Publications
256 results found
Finney LJ, Belchamber KBR, Mallia P, et al., 2016, HUMAN RHINOVIRUS IMPAIRS THE INNATE IMMUNE RESPONSE TO BACTERIA IN MONOCYTE DERIVED MACROPHAGES FROM PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE, British Thoracic Society Winter Meeting 2016, Publisher: BMJ PUBLISHING GROUP, Pages: A2-A2, ISSN: 0040-6376
Baker JR, Vuppusetty C, Colley T, et al., 2016, Oxidative stress dependent microRNA-34a activation via PI3Kα reduces the expression of sirtuin-1 and sirtuin-6 in epithelial cells, Scientific Reports, Vol: 6, ISSN: 2045-2322
Sirtuin-1 (SIRT1) and SIRT6, NAD(+)-dependent Class III protein deacetylases, are putative anti-aging enzymes, down-regulated in patients with chronic obstructive pulmonary disease (COPD), which is characterized by the accelerated ageing of the lung and associated with increased oxidative stress. Here, we show that oxidative stress (hydrogen peroxide) selectively elevates microRNA-34a (miR-34a) but not the related miR-34b/c, with concomitant reduction of SIRT1/-6 in bronchial epithelial cells (BEAS2B), which was also observed in peripheral lung samples from patients with COPD. Over-expression of a miR-34a mimic caused a significant reduction in both mRNA and protein of SIRT1/-6, whereas inhibition of miR-34a (antagomir) increased these sirtuins. Induction of miR-34a expression with H2O2 was phosphoinositide-3-kinase (PI3K) dependent as it was associated with PI3Kα activation as well as phosphatase and tensin homolog (PTEN) reduction. Importantly, miR-34a antagomirs increased SIRT1/-6 mRNA levels, whilst decreasing markers of cellular senescence in airway epithelial cells from COPD patients, suggesting that this process is reversible. Other sirtuin isoforms were not affected by miR-34a. Our data indicate that miR-34a is induced by oxidative stress via PI3K signaling, and orchestrates ageing responses under oxidative stress, therefore highlighting miR-34a as a new therapeutic target and biomarker in COPD and other oxidative stress-driven aging diseases.
Bewley M, Belchamber K, Chana K, et al., 2016, Differential effects of p38, MAPK, PI3K or Rho kinase inhibitors on bacterial phagocytosis and efferocytosis by macrophages in COPD, PLOS One, Vol: 11, ISSN: 1932-6203
Pulmonary inflammation and bacterial colonization are central to the pathogenesis of chronic obstructive pulmonary disease (COPD). Defects in macrophage phagocytosis of both bacteria and apoptotic cells contribute to the COPD phenotype. Small molecule inhibitors with anti-inflammatory activity against p38 mitogen activated protein kinases (MAPKs), phosphatidyl-inositol-3 kinase (PI3K) and Rho kinase (ROCK) are being investigated as novel therapeutics in COPD. Concerns exist, however, about off-target effects. We investigated the effect of p38 MAPK inhibitors (VX745 and SCIO469), specific inhibitors of PI3K α (NVS-P13K-2), δ (NVS-P13K-3) or γ (NVS-P13K-5) and a ROCK inhibitor PF4950834 on macrophage phagocytosis, early intracellular killing of bacteria and efferocytosis of apoptotic neutrophils. Alveolar macrophages (AM) obtained from broncho-alveolar lavage (BAL) or monocyte-derived macrophages (MDM) from COPD patients (GOLD stage II/III) enrolled from a well characterized clinical cohort (MRC COPD-MAP consortium) or from healthy ex-smoker controls were studied. Both COPD AM and MDM exhibited lower levels of bacterial phagocytosis (using Streptococcus pneumoniae and non-typeable Haemophilus influenzae) and efferocytosis than healthy controls. None of the inhibitors altered bacterial internalization or early intracellular bacterial killing in AM or MDM. Conversely PF4950834, but not other inhibitors, enhanced efferocytosis in COPD AM and MDM. These results suggest none of these inhibitors are likely to exacerbate phagocytosis-related defects in COPD, while confirming ROCK inhibitors can enhance efferocytosis in COPD.
