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  • Conference paper
    Gallagher A, Simonds A, Cowie MR, 2018,

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

    , Heart Failure 2018 and the World Congress on Acute Heart Failure, Publisher: Wiley, Pages: 239-239, ISSN: 1388-9842
  • Journal article
    Waithe D, Schneider F, Chojnacki J, Clausen MP, Shrestha D, de la Serna JB, Eggeling Cet al., 2018,

    Optimized processing and analysis of conventional confocal microscopy generated scanning FCS data

    , Methods, Vol: 140-141, Pages: 62-73, ISSN: 1046-2023

    Scanning Fluorescence Correlation Spectroscopy (scanning FCS) is a variant of conventional point FCS that allows molecular diffusion at multiple locations to be measured simultaneously. It enables disclosure of potential spatial heterogeneity in molecular diffusion dynamics and also the acquisition of a large amount of FCS data at the same time, providing large statistical accuracy. Here, we optimize the processing and analysis of these large-scale acquired sets of FCS data. On one hand we present FoCuS-scan, scanning FCS software that provides an end-to-end solution for processing and analysing scanning data acquired on commercial turnkey confocal systems. On the other hand, we provide a thorough characterisation of large-scale scanning FCS data over its intended time-scales and applications and propose a unique solution for the bias and variance observed when studying slowly diffusing species. Our manuscript enables researchers to straightforwardly utilise scanning FCS as a powerful technique for measuring diffusion across a broad range of physiologically relevant length scales without specialised hardware or expensive software.

  • Journal article
    Sonnappa S, McQueen B, Postma DS, Martin RJ, Roche N, Grigg J, Guilbert T, Gouder C, Pizzichini E, Niimi A, Phipatanakul W, Chisholm A, Dandurand RJ, Kaplan A, Israel E, Papi A, van Aalderen WMC, Usmani OS, Price DBet al., 2018,

    Extrafine versus fine inhaled corticosteroids in relation to asthma control: a systematic review and meta-analysis of observational real-life studies

    , The journal of allergy and clinical immunology. In practice, Vol: 6, Pages: 907-915.e7, ISSN: 2213-2198

    BACKGROUND: The particle size of inhaled corticosteroids (ICSs) may affect airway drug deposition and effectiveness. OBJECTIVE: To compare the effectiveness of extrafine ICSs (mass median aerodynamic diameter, <2 μm) versus fine-particle ICSs administered as ICS monotherapy or ICS-long-acting β-agonist combination therapy by conducting a meta-analysis of observational real-life asthma studies to estimate the treatment effect of extrafine ICSs. METHODS: MEDLINE and EMBASE databases were reviewed for asthma observational comparative effectiveness studies from January 2004 to June 2016. Studies were included if they reported odds and relative risk ratios and met all inclusion criteria (Respiratory Effectiveness Group/European Academy of Allergy and Clinical Immunology quality standards, comparison of extrafine ICSs with same or different ICS molecule, ≥12-month follow-up). End-point data (asthma control, exacerbations, prescribed ICS dose) were pooled. Random-effects meta-analysis modeling was used. The study protocol is published in the PROSPERO register CRD42016039137. RESULTS: Seven studies with 33,453 subjects aged 5 to 80 years met eligibility criteria for inclusion. Six studies used extrafine beclometasone propionate and 1 study used both extrafine beclometasone propionate and extrafine ciclesonide as comparators with fine-particle ICSs. The overall odds of achieving asthma control were significantly higher for extrafine ICSs compared with fine-particle ICSs (odds ratio, 1.34; 95% CI, 1.22-1.46). Overall exacerbation rate ratios (0.84; 95% CI, 0.73-0.97) and ICS dose (weighted mean difference, -170 μg; 95% CI, -222 to -118 μg) were significantly lower for extrafine ICSs compared with fine-particle ICSs. CONCLUSIONS: This meta-analysis demonstrates that extrafine ICSs have significantly higher odds of achieving asthma control with lower exacerbation rates at significantly lower prescribed doses than fine-particle ICSs.

  • Journal article
    Jarvis IWH, Enlo-Scott Z, Nagy E, Mudway IS, Tetley TD, Arlt VM, Phillips DHet al., 2018,

    Genotoxicity of fine and coarse fraction ambient particulate matter in immortalised normal (TT1) and cancer-derived (A549) alveolar epithelial cells

    , ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Vol: 59, Pages: 290-301, ISSN: 0893-6692
  • Journal article
    Ghebre MA, Pang PH, Diver S, Desai D, Bafadhel M, Haldar K, Kebadze T, Cohen S, Newbold P, Rapley L, Woods J, Rugman P, Pavord ID, Johnston SL, Barer M, May RD, Brightling CEet al., 2018,

    Biological exacerbation clusters demonstrate asthma and COPD overlap with distinct mediator and microbiome profiles.

