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  • Journal article
    Barnes PJ, 2018,

    Targeting cytokines to treat asthma and chronic obstructive pulmonary disease

    , NATURE REVIEWS IMMUNOLOGY, Vol: 18, Pages: 454-466, ISSN: 1474-1733
  • Journal article
    Chung K, 2018,

    "International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma." Kian Fan Chung, Sally E. Wenzel, Jan L. Brozek, Andrew Bush, Mario Castro, Peter J. Sterk, Ian M. Adcock, Eric D. Bateman, Elisabeth H. Bel, Eugene R. Bleecker, Louis-Philippe Boulet, Christopher Brightling, Pascal Chanez, Sven-Erik Dahlen, Ratko Djukanovic, Urs Frey, Mina Gaga, Peter Gibson, Qutayba Hamid, Nizar N. Jajour, Thais Mauad, Ronald L. Sorkness and W. Gerald Teague. Eur Respir J 2014; 43: 343-373.

    , Eur Respir J, Vol: 52
  • Journal article
    Ellis T, Chiappi M, García-Trenco A, Al-Ejji M, Sarkar S, Georgiou TK, Shaffer MSP, Tetley TD, Schwander S, Ryan MP, Porter AEet al., 2018,

    Multimetallic microparticles increase the potency of rifampicin against intracellular mycobacterium tuberculosis

    , ACS Nano, Vol: 12, Pages: 5228-5240, ISSN: 1936-0851

    Mycobacterium tuberculosis ( M.tb) has the extraordinary ability to adapt to the administration of antibiotics through the development of resistance mechanisms. By rapidly exporting drugs from within the cytosol, these pathogenic bacteria diminish antibiotic potency and drive the presentation of drug-tolerant tuberculosis (TB). The membrane integrity of M.tb is pivotal in retaining these drug-resistant traits. Silver (Ag) and zinc oxide (ZnO) nanoparticles (NPs) are established antimicrobial agents that effectively compromise membrane stability, giving rise to increased bacterial permeability to antibiotics. In this work, biodegradable multimetallic microparticles (MMPs), containing Ag NPs and ZnO NPs, were developed for use in pulmonary delivery of antituberculous drugs to the endosomal system of M.tb-infected macrophages. Efficient uptake of MMPs by M.tb-infected THP1 cells was demonstrated using an in vitro macrophage infection model, with direct interaction between MMPs and M.tb visualized with the use of electron FIB-SEM tomography. The release of Ag NPs and ZnO NPs within the macrophage endosomal system increased the potency of the model antibiotic rifampicin by as much as 76%, realized through an increase in membrane disorder of intracellular M.tb. MMPs were effective at independently driving membrane destruction of extracellular bacilli located at the exterior face of THP1 macrophages. This MMP system presents as an effective drug delivery vehicle that could be used for the transport of antituberculous drugs such as rifampicin to infected alveolar macrophages, while increasing drug potency. By increasing M.tb membrane permeability, such a system may prove effectual in improving treatment of drug-susceptible TB in addition to M.tb strains considered drug-resistant.

  • Journal article
    Cowie MR, Gallagher AM, Simonds AK, 2018,

    The search for cardiovascular benefit from treating obstructive sleep apnoea with CPAP therapy

    , European Heart Journal, Vol: 39, Pages: 2298-2300, ISSN: 1522-9645
  • Journal article
    Martinez F, Han M, Allinson J, Barr G, Boucher R, Calverley PMA, Celli BR, Christenson SA, Crystal RG, Fageras M, Freeman CM, Groenke L, Hoffman EA, Kesimer M, Kostikas K, Paine III R, Rafii S, Rennard SI, Segal LN, Shaykhiev R, Stevenson C, Ruth T-S, Vestbo J, Woodruff P, Curtis J, Wedzicha Jet al., 2018,

    At the root: defining and halting progression of early chronic obstructive pulmonary disease

