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  • 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

  • Conference paper
    Price L, Kempny A, Mccabe C, Dimopoulos K, Kotecha J, Harries C, Barbosa J, Hopkinson N, Simonds A, Wells A, Wort Jet al., 2018,

    Sildenafil in Patients with Severe Group 3 Pulmonary Hypertension

    , 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
  • Conference paper
    Garner J, Soni S, O'Dea K, Srikanthan K, Tenda E, Aboelhassan A, Singh S, Kemp SV, Wilson MR, Usmani OS, Shah PL, Takata Met al., 2018,

    Late Breaking Abstract - Intra-alveolar neutrophil-derived microvesicles: a biomarker of COPD severity

    , 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
  • Conference paper
    Bolaji JA, Adcock JJ, Sandstrom T, Mudway I, Bloomberg A, Bosson J, Tetley TD, Birrell MA, Belvisi MGet al., 2018,

    Biodiesel: is it any safer to use?

    , 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
  • Conference paper
    Wortley M, Bonvini SJ, Flajolet PLM, Belvisi MG, Birrell MAet al., 2018,

    The anti-tussive effects of an inhaled LABA are maintained after chronic treatment

    , 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
  • Journal article
    Mackay AJ, Kostikas K, Murray L, Martinez FJ, Miravitlles M, Donaldson G, Banerji D, Patalano F, Wedzicha JAet al., 2018,

    Patient reported outcomes for the detection, quantification and evaluation of chronic obstructive pulmonary disease exacerbations

    , American Journal of Respiratory and Critical Care Medicine, Vol: 198, Pages: 730-738, ISSN: 1073-449X

    An exacerbation of Chronic Obstructive Pulmonary Disease (COPD) is an acute worsening of respiratory symptoms, accompanied by a variable degree of physiological deterioration. The traditional assessment of an exacerbation consists of the reporting of symptoms directly by the patient to a clinician and subsequent clinical assessment. It would be valuable to also gather symptom reports directly from patients and thus patient-reported outcome (PRO) tools should be ideally suited to the evaluation of COPD exacerbations. However, most pharmaceutical and large academic-sponsored studies have used a healthcare resource utilization definition alone based on sustained worsening of a patient's condition from the stable state that requires a change in regular medication. This review explores the use of PROs for the detection, quantification, and evaluation of COPD exacerbations. It examines symptom diary cards as exacerbation detection tools and their evolution into electronic diaries used in pharmaceutical trials. This paper also describes the development of specifically designed PROs that have been used in exacerbation settings, focusing on the Exacerbations and Symptoms in COPD (ESCO) e-Diary, EXAcerbations of Chronic Obstructive Pulmonary Disease Tool (EXACT®), COPD Assessment Test™ (CAT) and Chronic Respiratory Disease Questionnaire (CRQ), highlighting the strengths and weaknesses of these instruments. We describe the effectiveness of these tools to enhance exacerbation reporting, quantify exacerbation characteristics, including the frequency, duration, and severity of events, and evaluate the outcome. We also explore the potential use of PROs in future studies to discriminate the effect of therapies on different exacerbation phenotypes and thus enhance personalized therapeutic approaches.

  • Conference paper
    Chen X, Bonvini SJ, Dubuis E, Birrell MA, Belvisi MGet al., 2018,

    Characterisation of TRPA1 activation on sensory nerves

    , 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
  • Journal article
    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.

  • Conference paper
    Finney L, Belchamber K, Fenwick P, Kemp S, Johnston S, Donnelly L, Wedzicha Jet al., 2018,

    Human rhinovirus impairs macrophage innate immune responses to bacteria via the interferon pathway in COPD

    , 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
  • Journal article
    Morrell MJ, 2018,

    Controlling for Obesity in OSA: Results from Dynamic MR Imaging.

