Publications
256 results found
Donnelly LE, Barnes PJ, 2012, Defective Phagocytosis in Airways Disease, CHEST, Vol: 141, Pages: 1055-1062, ISSN: 0012-3692
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- Citations: 139
Koarai A, Traves SL, Fenwick PS, et al., 2012, Expression of muscarinic receptors by human macrophages., Eur Respir J, Vol: 39, Pages: 698-704
Macrophages increase in number and are highly activated in chronic obstructive pulmonary disease (COPD). Muscarinic receptor antagonists inhibit acetylcholine-stimulated release of neutrophilic chemoattractants, suggesting that acetylcholine may regulate macrophage responses. Therefore, expression and function of components of the non-neuronal cholinergic system in monocyte-macrophage cells was investigated. RNA was isolated from monocytes, monocyte-derived macrophages (MDMs), lung and alveolar macrophages from nonsmokers, smokers and COPD patients, and expression of the high-affinity choline transporter, choline acetyltransferase, vesicular acetylcholine transporter and muscarinic receptors (M(1)-M(5)) ascertained using real-time PCR. M(2) and M(3) receptor expression was confirmed using immunocytochemistry. Release of interleukin (IL)-8, IL-6 and leukotriene (LT)B(4) were measured by ELISA or EIA. All monocyte-macrophage cells expressed mRNA for components of the non-neuronal cholinergic system. Lung macrophages expressed significantly more M(1) mRNA compared with monocytes, and both lung macrophages and alveolar macrophages expressed the highest levels of M(3) mRNA. Expression of M(2) and M(3) protein was confirmed in MDMs and lung macrophages. Carbachol stimulated release of LTB(4) from lung macrophages (buffer 222.3 ± 75.1 versus carbachol 1,118 ± 622.4 pg · mL(-1); n = 15, p<0.05) but not IL-6 or IL-8. LTB(4) release was attenuated by the M(3) antagonist, 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP; half maximal effective concentration 5.2 ± 2.2 nM; n = 9). Stimulation of macrophage M(3) receptors promotes release of LTB(4), suggesting that anti-muscarinic agents may be anti-inflammatory.
Ward AJN, Chana KK, Thomas CM, et al., 2011, DIFFERENTIAL RESPONSES OF M1 AND M2 MONOCYTE-DERIVED MACROPHAGE PHENOTYPES IN COPD, Winter Meeting of the British-Thoracic-Society, Publisher: B M J PUBLISHING GROUP, Pages: A116-A116, ISSN: 0040-6376
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- Citations: 1
Thomas CMR, Taylor AE, Bruijnzeel P, et al., 2011, ASSOCIATION OF MICROTUBULE INSTABILITY WITH DEFECTIVE PHAGOCYTOSIS IN COPD, Winter Meeting of the British-Thoracic-Society, Publisher: B M J PUBLISHING GROUP, Pages: A26-A26, ISSN: 0040-6376
Pridgeon C, Bugeon L, Donnelly L, et al., 2011, Regulation of IL-17 in chronic inflammation in the human lung., Clin Sci (Lond), Vol: 120, Pages: 515-524
The regulation of human Th17 cell effector function by Treg cells (regulatory T-cells) is poorly understood. In the present study, we report that human Treg (CD4(+)CD25(+)) cells inhibit the proliferative response of Th17 cells but not their capacity to secrete IL (interleukin)-17. However, they could inhibit proliferation and cytokine production by Th1 and Th2 cells as determined by IFN-γ (interferon-γ) and IL-5 biosynthesis. Currently, as there is interest in the role of IL-17-producing cells and Treg cells in chronic inflammatory diseases in humans, we investigated the presence of CD4(+)CD25(+) T-cells and IL-17 in inflammation in the human lung. Transcripts for IL-17 were expressed in mononuclear cells and purified T-cells from lung tissue of patients with chronic pulmonary inflammation and, when activated, these cells secrete soluble protein. The T-cell-specific transcription factors RORCv2 (retinoic acid-related orphan receptor Cv2; for Th17) and FOXP3 (forkhead box P3; for Treg cells) were enriched in the T-cell fraction of lung mononuclear cells. Retrospective stratification of the patient cohort into those with COPD (chronic obstructive pulmonary disease) and non-COPD lung disease revealed no difference in the expression of IL-17 and IL-23 receptor between the groups. We observed that CD4(+)CD25(+) T-cells were present in comparable numbers in COPD and non-COPD lung tissue and with no correlation between the presence of CD4(+)CD25(+) T-cells and IL-17-producing cells. These results suggest that IL-17-expressing cells are present in chronically inflamed lung tissue, but there is no evidence to support this is due to the recruitment or expansion of Treg cells.