    , American Journal of Respiratory and Critical Care Medicine, Vol: 197, Pages: 1540-1551, ISSN: 1073-449X

    Chronic obstructive pulmonary disease (COPD) is a prevalent, heterogeneous disorder with varying presentation and progression but with a limited number of disease-modifying therapies (1). This marked heterogeneity impedes identification of subpopulations at risk for accelerated progression, thwarting therapeutic advances. Most COPD studies have included populations with mean ages older than 60 years (2). However, it is increasingly evident that lung function trajectories in COPD differ significantly and that differences are detectable in young adulthood (3–5). In this Perspective, we highlight the need to distinguish “early disease” from late “mild disease,” propose an operational definition of early COPD for use in research studies, and attempt to unify current views on potential disease mechanisms. We focus on smoking, the chief etiologic factor for COPD in the industrialized world. Whether pathogenic mechanisms and effective treatments are shared with the sizable fraction of COPD in never-smokers or resulting from biomass fuel, electronic nicotine delivery systems, and other exposures, are separate, significant questions. We argue that refocusing investigation on early COPD could revolutionize understanding and therapies of this leading cause of worldwide death.

  • Journal article
    Singanayagam A, Glanville N, Girkin J, Ching YM, Marcellini A, Porter J, Toussaint M, Walton R, Finney L, Julia A, Zhu J, Trujillo-Torralbo M, Calderazzo M, Grainge C, Loo S-L, Veerati PC, Pathinayake P, Nichol K, Reid A, James P, Solari R, Wark P, Knight D, Moffatt M, Cookson W, Edwards M, Mallia P, Bartlett N, Johnston SLet al., 2018,

    Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations

    , Nature Communications, Vol: 9, ISSN: 2041-1723

    Inhaled corticosteroids (ICS) have limited efficacy in reducing chronic obstructive pulmonary disease (COPD) exacerbations and increase pneumonia risk, through unknown mechanisms. Rhinoviruses precipitate most exacerbations and increase susceptibility to secondary bacterial infections. Here, we show that the ICS fluticasone propionate (FP) impairs innate and acquired antiviral immune responses leading to delayed virus clearance and previously unrecognised adverse effects of enhanced mucus, impaired antimicrobial peptide secretion and increased pulmonary bacterial load during virus-induced exacerbations. Exogenous interferon-β reverses these effects. FP suppression of interferon may occur through inhibition of TLR3- and RIG-I virus-sensing pathways. Mice deficient in the type I interferon-α/β receptor (IFNAR1−/−) have suppressed antimicrobial peptide and enhanced mucin responses to rhinovirus infection. This study identifies type I interferon as a central regulator of antibacterial immunity and mucus production. Suppression of interferon by ICS during virus-induced COPD exacerbations likely mediates pneumonia risk and raises suggestion that inhaled interferon-β therapy may protect.

  • Journal article
    Bhavsar PK, 2018,

    Role of humoral defense in severe asthma

    , American Journal of Respiratory and Critical Care Medicine, Vol: 197, Pages: 1369-1371, ISSN: 1073-449X
  • Journal article
    Pereira M, Williams S, Restrick L, Cullinan P, Hopkinson NSet al., 2018,

    Response

    , Clinical Medicine, Vol: 18, Pages: 268-269, ISSN: 1470-2118
  • Conference paper
    Gallagher A, Simonds A, Cowie M, 2018,

    What is the prevalence of heart failure with preserved ejection fraction (HFPEF) in patients referred for sleep apnoea assessment?

