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  • Journal article
    Barnes PJ, 2015,

    Identifying Molecular Targets for New Drug Development for Chronic Obstructive Pulmonary Disease: What Does the Future Hold?

    , SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 36, Pages: 508-522, ISSN: 1069-3424
  • Journal article
    Tetley TD, Ruenraroengsak P, 2015,

    Differential bioreactivity of neutral, cationic and anionic polystyrene nanoparticles with cells from the human alveolar compartment: robust response of alveolar type 1 epithelial cells

    , Particle and Fibre Toxicology, Vol: 12, ISSN: 1743-8977

    BackgroundEngineered nanoparticles (NP) are being developed for inhaled drug delivery. This route is non-invasive and the major target; alveolar epithelium provides a large surface area for drug administration and absorption, without first pass metabolism. Understanding the interaction between NPs and target cells is crucial for safe and effective NP-based drug delivery. We explored the differential effect of neutral, cationic and anionic polystyrene latex NPs on the target cells of the human alveolus, using primary human alveolar macrophages (MAC) and primary human alveolar type 2 (AT2) epithelial cells and a unique human alveolar epithelial type I-like cell (TT1). We hypothesized that the bioreactivity of the NPs would relate to their surface chemistry, charge and size as well as the functional role of their interacting cells in vivo.MethodsAmine- (ANP) and carboxyl- surface modified (CNP) and unmodified (UNP) polystyrene NPs, 50 and 100 nm in diameter, were studied. Cells were exposed to 1–100 μg/ml (1.25-125 μg/cm 2 ; 0 μg/ml control) NP for 4 and 24 h at 37 °C with or without the antioxidant, N-acetyl cysteine (NAC). Cells were assessed for cell viability, reactive oxygen species (ROS), oxidised glutathione (GSSG/GSH ratio), mitochondrial integrity, cell morphology and particle uptake (using electron microscopy and laser scanning confocal microscopy).ResultsANP-induced cell death occurred in all cell types, inducing increased oxidative stress, mitochondrial disruption and release of cytochrome C, indicating apoptotic cell death. UNP and CNP exhibited little cytotoxicity or mitochondrial damage, although they induced ROS in AT2 and MACs. Addition of NAC reduced epithelial cell ROS, but not MAC ROS, for up to 4 h. TT1 and MAC cells internalised all NP formats, whereas only a small fraction of AT2 cells internalized ANP (not UNP or CNP). TT1 cells were the most resistant to the effects of UNP and CNP.ConclusionANP induced marked oxidative damage

  • Journal article
    Barnes PJ, 2015,

    Mechanisms of development of multimorbidity in the elderly

    , EUROPEAN RESPIRATORY JOURNAL, Vol: 45, Pages: 790-806, ISSN: 0903-1936
  • Journal article
    Khorasani N, Baker J, Johnson M, Chung KF, Bhavsar PKet al., 2015,

    Reversal of corticosteroid insensitivity by p38 MAPK inhibition in peripheral blood mononuclear cells from COPD

    , International Journal of Chronic Obstructive Pulmonary Disease, Vol: 10, Pages: 283-291, ISSN: 1176-9106

    Background: Corticosteroids (CS) have limited efficacy in the treatment of chronic obstructivepulmonary disease (COPD). p38 mitogen-activated protein kinase (MAPK) activation isincreased in lung macrophages of COPD. We investigated whether p38 MAPK inhibitioncan modulate CS insensitivity of peripheral blood mononuclear cells (PBMCs) from patientswith COPD.Methods: PBMCs from patients with COPD (n=8) or healthy smokers (n=8) were exposed tolipopolysaccharide (LPS) with a selective p38 MAPK inhibitor (GW856553; 10-10–10-6 M),with dexamethasone (10-10–10-6 M), or with both. Phosphorylated glucocorticoid receptor (GR)was measured by Western blot.Results: Baseline (P,0.01) and LPS-induced (P,0.05) CXCL8 release was greater in PBMCsfrom COPD compared to healthy smokers. Inhibition of LPS-induced CXCL8 release by dexamethasone(10-6 M) was reduced, and baseline and LPS-induced p38 MAPK activation increasedin PBMCs of COPD. GW856553 (10-9 and 10-10 M) synergistically increased the inhibitoryeffect of dexamethasone (10-8 and 10-6 M) on LPS-induced CXCL8 release in COPD. Similarresults were obtained for IL-6 release. GW856553 inhibited dexamethasone- and LPS-activatedphosphorylation of serine 211 on GR. CS insensitivity in COPD PBMCs is reversed by inhibitionof p38 MAPK activity, partly by preventing phosphorylation of GR at serine 211.Conclusion: p38 MAPK inhibition may be beneficial in COPD by restoring CS sensitivity.