Donnelly LE, Barnes PJ, 2011, CHEMOKINE RECEPTOR CXCR2 ANTAGONISM TO PREVENT AIRWAYS INFLAMMATION, DRUGS OF THE FUTURE, Vol: 36, Pages: 465-472, ISSN: 0377-8282
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- Citations: 14
Mercado N, Thimmulappa R, Thomas CM, et al., 2011, Decreased histone deacetylase 2 impairs Nrf2 activation by oxidative stress., Biochem Biophys Res Commun, Vol: 406, Pages: 292-298
Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a crucial role in cellular defence against oxidative stress by inducing the expression of multiple anti-oxidant genes. However, where high levels of oxidative stress are observed, such as chronic obstructive pulmonary disease (COPD), Nrf2 activity is reduced, although the molecular mechanism for this defect is uncertain. Here, we show that down-regulation of histone deacetylase (HDAC) 2 causes Nrf2 instability, resulting in reduced anti-oxidant gene expression and increase sensitivity to oxidative stress. Although Nrf2 protein was clearly stabilized after hydrogen peroxide (H(2)O(2)) stimulation in a bronchial epithelial cell line (BEAS2B), Nrf2 stability was decreased and Nrf2 acetylation increased in the presence of an HDAC inhibitor, trichostatin A (TSA). TSA also reduced Nrf2-regulated heme-oxygenase-1 (HO-1) expression in these cells, and this was confirmed in acute cigarette-smoke exposed mice in vivo. HDAC2 knock-down by RNA interference resulted in reduced H(2)O(2)-induced Nrf2 protein stability and activity in BEAS2B cells, whereas HDAC1 knockdown had no effect. Furthermore, monocyte-derived macrophages obtained from healthy volunteers (non-smokers and smokers) and COPD patients showed a significant correlation between HDAC2 expression and Nrf2 expression (r=0.92, p<0.0001). Thus, reduced HDAC2 activity in COPD may account for increased Nrf2 acetylation, reduced Nrf2 stability and impaired anti oxidant defences.
Donnelly LE, Barnes PJ, 2011, Chemokine receptor CXCR2 antagonism to prevent airways inflammation, Drugs of the Future, Vol: 36, Pages: 465-472, ISSN: 0377-8282
Neutrophilic inflammation is associated with several pulmonary conditions, including chronic obstructive pulmonary disease (COPD), severe asthma and cystic fibrosis, and contributes to disease pathophysiology. The underlying inflammation in each of these diseases is resistant to glucocorticosteroid therapy and is therefore persistent and difficult to treat. The chemokine receptor CXCR2 is highly expressed on the surface of neutrophils and has been targeted by a number of pharmaceutical companies as a potential antiinflammatory therapy. CXCR2 receptor antagonists have been shown to inhibit neutrophil accumulation in a number of preclinical models of pulmonary inflammation and show good selectivity in human cells ex vivo. Few CXCR2 receptor antagonists have been reported in clinical trials, although SCH-527123 and SB-656933 have both been shown to be effective in reducing ozone-induced airways neutrophilia in healthy volunteers. Studies are now under way in patients with COPD and preliminary data have indicated efficacy for SCH-527123. Further studies on the effects of CXCR2 receptor antagonists are required; however, they appear to be promising, novel antiinflammatory therapies for a number of pulmonary inflammatory diseases. Copyright © 2011 Prous Science, S.A.U. or its licensors. All rights reserved.