    , Annual Conference of the British-Cardiovascular-Society on High Performing Teams, Publisher: BMJ Publishing Group, Pages: A38-A38, ISSN: 1355-6037
  • Journal article
    Pereira M, Williams S, Restrick L, Cullinan P, Hopkinson NSet al., 2018,

    Reponse to "Flu-related absence, a small proportion of all-causesickness absence"; Clin Med June 1, 2018 vol. 18 no. 3 268

    , Clinical Medicine, Vol: 18, Pages: 268-269, ISSN: 1470-2118
  • Journal article
    De Meulder B, Lefaudeux D, Bansal AT, Mazein A, Chaiboonchoe A, Ahmed H, Balaur I, Saqi M, Pellet J, Ballereau S, Lemonnier N, Sun K, Pandis I, Yang X, Batuwitage M, Kretsos K, van Eyll J, Bedding A, Davison T, Dodson P, Larminie C, Postle A, Corfield J, Djukanovic R, Chung KF, Adcock IM, Guo Y-K, Sterk PJ, Manta A, Rowe A, Baribaud F, Auffray C, U-BIOPRED Study Group and the eTRIKS Consortiumet al., 2018,

    A computational framework for complex disease stratification from multiple large-scale datasets

    , BMC Systems Biology, Vol: 12, ISSN: 1752-0509

    BACKGROUND: Multilevel data integration is becoming a major area of research in systems biology. Within this area, multi-'omics datasets on complex diseases are becoming more readily available and there is a need to set standards and good practices for integrated analysis of biological, clinical and environmental data. We present a framework to plan and generate single and multi-'omics signatures of disease states. METHODS: The framework is divided into four major steps: dataset subsetting, feature filtering, 'omics-based clustering and biomarker identification. RESULTS: We illustrate the usefulness of this framework by identifying potential patient clusters based on integrated multi-'omics signatures in a publicly available ovarian cystadenocarcinoma dataset. The analysis generated a higher number of stable and clinically relevant clusters than previously reported, and enabled the generation of predictive models of patient outcomes. CONCLUSIONS: This framework will help health researchers plan and perform multi-'omics big data analyses to generate hypotheses and make sense of their rich, diverse and ever growing datasets, to enable implementation of translational P4 medicine.

  • Journal article
    Meldrum K, Robertson SB, Roemer I, Marczylo T, Dean LSN, Rogers A, Gant TW, Smith R, Tetley TD, Leonard MOet al., 2018,

    Cerium dioxide nanoparticles exacerbate house dust mite induced type II airway inflammation

    , PARTICLE AND FIBRE TOXICOLOGY, Vol: 15, ISSN: 1743-8977

    BackgroundNanomaterial inhalation represents a potential hazard for respiratory conditions such as asthma. Cerium dioxide nanoparticles (CeO2NPs) have the ability to modify disease outcome but have not been investigated for their effect on models of asthma and inflammatory lung disease. The aim of this study was to examine the impact of CeO2NPs in a house dust mite (HDM) induced murine model of asthma.ResultsRepeated intranasal instillation of CeO2NPs in the presence of HDM caused the induction of a type II inflammatory response, characterised by increased bronchoalveolar lavage eosinophils, mast cells, total plasma IgE and goblet cell metaplasia. This was accompanied by increases in IL-4, CCL11 and MCPT1 gene expression together with increases in the mucin and inflammatory regulators CLCA1 and SLC26A4. CLCA1 and SLC26A4 were also induced by CeO2NPs + HDM co-exposure in air liquid interface cultures of human primary bronchial epithelial cells. HDM induced airway hyperresponsiveness and airway remodelling in mice were not altered with CeO2NPs co-exposure. Repeated HMD instillations followed by a single exposure to CeO2NPs failed to produce changes in type II inflammatory endpoints but did result in alterations in the neutrophil marker CD177. Treatment of mice with CeO2NPs in the absence of HDM did not have any significant effects. RNA-SEQ was used to explore early effects 24 h after single treatment exposures. Changes in SAA3 expression paralleled increased neutrophil BAL levels, while no changes in eosinophil or lymphocyte levels were observed. HDM resulted in a strong induction of type I interferon and IRF3 dependent gene expression, which was inhibited with CeO2NPs co-exposure. Changes in the expression of genes including CCL20, CXCL10, NLRC5, IRF7 and CLEC10A suggest regulation of dendritic cells, macrophage functionality and IRF3 modulation as key early events in how CeO2NPs may guide pulmonary responses to HDM towards type II inflammation.Conclusi