Batista C, McIntosh M, Hansel T, et al., 2016, Elevated concentrations of CXCL8 in the nasal mucosal lining fluid of COPD patients as an accessible surrogate measure of bronchial levels, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Nicholson GC, Holloway RA, Leaker BR, et al., 2016, A novel flow cytometric-based method to measure kinase inhibition in sputum from COPD subjects, BMJ Open Respiratory Research, Vol: 3, ISSN: 2052-4439
INTRODUCTION: Janus kinases (JAKs) regulate inflammatory gene expression through phosphorylation of signal transducer and activator of transcription (STAT) proteins. Expression of STAT proteins is increased in chronic obstructive pulmonary disease (COPD), and may be involved in driving chronic inflammation. Oral JAK inhibitors are effective as anti-inflammatory therapy but exhibit dose-limiting adverse effects. Development of inhaled compounds would be enhanced by robust biomarkers that directly reflect the anti-inflammatory and pharmacological activity in the lung. METHODS: A novel flow cytometry assay was developed to measure STAT1 phosphorylation in sputum inflammatory cells. The standard sputum processing method was refined to improve sputum cell viability. The flow cytometric assay was used to assess the reproducibility of the measurement of STAT1 phosphorylation and the in vitro activity of a pan JAK-inhibitor on three separate visits in patients with COPD. RESULTS: Upregulation of STAT1 phosphorylation was measured following in vitro IFNγ stimulation of sputum macrophages (stimulated/unstimulated ratio 1.57; p<0.00001). Upregulation was inhibited following in vitro preincubation with a pan JAK-inhibitor (inhibited+stimulated/unstimulated ratio 0.97). STAT1 phosphorylation activity could only be measured in macrophages. CONCLUSIONS: Sputum from patients with COPD can be used to reproducibly measure phospho-STAT expression in sputum macrophages. The flow cytometry-based method can be used to evaluate kinase inhibitors in vitro and subsequently in ex vivo studies. The assay is particularly useful for the assessment of inhaled compounds where whole blood assays may not be relevant.
Donnelly LE, 2016, Could Protecting the Immunoproteasome Reduce Exacerbations in Chronic Obstructive Pulmonary Disease?, American Journal of Respiratory and Critical Care Medicine, Vol: 193, Pages: 1188-1190, ISSN: 1535-4970
Costa C, Traves S, Tudhope SJ, et al., 2016, Enhanced monocyte migration to CXCR3 and CCR5 chemokines in COPD, European Respiratory Journal, Vol: 47, ISSN: 1399-3003
Chronic obstructive pulmonary disease (COPD) patients exhibit chronic inflammation, both in the lung parenchyma and the airways, which is characterised by an increased infiltration of macrophages and T-lymphocytes, particularly CD8+ cells. Both cell types can express chemokine (C-X-C motif) receptor (CXCR)3 and C-C chemokine receptor 5 and the relevant chemokines for these receptors are elevated in COPD. The aim of this study was to compare chemotactic responses of lymphocytes and monocytes of nonsmokers, smokers and COPD patients towards CXCR3 ligands and chemokine (C-C motif) ligand (CCL)5.Migration of peripheral blood mononuclear cells, monocytes and lymphocytes from nonsmokers, smokers and COPD patients toward CXCR3 chemokines and CCL5 was analysed using chemotaxis assays.There was increased migration of peripheral blood mononuclear cells from COPD patients towards all chemokines studied when compared with nonsmokers and smokers. Both lymphocytes and monocytes contributed to this enhanced response, which was not explained by increased receptor expression. However, isolated lymphocytes failed to migrate and isolated monocytes from COPD patients lost their enhanced migratory capacity.Both monocytes and lymphocytes cooperate to enhance migration towards CXCR3 chemokines and CCL5. This may contribute to increased numbers of macrophages and T-cells in the lungs of COPD patients, and inhibition of recruitment using selective antagonists might be a treatment to reduce the inflammatory response in COPD.
Singh D, Donnelly LE, 2016, Now We Know Who You Are: A Clear Description of Mononuclear Phagocyte Subsets in the Human Lung, American Journal of Respiratory and Critical Care Medicine, Vol: 193, Pages: 594-596, ISSN: 1073-449X
Tilman J, Barnes PJ, Donnelly L, 2016, Gm-Csf Drives Human Lung Tissue Macrophages Towards A More Pro-Inflammatory Phenotype, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Belchamber KBR, Shah A, Barnes PJ, et al., 2016, Defective Phagocytosis Of Aspergillus Fumigatus By COPD Macrophages, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Finney LJ, Belchamber KBR, Edwards MR, et al., 2016, Rhinovirus Impairs Phagocytosis Of Bacteria By Monocyte Derived Macrophages In Chronic Obstructive Pulmonary Disease, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Donaldson GC, Belchamber KBR, Singh R, et al., 2016, Dissociation Between Airway And Systemic Inflammatory Changes At Exacerbation In COPD, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Singh R, Mackay A, Brill S, et al., 2015, Effect of lower airway bacterial colonisation on time to acute exacerbation in patients with COPD, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Davies C, Rhodes JA, Barnes P, et al., 2015, Elevated CCL2 responses in COPD and