Pridgeon C, Bugeon L, Donnelly L, et al., 2011, Regulation of IL-17 in chronic inflammation in the human lung, Clinical Science, Vol: 120, Pages: 515-524
Finney-Hayward TK, Popa MO, Bahra P, et al., 2010, Expression of Transient Receptor Potential C6 Channels in Human Lung Macrophages, AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, Vol: 43, Pages: 296-304, ISSN: 1044-1549
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- Citations: 46
Donnelly LE, Tudhope SJ, Fenwick PS, et al., 2010, Effects of formoterol and salmeterol on cytokine release from monocyte-derived macrophages., Eur Respir J, Vol: 36, Pages: 178-186
Pulmonary macrophages are a target for inhaled therapies. Combinations of long-acting beta(2)-agonists (LABA) and glucocorticosteroids have been developed for asthma and chronic obstructive pulmonary disease (COPD). This study examined two LABA, salmeterol and formoterol, and the glucocorticosteroid, budesonide, on cytokine release from monocyte-derived macrophages (MDM) to determine whether anti-inflammatory effects observed in patients are due to inhibition of macrophages. MDM were incubated in the absence or presence of LABA or budesonide prior to stimulation with lipopolysaccharide (LPS). Tumour necrosis factor (TNF)-alpha, granulocyte macrophage-colony stimulating factor (GM-CSF) and CXC chemokine ligand (CXCL)8 were measured by ELISA. Formoterol and salmeterol inhibited LPS-stimulated release of TNF-alpha (mean effective concentration (EC(50)) 2.4+/-1.8 and 3.5+/-2.7 nM, respectively; n = 11-16), GM-CSF (EC(50) 24.6+/-2.1 and 52.4+/-40.8 nM, respectively, n = 11-12) but not CXCL8 from LPS-stimulated MDM. Budesonide inhibited release of all three cytokines (EC(50) TNF-alpha: 1.2+/-0.4 nM; GM-CSF: 0.4+/-0.2 nM; CXCL8: 0.4+/-0.1 nM; n = 3-4). Formoterol but not salmeterol elevated cAMP in these cells. These effects were attenuated by beta-adrenoceptor antagonists, propranolol and ICI118551. Salmeterol (10(-7) M) also inhibited formoterol-induced cAMP and formoterol-mediated attenuation of cytokine release. Combining budesonide (0.3 nM) with formoterol, inhibited TNF-alpha release additively. LABA may inhibit inflammatory cytokine release from macrophages in a cAMP-independent manner and act additively with budesonide.
Taylor AE, Finney-Hayward TK, Quint JK, et al., 2010, Defective macrophage phagocytosis of bacteria in COPD, EUROPEAN RESPIRATORY JOURNAL, Vol: 35, Pages: 1039-1047, ISSN: 0903-1936
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- Citations: 251
Donnelly LE, 2010, Exhaled breath condensate: nitric oxide-related compounds, EXHALED BIOMARKERS, Editors: Horvath, DeJongste, Publisher: EUROPEAN RESPIRATORY SOCIETY, Pages: 207-216
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- Citations: 9
Fenwick PS, Kilty IC, Yeadon M, et al., 2010, Effects Of PF-956980, A Pan JAK Inhibitor, On Glucocorticosteroid Resistant Release Of CXCR3 Chemokines From Human bronchial Epithelial Cells, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Renshaw J, Fenwick P, Thomas C, et al., 2009, ROLE OF MUSCARINIC RECEPTORS IN REGULATION OF NEUTROPHILIC CHEMOKINE RELEASE FROM HUMAN LUNG MACROPHAGES, Winter Meeting of the British-Thoracic-Society, Publisher: B M J PUBLISHING GROUP, Pages: A136-A136, ISSN: 0040-6376
Thomas CMR, Saunders MA, Wedzicha JA, et al., 2009, DECREASED MACROPHAGE FUNCTION IN COPD, Winter Meeting of the British-Thoracic-Society, Publisher: B M J PUBLISHING GROUP, Pages: A55-A56, ISSN: 0040-6376
Finney-Hayward TK, Bahra P, Li S, et al., 2009, Leukotriene B4 release by human lung macrophages via receptor- not voltage-operated Ca2+ channels., Eur Respir J, Vol: 33, Pages: 1105-1112