  • Journal article
    Sadaka AS, Montgomery AJ, Mourad SM, Polkey MI, Hopkinson NSet al., 2018,

    Exercise response to oxygen supplementation is not associated with survival in hypoxemic patients with obstructive lung disease

    , International Journal of COPD, Vol: 13, Pages: 1607-1612, ISSN: 1176-9106

    Purpose: Hypoxemia is associated with more severe lung disease and worse outcomes. In some patients with chronic obstructive lung diseases who desaturate on exertion, supplemental oxygen improves exercise capacity. The clinical significance of this exercise response to oxygen supplementation is not known.Patient and methods: We identified chronic obstructive lung disease patients at our center who underwent a six-minute walking test (6MWT) for ambulatory oxygen assessment and who desaturated breathing air and therefore had an additional walk test on supplemental oxygen, between August 2006 and June 2016. Responders were defined as walking >26m further with oxygen. Survival was determined up to 1st February 2017. We compared survival in oxygen responders and non-responders in patients with obstructive lung diseases.Results: 174 patients were included in the study, median age 70 years. 77(44.3%) of the patients were oxygen responders. Borg dyspnea score improved by 1.4(±1.4) units (P<0.0005) on oxygen. Median survival was 66 months with death occurring in 84(48.2%) patients. Kaplan-Meier analysis revealed no survival difference between both responders and non-responders (P=0.571). Cox regression analysis showed that more 6MWT desaturation, lower 6MWD on room air, male gender, lower hemoglobin and BMI were associated with higher mortality risk.Conclusion: Acute exercise response to supplemental oxygen is not associated with long-term survival in patients with obstructive lung disease. This supports the use of ambulatory oxygen treatment for symptomatic purposes only.

  • Journal article
    Custovic A, Belgrave D, Lin L, Bakhsoliani E, Telcian AG, Solari R, Murray CS, Walton RP, Curtin J, Edwards MR, Simpson A, Rattray M, Johnston SLet al., 2018,

    Cytokine responses to rhinovirus and development of asthma, allergic sensitization and respiratory infections during childhood

    , American Journal of Respiratory and Critical Care Medicine, Vol: 197, Pages: 1265-1274, ISSN: 1073-449X

    BACKGROUND: Immunophenotypes of anti-viral responses, and their relationship with asthma, allergy and lower respiratory tract infections (LRTIs) are poorly understood. We characterized multiple cytokine responses of peripheral-blood mononuclear cells to rhinovirus stimulation, and their relationship with clinical outcomes. METHODS: In a population-based birth cohort, we measured 28 cytokines post-stimulation with rhinovirus-16 in 307 children aged 11 years. We used machine learning to identify patterns of cytokine responses, and related these patterns to clinical outcomes using longitudinal models. We also ascertained phytohaemagglutinin-induced TH2-cytokine responses [PHA-TH2]. RESULTS: We identified six clusters of children based on their rhinovirus-16 responses, which were differentiated by the expression of four cytokine/chemokine groups: interferon-related-(IFN); pro-inflammatory-(Inflam); TH2-chemokine-(TH2-chem); regulatory-(Reg). Clusters differed in their clinical characteristics. Children with IFNmodInflamhighestTH2-chemhighestReghighestrhinovirus-16-induced pattern had PHA-TH2lowresponse, and a very low asthma risk (OR:0.08 [95%CI 0.01-0.81], P=0.03). Two clusters had high risk of asthma and allergic sensitization, but with different trajectories from infancy to adolescence. The IFNlowestInflamhighTH2-chemlowRegmodcluster exhibited PHA-TH2lowestresponse, and was associated with early-onset asthma and sensitization, and the highest risk of asthma exacerbations (1.37 [1.07-1.76], P=0.014) and LRTI hospitalizations (2.40 [1.26-4.58], P=0.008) throughout childhood. In contrast, cluster with IFNhighestInflammodTH2-chemmodReghighrhinovirus-16-cytokine pattern was characterized by PHA-TH2highestresponse, and a low prevalence of asthma/sensitization in infancy which increased sharply to become the highest among all clusters by adolescence (but with low risk of asthma exacerbations). CONCLUSIONS: Early-onset troublesome asthma with early-life sensitization, later-

