T2- and non-T2-driven asthma. Future clinical research should examine the effects of T2 inhibitors on IFN responses and other T1 immune pathways, in addition to any effects on the frequency and severity of viral and other infections and related exacerbations in patients with asthma as a priority.

Journal article

Leaker BR, Singh D, Nicholson GC, Hezelova B, Goodin T, Ozol-Godfrey A, Galluppi G, Barnes PJet al., 2019, Evaluation of systemic absorption and bronchodilator effect of glycopyrronium bromide delivered by nebulizer or a dry powder inhaler in subjects with chronic obstructive pulmonary disease, RESPIRATORY RESEARCH, Vol: 20, ISSN: 1465-993X

Journal article

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.

Journal article

Barnes PJ, Baker J, Donnelly LE, 2019, Cellular senescence as a mechanism and target in chronic lung diseases, American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X

Cellular senescence is now considered an important driving mechanism for chronic lung diseases, particularly COPD and idiopathic pulmonary fibrosis. Cellular senescence is due to replicative and stress-related senescence with activation of p53 and p16INK4a respectively, leading to activation of p21CIP1 and cell cycle arrest. Senescent cells secrete multiple inflammatory proteins known as the senescence-associated secretory phenotype (SASP), leading to low grade chronic inflammation, which further drives senescence. Loss of key anti-aging molecules sirtuin-1 and sirtuin-6 may be important in acceleration of aging and arises from oxidative stress reducing phosphatase PTEN, thereby activating PI3K (phosphoinositide-3-kinase) and mTOR (mammalian target of rapamycin). MicroRNA-34a, which is regulated by PI3K-mTOR signaling, plays a pivotal role in reducing sirtuin-1/6 and its inhibition with an antagomir results in their restoration, reducing markers of senescence, reducing SASP and reversing cell cycle arrest in epithelial cells from peripheral airways of COPD patients. MiR-570 is also involved in reduction of sirtuin-1 and cellular senescence and is activated by p38 MAP kinase. These miRNAs may be released from cells in extracellular vesicles that are taken up by other cells, thereby spreading senescence locally within the lung but outside the lung through the circulation; this may account for comorbidities of COPD and other lung diseases. Understanding the mechanisms of cellular senescence may result in new treatments for chronic lung disease, either by inhibiting PI3K-mTOR signaling, by inhibiting specific miRNAs or by deletion of senescent cells with senolytic therapies, already shown to be effective in experimental lung fibrosis.

Journal article

Singh D, Agusti A, Anzueto A, Barnes PJ, Bourbeau J, Celli BR, Criner GJ, Frith P, Halpin DMG, Han M, López Varela MV, Martinez F, Montes de Oca M, Papi A, Pavord ID, Roche N, Sin DD, Stockley R, Vestbo J, Wedzicha JA, Vogelmeier Cet al., 2019, Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease: The GOLD Science Committee Report 2019, European Respiratory Journal, ISSN: 0903-1936

Precision medicine is a patient specific approach that integrates all relevant clinical, genetic and biological information in order to optimise the therapeutic benefit relative to the possibility of side effects for each individual. Recent clinical trials have shown that higher blood eosinophil counts are associated with a greater efficacy of inhaled corticosteroids (ICS) in COPD patients. Blood eosinophil counts are a biomarker with potential to be used in clinical practice, to help target ICS treatment with more precision in COPD patients with a history of exacerbations despite appropriate bronchodilator treatment.The Global initiative for the management of chronic Obstructive Lung Disease (GOLD) 2017 pharmacological treatment algorithms, based on the ABCD assessment, can be applied relatively easily to treatment naïve individuals at initial presentation. However, their use is more problematic during follow up in patients who are already on maintenance treatment. There is a need for a different system to guide COPD pharmacological management during follow up.Recent large randomised controlled trials have provided important new information concerning the therapeutic effects of ICS and long-acting bronchodilators on exacerbations. The new evidence regarding blood eosinophils and inhaled treatments, and the need to distinguish between initial and follow up pharmacological management, led to changes in the GOLD pharmacological treatment recommendations. This paper explains the evidence and rationale for the GOLD 2019 pharmacological treatment recommendations.

Journal article

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.