Increased numbers of macrophages and neutrophils in the lung is a key feature of chronic obstructive pulmonary disease (COPD). The major neutrophil chemotactic agent in the airways of COPD patients is leukotriene (LT)B(4) and is released by macrophages. The present study examines the role and mechanism of Ca(2+) in platelet-activating factor (PAF)-stimulated LTB(4) release from human lung macrophages. Macrophages were isolated from lung tissue of subjects undergoing lung resection surgery and monocyte-derived macrophages (MDM) were obtained from nonsmokers, smokers without obstruction and COPD patients. Cells were stimulated with PAF and LTB(4) release and [Ca(2+)](i) was measured. Lung macrophages and MDM released LTB(4) following stimulation with PAF (mean effective concentration: 0.08+/-0.06 microM (n = 5) versus 0.17+/-0.12 microM (n = 17), respectively). Compared with MDM, lung macrophages released approximately eight-fold more LTB(4). Neither smoking nor COPD altered MDM responses. PAF-stimulated LTB(4) release was abrogated by ethylene glycol tetraacetic acid suggesting a role for extracellular Ca(2+). This was substantiated by using store-operated channel blockers econazole, SK&F96365 and Gd(3+). However, econazole and SK&F96365 were more effective in MDM than lung macrophages. Neither LOE908 nor nifedipine could attenuate this response. These data suggest that platelet-activating factor-stimulated leukotriene B(4) release from human lung macrophages is mediated, in part, by Ca(2+) influx through receptor- but not voltage-operated Ca(2+) channels.
Brown SM, Sturton RG, Koarai A, et al., 2009, Contribution of M2 and M3 Muscarinic Receptors in Small Airway Contraction, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Hidaka J, Wray JA, Itoh MN, et al., 2009, Inhibition of Th2 Cytokine Production from Differentiated T Cells by a Novel Anti-Inflammatory Agent., Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Taylor AE, Quint J, Wedzicha JA, et al., 2009, Microtubule Instability in COPD Leads to Defective Macrophage Phagocytosis of Bacteria, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Traves SL, Donnelly LE, 2008, Th17 cells in airway diseases, CURRENT MOLECULAR MEDICINE, Vol: 8, Pages: 416-426, ISSN: 1566-5240
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- Citations: 69
Donnelly LE, Rogers DF, 2008, Novel targets and drugs in inflammatory lung disease, CURRENT OPINION IN PHARMACOLOGY, Vol: 8, Pages: 219-221, ISSN: 1471-4892
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- Citations: 5
Costa C, Rufino R, Traves SL, et al., 2008, CXCR3 and CCR5 chemokines in induced sputum from patients with COPD, CHEST, Vol: 133, Pages: 26-33, ISSN: 0012-3692
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- Citations: 121
Tudhope SJ, Catley MC, Fenwick PS, et al., 2007, The role of IkappaB kinase 2, but not activation of NF-kappaB, in the release of CXCR3 ligands from IFN-gamma-stimulated human bronchial epithelial cells., J Immunol, Vol: 179, Pages: 6237-6245, ISSN: 0022-1767
The severity of chronic obstructive pulmonary disease correlates with increased numbers of cytotoxic CD8(+) T lymphocytes in the lung parenchyma. CD8(+) T lymphocytes release IFN-gamma which stimulates airway epithelial cells to produce CXCR3 chemokines leading to further recruitment of CD8(+) T lymphocytes. To evaluate the signaling pathways involved in regulation of CXCR3 ligands, the human bronchial epithelial cell line BEAS-2B was stimulated with IFN-gamma and the release of the CXCR3 ligands was measured by ELISA. The release of