attenuation by selective chemokine receptor antagonists, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Ghosh B, Pyasi K, Londhe J, et al., 2015, Monocyte-derived macrophages from non-smoker COPD subjects exhibit defective bacterial phagocytosis, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Tilman J, Day A, Madge N, et al., 2015, Macrophage phenotype does not affect protease anti-protease imbalance in COPD, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Day A, Barnes P, Donnelly L, 2015, Monocyte sub-populations do not reflect differences in COPD macrophage phenotype, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Madge N, Donnelly L, Rogers D, 2015, Neutrophil elastase contributes to activated human neutrophil-induced rat small airway dysfunction, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Loveridge A, Rhodes JA, Barnes P, et al., 2015, Differential cigarette smoke and H<sub>2</sub>O<sub>2</sub> induced cytokine release from macrophages in COPD, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Belchamber K, Singh R, Wedzicha J, et al., 2015, Elevated mitochondrial reactive oxygen species in COPD macrophages at exacerbation, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Yeo SCM, Fenwick PS, Barnes PJ, et al., 2015, Anti-inflammatory effects of resveratrol analogues in cellular models of airway inflammation, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Fenwick PS, Macedo P, Barnes PJ, et al., 2015, Effect of JAK inhibitors on release of CXCL9, CXCL10 and CXCL11 from human airway epithelial cells, PLOS One, Vol: 10, ISSN: 1932-6203
BackgroundCD8+ T-cells are located in the small airways of COPD patients and may contribute to pathophysiology. CD8+ cells express the chemokine receptor, CXCR3 that binds CXCL9, CXCL10 and CXCL11, which are elevated in the airways of COPD patients. These chemokines are released from airway epithelial cells via activation of receptor associated Janus kinases (JAK). This study compared the efficacy of two structurally dissimilar pan-JAK inhibitors, PF956980 and PF1367550, and the glucocorticosteroid dexamethasone, in BEAS-2B and human primary airway epithelial cells from COPD patients and control subjects.MethodsCells were stimulated with either IFNγ alone or with TNFα, and release of CXCL9, CXCL10 and CXCL11 measured by ELISA and expression of CXCL9, CXCL10 and CXCL11 by qPCR. Activation of JAK signalling was assessed by STAT1 phosphorylation and DNA binding.ResultsThere were no differences in the levels of release of CXCL9, CXCL10 and CXCL11 from primary airway epithelial cells from any of the subjects or following stimulation with either IFNγ alone or with TNFα. Dexamethasone did not inhibit CXCR3 chemokine release from stimulated BEAS-2B or primary airway epithelial cells. However, both JAK inhibitors suppressed this response with PF1367550 being ~50-65-fold more potent than PF956980. The response of cells from COPD patients did not differ from controls with similar responses regardless of whether inhibitors were added prophylactically or concomitant with stimuli. These effects were mediated by JAK inhibition as both compounds suppressed STAT1 phosphorylation and DNA-binding of STAT1 and gene transcription.ConclusionsThese data suggest that the novel JAK inhibitor, PF1367550, is more potent than PF956980 and that JAK pathway inhibition in airway epithelium could provide an alternative anti-inflammatory approach for glucocorticosteroid-resistant diseases including COPD.
Ilott NE, Heward JA, Roux B, et al., 2015, Long non-coding RNAs and enhancer RNAs regulate the lipopolysaccharide-induced inflammatory response in human monocytes (vol 5, 3979, 2014), Nature Communications, Vol: 6, ISSN: 2041-1723
Day AMW, Barnes PJ, Donnelly LE, 2015, Differential macrophage functions in COPD are not reflected by cell surface markers, ERS Lung Science Conference
Belchamber KBR, Singh R, Wedzicha JA, et al., 2015, Elevated Mitochondrial Reactive Oxygen Species In COPD Macrophages At Exacerbation And With Bacterial Phagocytosis, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
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Belchamber KBR, Holloway R, Dunne A, et al., 2015, Comparison Of Budesonide And Fluticasone Propionate On COPD Macrophage And Neutrophil Phagocytosis And Killing Of Bacteria, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Bewley MA, Budd R, Singh D, et al., 2015, Bacterial Phagocytosis And Killing Is Unaltered By P38 Mapk, Rho Kinase Or Pi3k Inhibition In COPD Alveolar Macrophages, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Singh R, Belchamber K, Donaldson GC, et al., 2015, The Independent Effect Of Bacterial And Viral Pathogens On Sputum Inflammatory Markers At COPD Exacerbation, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Belchamber K, Singh R, Wedzicha J, et al., 2014, Oxidative stress drives defective efferocytosis in COPD M2-like macrophages, Publisher: WILEY-BLACKWELL, Pages: 156-157, ISSN: 0019-2805
Bewley MA, Budd R, Singh D, et al., 2014, Alveolar macrophages from COPD patients show reduced apoptosis and bacterial killing linked to a failure to induce mitochondrial reactive oxygen species upon Spn challenge, Publisher: WILEY-BLACKWELL, Pages: 113-113, ISSN: 0019-2805
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