    , Am J Respir Crit Care Med
  • Journal article
    Wedzicha JA, Martinez FD, 2018,

    Asthma: upcoming themed issue

    , American Journal of Respiratory and Critical Care Medicine, Vol: 198, Pages: 549-549, ISSN: 1073-449X
  • Journal article
    Harhay MO, Porcher R, Cantu E, Crowther MJ, Christie JD, Thabut G, Donaldson GCet al., 2018,

    An alternative approach for the analysis of time-to-event and survival outcomes in pulmonary medicine

    , American Journal of Respiratory and Critical Care Medicine, Vol: 198, ISSN: 1073-449X
  • Journal article
    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
    Maneechotesuwan K, Yao X, Ito K, Jazrawi E, Usmani OS, Adcock IM, Barnes PJet 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.].

  • Journal article
    Baker J, Vuppusetty C, Colley T, Hassibi S, Fenwick P, Donnelly L, Ito K, Barnes Pet 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.

  • Journal article
    Willis-Owen SAG, Thompson AR, Kemp P, Moffatt MF, Polkey M, Cookson W, Natanek Set al., 2018,

    COPD is accompanied by co-ordinated transcriptional perturbation in the quadriceps affecting the mitochondria and extracellular matrix

    , Scientific Reports, Vol: 8, ISSN: 2045-2322

    Skeletal muscle dysfunction is a frequent extra-pulmonary manifestation of Chronic Obstructive Pulmonary Disease (COPD) with implications for both quality of life and survival. The underlying biology nevertheless remains poorly understood. We measured global gene transcription in the quadriceps using Affymetrix HuGene1.1ST arrays in an unselected cohort of 79 stable COPD patients in secondary care and 16 healthy age- and gender-matched controls. We detected 1,826 transcripts showing COPD-related variation. Eighteen exhibited ≥2fold changes (SLC22A3, FAM184B, CDKN1A, FST, LINC01405, MUSK, PANX1, ANKRD1, C12orf75, MYH1, POSTN, FRZB, TNC, ACTC1, LINC00310, MYH3, MYBPH and AREG). Thirty-one transcripts possessed previous reported evidence of involvement in COPD through genome-wide association, including FAM13A. Network analysis revealed a substructure comprising 6 modules of co-expressed genes. We identified modules with mitochondrial and extracellular matrix features, of which IDH2, a central component of the mitochondrial antioxidant pathway, and ABI3BP, a proposed switch between proliferation and differentiation, represent hubs respectively. COPD is accompanied by coordinated patterns of transcription in the quadriceps involving the mitochondria and extracellular matrix and including genes previously implicated in primary disease processes.

  • Journal article
    Zafeiridou M, Hopkinson NS, Voulvoulis N, 2018,

    Cigarette Smoking: An assessment of tobacco's global environmental footprint across its entire supply chain.

    , Environmental Science and Technology, Vol: 52, Pages: 8087-8094, ISSN: 0013-936X

    While the health effects of cigarette smoking are well recognised and documented, the environmental impacts of tobacco are less appreciated and often overlooked. Here we evaluate tobacco's global footprint across its entire supply chain, looking at resources needs, wastes and emissions of the full cradle-to-grave life cycle of cigarettes. The cultivation of 32.4 Mt of green tobacco used for the production of 6.48 Mt of dry tobacco in the six trillion cigarettes manufactured worldwide in 2014, were shown to contribute almost 84 Mt CO2 eq emissions to climate change - approximately 0.2% of the global total, 490,000 tonnes 1,4 dichlorobenzene eq to ecosystem ecotoxicity levels, over 22 billion m3 and 21 Mt oil eq to water and fossil fuel depletion respectively. A typical cigarette was shown to have a water footprint of 3.7 litres, a climate change contribution of 14 g CO2 eq, and a fossil fuel depletion contribution of 3.5 g oil eq. Tobacco competes with essential commodities for resources and places significant pressures on the health of our planet and its most vulnerable inhabitants. Increased awareness as well as better monitoring and assessment of the environmental issues associated with tobacco should support the current efforts to reduce global tobacco use as an important element of sustainable development.