CXCL9, CXCL10, and CXCL11 was inhibited by an IkappaB kinase 2 (IKK2) selective inhibitor 2-[(Aminocarbonyl)amino]-5-[4-fluorophenyl]-3-thiophenecarboxamide (TPCA-1) (EC(50) values were 0.50 +/- 0.03, 0.17 +/- 0.06, and 0.45 +/- 0.10 microM, respectively (n = 6)) and an IKK1/2 selective inhibitor 2-amino-6-(2'cyclopropylemethoxy-6'-hydroxy-phenyl)-4-piperidin-3-yl-pyridine-3-carbonitrile (EC(50) values 0.74 +/- 0.40, 0.27 +/- 0.06, and 0.88 +/- 0.29 microM, respectively (n = 6)). The glucocorticosteroid dexamethasone had no effect on CXCR3 ligand release. The release of CXCL10 was most sensitive to inhibition by IKK2 and a role for IKK2 in CXCL10 release was confirmed by overexpression of dominant-negative adenoviral constructs to IKK2 (68.2 +/- 8.3% n = 5), but not of IKK1. Neither phosphorylation of IkappaBalpha, translocation of p65 to the nucleus, or activation of a NF-kappaB-dependent reporter (Ad-NF-kappaB-luc) were detected following stimulation of BEAS-2B cells with IFN-gamma. These data suggest that IKK2 is also involved in the IFN-gamma-stimulated release of the CXCR3 ligands through a novel mechanism that is independent NF-kappaB.
Tudhope SJ, Finney-Hayward TK, Nicholson AG, et al., 2007, Different MAP-Kinase-Dependent Cytokine Responses in Cells of the Monocyte Lineage, Journal of Pharmacological and Experimental Pharmaceutics
Grandhi S, Donnelly LE, Rogers DF, 2007, Phytoceuticals: the new 'physic garden' for asthma and chronic obstructive pulmonary disease., Expert Rev Respir Med, Vol: 1, Pages: 227-246
Phytoceuticals (non-nutritional but beneficial plant chemicals) merit investigation as pharmacotherapy for asthma and chronic obstructive pulmonary disease (COPD). Although asthma is mostly treated adequately, COPD is not. Thus, there is a need for new drugs with improved therapeutic benefit, especially in COPD. Recent interest in herbal remedies has redirected attention towards plants as sources of improved treatments for lung disease. Phytoceuticals from a variety of plants and plant products, including butterbur, English ivy, apples, chocolate, green tea and red wine, demonstrate broad-spectrum pharmacotherapeutic activities that could be exploited in the clinic. Well-designed clinical trials are required to determine whether these beneficial activities are reproduced in patients, with the prospect that phytoceuticals are the new physic garden for asthma and COPD.
Gwilt CR, Donnelly LE, Rogers DF, 2007, The non-neuronal cholinergic system in the airways: An unappreciated regulatory role in pulmonary inflammation?, PHARMACOLOGY & THERAPEUTICS, Vol: 115, Pages: 208-222, ISSN: 0163-7258
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- Citations: 131
Chivers JE, Gong W, King EM, et al., 2006, Analysis of the dissociated steroid RU24858 does not exclude a role for inducible genes in the anti-inflammatory actions of glucocorticoids, MOLECULAR PHARMACOLOGY, Vol: 70, Pages: 2084-2095, ISSN: 0026-895X
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- Citations: 57
Boyd RS, Donnelly LE, MacDermot J, 2006, Opiate-dependent changes in the sensitivity of adenylate cyclase to stimulatory agonists and 5'-guanylylimidodiphosphate are independent of G protein abundance and eukaryotic ADP-ribosyltransferase activity in NG108-15 cells, Journal of Neurochemistry, ISSN: 1471-4159
Smith SJ, Fenwick PS, Nicholson AG, et al., 2006, Inhibitory effect of p38 mitogen-activated protein kinase inhibitors on cytokine release from human macrophages, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 149, Pages: 393-404, ISSN: 0007-1188
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