  • Journal article
    Mousnier A, Bell AS, Swieboda DP, Morales-Sanfrutos J, Pérez-Dorado I, Brannigan JA, Newman J, Ritzefeld M, Hutton JA, Guedán A, Asfor AA, Robinson SW, Hopkins-Navratilova I, Wilkinson AJ, Johnston SL, Leatherbarrow RJ, Tuthill TJ, Solari R, Tate EWet al., 2018,

    Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus

    , Nature Chemistry, Vol: 10, Pages: 599-606, ISSN: 1755-4330

    Rhinoviruses are the pathogens most often responsible for the common cold, and are a frequent cause of exacerbations in asthma, chronic obstructive pulmonary disease and cystic fibrosis. Here we report discovery of IMP-1088, a picomolar dual inhibitor of the human N-myristoyltransferases NMT1 and NMT2, and use it to demonstrate that pharmacological inhibition of host cell N-myristoylation rapidly and completely prevents rhinoviral replication without inducing cytotoxicity. Identification of cooperative binding between weak-binding fragments led to rapid inhibitor optimization through fragment reconstruction, structure-guided fragment linking, and conformational control over linker geometry. We show that inhibition of co-translational myristoylation of a specific virus-encoded protein (VP0) by IMP-1088 potently blocks a key step in viral capsid assembly, delivering low nanomolar antiviral activity against multiple rhinovirus strains, poliovirus and foot-and-mouth disease virus, and protection of cells against virus-induced killing, highlighting the potential of host myristoylation as a drug target in picornaviral infections.

  • Journal article
    Belvisi MG, Baker K, Malloy N, Raemdonck K, Dekkak B, Pieper M, Nials AT, Birrell MAet al., 2018,

    Modelling the asthma phenotype: impact of cigarette smoke exposure

    , Respiratory Research, Vol: 19, ISSN: 1465-9921

    BackgroundAsthmatics that are exposed to inhaled pollutants such as cigarette smoke (CS) have increased symptom severity. Approximately 25% of adult asthmatics are thought to be active smokers and many sufferers, especially in the third world, are exposed to high levels of inhaled pollutants. The mechanism by which CS or other airborne pollutants alter the disease phenotype and the effectiveness of treatment in asthma is not known. The aim of this study was to determine the impact of CS exposure on the phenotype and treatment sensitivity of rodent models of allergic asthma.MethodsModels of allergic asthma were configured that mimicked aspects of the asthma phenotype and the effect of CS exposure investigated. In some experiments, treatment with gold standard asthma therapies was investigated and end-points such as airway cellular burden, late asthmatic response (LAR) and airway hyper-Reactivity (AHR) assessed.ResultsCS co-exposure caused an increase in the LAR but interestingly attenuated the AHR. The effectiveness of LABA, LAMA and glucocorticoid treatment on LAR appeared to be retained in the CS-exposed model system. The eosinophilia or lymphocyte burden was not altered by CS co-exposure, nor did CS appear to alter the effectiveness of glucocorticoid treatment. Steroids, however failed to reduce the neutrophilic inflammation in sensitized mice exposed to CS.ConclusionsThese model data have certain parallels with clinical findings in asthmatics, where CS exposure did not impact the anti-inflammatory efficacy of steroids but attenuated AHR and enhanced symptoms such as the bronchospasm associated with the LAR. These model systems may be utilised to investigate how CS and other airborne pollutants impact the asthma phenotype; providing the opportunity to identify novel targets.