  • Journal article
    Chapman KR, Hurst JR, Frent S, Larbig M, Fogel R, Guerin T, Banerji D, Patalano F, Goyal P, Pfister P, Kostikas K, Wedzicha JAet al., 2018,

    Long-term triple therapy de-escalation to indacaterol/glycopyrronium in COPD patients (SUNSET): a randomized, double-blind, triple-dummy clinical trial

    , American Journal of Respiratory and Critical Care Medicine, Vol: 198, Pages: 329-339, ISSN: 1073-449X

    Rationale: There are no studies on ICS withdrawal in patients on long-term triple therapy in the absence of frequent exacerbations. Objective: To evaluate the efficacy and safety of the direct de-escalation from long-term triple therapy to indacaterol/glycopyrronium in non-frequently exacerbating COPD patients. Methods: This 26-week, randomized, double-blind, triple-dummy study assessed the direct change from long-term triple therapy to indacaterol/glycopyrronium (110/50μg once daily) or continuation of triple therapy (tiotropium 18μg once daily plus combination of salmeterol/fluticasone propionate [50/500μg] twice daily) in non-frequently exacerbating patients with moderate-to-severe COPD. Primary endpoint was non-inferiority on change from baseline in trough forced expiratory volume in 1 second (FEV1). Moderate or severe exacerbations were predefined secondary endpoints. Measurements and Main Results: 527 patients were randomized to indacaterol/glycopyrronium and 526 to triple therapy. ICS withdrawal led to a reduction in trough FEV1 of −26mL (95% confidence interval [CI], −53 to 1 mL) with confidence limits exceeding the non-inferiority margin of −50 mL. The annualized rate of moderate or severe COPD exacerbations did not differ between treatments (rate ratio 1.08; 95%CI, 0.83 to 1.40). Patients with ≥300 blood eosinophils/μL at baseline presented greater lung function loss and higher exacerbation risk. Adverse events were similar in the two groups. Conclusions: In COPD patients without frequent exacerbations on long-term triple therapy, the direct de-escalation to indacaterol/glycopyrronium led to a small decrease in lung function, with no difference in exacerbations. The higher exacerbation risk in patients with ≥300 blood eosinophils/µL suggests that these patients are likely to benefit from triple therapy. Clinical trial registration available at www.clinicaltrials.gov, ID NCT02603393.

  • Journal article
    Ritchie AI, Polkey MI, Donaldson GC, Wedzicha JAet al., 2018,

    Is peer review still anonymous?

    , American Journal of Respiratory and Critical Care Medicine, Vol: 198, Pages: 278-280, ISSN: 1073-449X
  • Journal article
    Schneider F, Waithe D, Galiani S, de la Serna JB, Sezgin E, Eggeling Cet al., 2018,

    Nanoscale spatiotemporal diffusion modes measured by simultaneous confocal and stimulated emission depletion nanoscopy imaging

    , Nano Letters, Vol: 18, Pages: 4233-4240, ISSN: 1530-6984

    The diffusion dynamics in the cellular plasma membrane provide crucial insights into molecular interactions, organization, and bioactivity. Beam-scanning fluorescence correlation spectroscopy combined with super-resolution stimulated emission depletion nanoscopy (scanning STED–FCS) measures such dynamics with high spatial and temporal resolution. It reveals nanoscale diffusion characteristics by measuring the molecular diffusion in conventional confocal mode and super-resolved STED mode sequentially for each pixel along the scanned line. However, to directly link the spatial and the temporal information, a method that simultaneously measures the diffusion in confocal and STED modes is needed. Here, to overcome this problem, we establish an advanced STED–FCS measurement method, line interleaved excitation scanning STED–FCS (LIESS–FCS), that discloses the molecular diffusion modes at different spatial positions with a single measurement. It relies on fast beam-scanning along a line with alternating laser illumination that yields, for each pixel, the apparent diffusion coefficients for two different observation spot sizes (conventional confocal and super-resolved STED). We demonstrate the potential of the LIESS–FCS approach with simulations and experiments on lipid diffusion in model and live cell plasma membranes. We also apply LIESS–FCS to investigate the spatiotemporal organization of glycosylphosphatidylinositol-anchored proteins in the plasma membrane of live cells, which, interestingly, show multiple diffusion modes at different spatial positions.

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