  • Journal article
    Chang P-J, Michaeloudes C, Zhu J, Shaikh N, Baker J, Chung KF, Bhavsar PKet al., 2015,

    Impaired Nuclear Translocation of the Glucocorticoid Receptor in Corticosteroid-Insensitive Airway Smooth Muscle in Severe Asthma

    , AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 191, Pages: 54-62, ISSN: 1073-449X
  • Journal article
    Mortaz E, Adcock IM, Tabarsi P, Masjedi MR, Masjedi MR, Mansouri D, Velayati AA, Casanova J-L, Barnes PJet al., 2015,

    Interaction of Pattern Recognition Receptors with Mycobacterium Tuberculosis.

    , Journal of clinical immunology, Vol: 35, Pages: 1-10, ISSN: 0271-9142

    Tuberculosis (TB) is considered a major worldwide health problem with 10 million new cases diagnosed each year. Our understanding of TB immunology has become greater and more refined since the identification of Mycobacterium tuberculosis (MTB) as an etiologic agent and the recognition of new signaling pathways modulating infection. Understanding the mechanisms through which the cells of the immune system recognize MTB can be an important step in designing novel therapeutic approaches, as well as improving the limited success of current vaccination strategies. A great challenge in chronic disease is to understand the complexities, mechanisms, and consequences of host interactions with pathogens. Innate immune responses along with the involvement of distinct inflammatory mediators and cells play an important role in the host defense against the MTB. Several classes of pattern recognition receptors (PRRs) are involved in the recognition of MTB including Toll-Like Receptors (TLRs), C-type lectin receptors (CLRs) and Nod-like receptors (NLRs) linked to inflammasome activation. Among the TLR family, TLR1, TLR2, TLR4, and TLR9 and their down-stream signaling proteins play critical roles in the initiation of the immune response in the pathogenesis of TB. The inflammasome pathway is associated with the coordinated release of cytokines such as IL-1β and IL-18 which also play a role in the pathogenesis of TB. Understanding the cross-talk between these signaling pathways will impact on the design of novel therapeutic strategies and in the development of vaccines and immunotherapy regimes. Abnormalities in PRR signaling pathways regulated by TB will affect disease pathogenesis and need to be elucidated. In this review we provide an update on PRR signaling during M. tuberculosis infection and indicate how greater knowledge of these pathways may lead to new therapeutic opportunities.

  • Journal article
    Liang Z, Zhang Q, Thomas CMR, Chana KK, Gibeon D, Barnes PJ, Chung KF, Bhavsar PK, Donnelly LEet al., 2014,

    Impaired macrophage phagocytosis of bacteria in severe asthma

    , RESPIRATORY RESEARCH, Vol: 15
  • Journal article
    Dubuis E, Wortley MA, Grace MS, Maher SA, Adcock JJ, Birrell MA, Belvisi MGet al., 2014,

    Theophylline inhibits the cough reflex through a novel mechanism of action

    , JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 133, Pages: 1588-1598, ISSN: 0091-6749
  • Journal article
    Birrell MA, Bonvini SJ, Dubuis E, Maher SA, Wortley MA, Grace MS, Raemdonck K, Adcock JJ, Belvisi MGet al., 2014,

    Tiotropium modulates transient receptor potential V1 (TRPV1) in airway sensory nerves: A beneficial off-target effect?

    , JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 133, Pages: 679-+, ISSN: 0091-6749
  • Journal article
    Damby DE, Horwell CJ, Baxter PJ, Delmelle P, Donaldson K, Dunster C, Fubini B, Murphy FA, Nattrass C, Sweeney S, Tetley TD, Tomatis Met al., 2013,

    The respiratory health hazard of tephra from the 2010 Centennial eruption of Merapi with implications for occupational mining of deposits

    , JOURNAL OF VOLCANOLOGY AND GEOTHERMAL RESEARCH, Vol: 261, Pages: 376-387, ISSN: 0377-0273
  • Journal article
    O'Rourke J, Wang WP, Donnelly L, Wang E, Kreutzer DLet al., 1987,

    Extravascular plasminogen activator and inhibitor activities detected at the site of a chronic mycobacterial-induced inflammation

    , American Journal of Pathology, ISSN: 1525-2191

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