  • Journal article
    Cui X, Gong J, Han H, He L, Teng Y, Tetley T, Sinharay R, Chung KF, Islam T, Gilliland F, Grady S, Garshick E, Li Z, Zhang JJet al., 2018,

    Relationship between free and total malondialdehyde, a well-established marker of oxidative stress, in various types of human biospecimens

    , JOURNAL OF THORACIC DISEASE, Vol: 10, Pages: 3088-+, ISSN: 2072-1439
  • Journal article
    Michaudel C, Maillet I, Fauconnier L, Quesniaux V, Chung KF, Wiegman C, Peter D, Ryffel Bet al., 2018,

    Interleukin-1 alpha mediates ozone-induced myeloid differentiation factor-88-dependent epithelial tissue injury and inflammation

    , Frontiers in Immunology, Vol: 9, ISSN: 1664-3224

    Air pollution associated with ozone exposure represents a major inducer of respiratory disease in man. In mice, a single ozone exposure causes lung injury with disruption of the respiratory barrier and inflammation. We investigated the role of interleukin-1 (IL-1)-associated cytokines upon a single ozone exposure (1 ppm for 1 h) using IL-1α-, IL-1β-, and IL-18-deficient mice or an anti-IL-1α neutralizing antibody underlying the rapid epithelial cell death. Here, we demonstrate the release of the alarmin IL-1α after ozone exposure and that the acute respiratory barrier injury and inflammation and airway hyperreactivity are IL-1α-dependent. IL-1α signaling via IL-1R1 depends on the adaptor protein myeloid differentiation factor-88 (MyD88). Importantly, epithelial cell signaling is critical, since deletion of MyD88 in lung type I alveolar epithelial cells reduced ozone-induced inflammation. In addition, intratracheal injection of recombinant rmIL-1α in MyD88acid mice led to reduction of inflammation in comparison with wild type mice treated with rmIL-1α. Therefore, a major part of inflammation is mediated by IL-1α signaling in epithelial cells. In conclusion, the alarmin IL-1α released upon ozone-induced tissue damage and inflammation is mediated by MyD88 signaling in epithelial cells. Therefore, IL-1α may represent a therapeutic target to attenuate ozone-induced lung inflammation and hyperreactivity.

  • Journal article
    Garcia E, de la Serna JB, 2018,

    Dissecting single-cell molecular spatiotemporal mobility and clustering at focal adhesions in polarised cells by fluorescence fluctuation spectroscopy methods

    , METHODS, Vol: 140, Pages: 85-96, ISSN: 1046-2023
  • Journal article
    Dekhuijzen R, Lavorini F, Usmani OS, van Boven JFMet al., 2018,

    Addressing the impact and unmet needs of nonadherence in asthma and chronic obstructive pulmonary disease: where do we go from here?

    , Journal of Allergy and Clinical Immunology: In Practice, Vol: 6, Pages: 785-793, ISSN: 2213-2198

    Nonadherence to treatment, and its associated health and economic burden, is particularly problematic in asthma and chronic obstructive pulmonary disease management because of heterogeneous patient populations and the need for an inhaled route of drug administration. Symptom variability, comorbidities, and device switching further add to suboptimal adherence rates. As opposed to controlled clinical trials, real-life studies show consistently low inhaler adherence in daily practice, yet exact adherence rates have long been affected by disagreement on standardized definitions. The recently developed Ascertaining Barriers to Compliance taxonomy helps to address adherence research disparities by identifying 3 phases of adherence (initiation, implementation [including correct inhaler technique], and discontinuation). This review considers the reasons for and impact of suboptimal adherence, together with summaries of key studies that demonstrate how improving adherence can reduce exacerbations, inhaled corticosteroid use (in cases of better inhaler technique), hospitalizations, and treatment costs. Strategies to help ensure optimal adherence are discussed, including the choice of a patient-tailored inhaler, patient empowerment, education and training, and the potential of electronic monitoring and digital technology. It is concluded that a combined effort from payers, health care professionals, and manufacturers could make a real difference to asthma and chronic obstructive pulmonary disease control, as well as to health care budgets.

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