Journal article

Criner GJ, Martinez FJ, Aaron S, Agusti A, Anzueto A, Bafadhel M, Barnes PJ, Bourbeau J, Chen R, Ewig J, Fabbri LM, Frith P, Halpin DMG, Han M, Montes de Oca M, Nishimura M, O'Donnell D, Papi A, Pavord I, Roche N, Rodriguez-Roisin R, Salvi S, Singh D, Sin DD, Stockley R, Lopez Varela MV, Vestbo J, Vogelmeier CF, Washko G, Wedzicha JA, Celli BRet 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

Journal article

Bateman E, O'Byrne PM, FitzGerald JM, Barnes PJ, Zhong N, Alagappan V, Whelan G, Lamarca R, Puu M, Reddel HKet 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

Conference paper

Jenkins CR, Wen F, Barnes PJ, Celli BR, Zhong N, Zheng J, Martin A, Berend Net 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

Conference paper

O'Byrne P, Bateman E, FitzGerald JM, Barnes PJ, Zhong N, Alagappan VKT, Ivanov S, Whelan G, Lamarca R, Puu M, Reddel HKet 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

Conference paper

Fenwick P, Taylor A, Ujetz J, Barnes PJ, Donnelly Let 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

Conference paper

Baker J, Fenwick PS, Tilman J, Barnes PJ, Donnelly LEet 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

Conference paper

Wrench CL, Baker JR, Fenwick PS, Donnelly LE, Barnes PJet 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

Conference paper

Anders KL, Belchamber KBR, Gaboriau DCA, Barnes PJ, Donnelly LEet al., 2019, Dynein Has Defective Activity in COPD Macrophage Phagocytosis, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Izuhara K, Barnes PJ, 2019, Can We Define Asthma-COPD Overlap (ACO) by Biomarkers?, J Allergy Clin Immunol Pract, Vol: 7, Pages: 146-147

Journal article

Ghosh B, Gaike AH, Pyasi K, Brashier B, Das VV, Londhe JD, Juvekar S, Shouche YS, Donnelly LE, Salvi SS, Barnes PJet al., 2018, Bacterial load and defective monocyte-derived macrophage bacterial phagocytosis in biomass-smoke COPD, European Respiratory Journal, 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.

Journal article

Hakim A, Khan Y, Esteban I, Meah S, Miller-Larsson A, Barnes PJ, Usmani OSet al., 2018, Low-dose budesonide/formoterol counteracts airway inflammation and improves lung function in COPD, American Journal of Respiratory and Critical Care Medicine, 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

Journal article

Barnes PJ, 2018, THERAPY FOR ASTHMA AND COPD, Publisher: BMJ PUBLISHING GROUP, Pages: A2-A3, ISSN: 0032-5473

Conference paper

Dunne A, Kawamatawong T, Fenwick P, Davies C, Tullett H, Barnes P, Donnelly Let al., 2018, Direct inhibitory rffect of the phosphodiesterase-4 inhibitor, roflumilast, on neutrophil migration in COPD, American Journal of Respiratory Cell and Molecular Biology, 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.

Journal article

Carpagnano GE, Scioscia G, Lacedonia D, Soccio P, Lepore G, Saetta M, Barbaro MPF, Barnes PJet 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

Journal article

Devereux G, Cotton S, Fielding S, McMeekin N, Bames PJ, Briggs A, Burns G, Chaudhuri R, Chrystyn H, Davies L, De Soyza A, Gompertz S, Haughney J, Innes K, Kaniewska J, Lee A, Morice A, Norrie J, Sullivan A, Wilson A, Price Det 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

Journal article

Jia M, Yan X, Jiang X, Wu Y, Xu J, Meng Y, Yang Y, Shan X, Zhang X, Mao S, Gu W, Pavlidis S, Barnes PJ, Adcock IM, Huang M, Yao Xet al., 2018, Ezrin, a Membrane Cytoskeleton Cross Linker Protein, as a Marker of Epithelial Damage in Asthma., Am J Respir Crit Care Med

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.

Journal article

Belchamber KBR, Thomas C, Dunne A, Barnes P, Donnelly Let 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

Journal article

O'Byrne P, Fitzgerald JM, Bateman ED, Barnes PJ, Zhong N, Keen C, Wang M, Lamarca R, Puu M, Reddel HKet 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

Conference paper

Bewley M, Budd R, Ryan E, Cole J, Collini P, Marshall J, Kolsum U, Beech G, Emes R, Tcherniaeva I, Berbers G, Walmsley S, Donaldson G, Wedzicha J, Kilty I, Rumsey W, Sanchez Y, Brightling C, Donnelly LE, Barnes P, Singh D, Whyte M, Dockrell Det 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.

Journal article

Cazzola M, Calzetta L, Barnes PJ, Criner GJ, Martinez FJ, Papi A, Matera MGet 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

Conference paper

Tregoning JS, Mallia P, Webber J, Gill SK, Trujillo-Torralbo, Calderazzo MA, Finney L, Bakhsoliani E, Farne H, Singanayagam A, Footitt J, Hewitt R, Kebadze, Aniscenko J, Padmanaban V, Molyneaux PL, Adcock, Barnes PJ, Ito K, Elkin SL, Kon OM, Cookson WO, MOffatt MF, Johnston SLet 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

Journal article

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