    , Journal of Allergy and Clinical Immunology, Vol: 141, Pages: 2027-2036.e12, ISSN: 0091-6749

    BACKGROUND: Exacerbations of asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous. OBJECTIVE: We sought to investigate the sputum cellular, mediator, and microbiome profiles of both asthma and COPD exacerbations. METHODS: Patients with severe asthma or moderate-to-severe COPD were prospectively recruited to a single centre. Sputum mediators were available in 32 asthma and 73 COPD patients assessed at exacerbation. Biologic clusters were determined using factor and cluster analyses on a panel of sputum mediators. Patterns of clinical parameters, sputum mediators, and microbiome communities were assessed across the identified clusters. RESULTS: The asthma and COPD patients had different clinical characteristics and inflammatory profiles, but similar microbial ecology. Three exacerbation biologic clusters were identified. Cluster 1 was COPD predominant, with 27 COPD and 7 asthma patients exhibiting elevated blood and sputum neutrophil counts, proinflammatory mediators (IL-1β, IL-6, IL-6R, TNFα, TNF-R1, TNF-R2, and VEGF), and proportion of the bacterial phylum Proteobacteria. Cluster 2 had 10 asthma and 17 COPD patients with elevated blood and sputum eosinophil counts, Type 2 (T2) mediators (IL-5, IL-13, CCL13, CCL17, and CCL26), and proportion of the bacterial phylum Bacteroidetes. Cluster 3 had 15 asthma and 29 COPD subjects with elevated Type 1 (T1) mediators (CXCL10, CXCL11, and IFN-ϒ) and proportions of phyla Actinobacteria and Firmicutes. CONCLUSIONS: A biologic clustering approach revealed three subgroups of asthma and COPD exacerbations each with different percentages of overlapping asthma and COPD patients. The sputum mediator and microbiome profiles were distinct between clusters. CLINICAL IMPLICATIONS: Sputum mediator and microbiome profiling can determine the distinct and overlapping asthma and COPD biologic exacerbation clusters, highlighting the heterogeneity of these exacerbations.

  • Journal article
    Vogelmeier CF, Chapman KR, Miravitlles M, Roche N, Vestbo J, Thach C, Banerji D, Fogel R, Patalano F, Olsson P, Kostikas K, Wedzicha JAet al., 2018,

    Exacerbation heterogeneity in COPD: subgroup analyses from the FLAME study

    , International Journal of Chronic Obstructive Pulmonary Disease, Vol: 13, Pages: 1125-1134, ISSN: 1176-9106

    Background: The FLAME study compared once-daily indacaterol/glycopyrronium (IND/GLY) 110/50 µg with twice-daily salmeterol/fluticasone (SFC) 50/500 µg in symptomatic patients with moderate to very severe COPD and a history of exacerbations in the previous year.Methods: This prespecified and post hoc subgroup analysis evaluated treatment efficacy on 1) moderate/severe exacerbations according to prior exacerbation history and treatment, and 2) types of exacerbations according to health care resource utilization (HCRU) during 1-year follow-up.Results: IND/GLY reduced the rate of moderate/severe exacerbations versus SFC in patients with a history of 1 exacerbation (rate ratio [RR]: 0.83, 95% CI: 0.75–0.93), ≥2 exacerbations (RR: 0.85, 95% CI: 0.70–1.03) and ≥2 exacerbations or ≥1 hospitalization in the previous year (RR: 0.86, 95% CI: 0.74–1.00). Prolonged time-to-first exacerbation was observed in all the groups according to exacerbation history. Moderate/severe exacerbations decreased with IND/GLY versus SFC, independent of previous treatment. IND/GLY significantly reduced rates of moderate/severe exacerbations treated with antibiotics (RR: 0.79, 95% CI: 0.67–0.93) and systemic corticosteroids and antibiotics (RR: 0.80, 95% CI: 0.70–0.91); rates of exacerbations treated with systemic corticosteroids alone were comparable (RR: 0.99, 95% CI: 0.80–1.22).Conclusion: Overall, IND/GLY demonstrated consistent beneficial effects versus SFC on moderate/severe exacerbations, independent of prior exacerbation history or treatment. The efficacy of IND/GLY on exacerbation prevention was superior to SFC for exacerbations treated with antibiotics with/without systemic corticosteroids and was similar for exacerbations treated with systemic corticosteroids alone.

  • Journal article
    Hillyer EV, Price DB, Chrystyn H, Martin RJ, Israel E, van Aalderen WMC, Papi A, Usmani OS, Roche Net al., 2018,

    Harmonizing the nomenclature for therapeutic aerosol particle size: a proposal

    , Journal of Aerosol Medicine and Pulmonary Drug Delivery, Vol: 31, Pages: 111-113, ISSN: 1941-2703
  • Journal article
    Katsumiti A, Thorley AJ, Arostegui I, Reip P, Valsami-Jones E, Tetley TD, Cajaraville MPet al., 2018,

    Cytotoxicity and cellular mechanisms of toxicity of CuO NPs in mussel cells in vitro and comparative sensitivity with human cells

    , TOXICOLOGY IN VITRO, Vol: 48, Pages: 146-158, ISSN: 0887-2333

    There is a need to assess human and ecosystem health effects of copper oxide nanoparticles (CuO NPs), extensively used in many industrial products. Here, we aimed to determine the cytotoxicity and cellular mechanisms involved in the toxicity of CuO NPs in mussel cells (hemocytes and gill cells) in parallel with exposures to ionic Cu and bulk CuO, and to compare the sensitivity of mussel primary cells with a well-established human cell line (pulmonary TT1 cells). At similar doses, CuO NPs promoted dose-dependent cytotoxicity and increased reactive oxygen species (ROS) production in mussel and human cells. In mussel cells, ionic Cu was more toxic than CuO NPs and the latter more than bulk CuO. Ionic Cu and CuO NPs increased catalase and acid phosphatase activities in both mussel cells and decreased gill cells Na-K-ATPase activity. All Cu forms produced DNA damage in hemocytes, whereas in gill cells only ionic Cu and CuO NPs were genotoxic. Induction of the MXR transport activity was found in gill cells exposed to all forms of Cu and in hemocytes exposed to ionic Cu and CuO NPs. Phagocytosis increased only in hemocytes exposed to CuO NPs, indicating a nanoparticle-specific immunostimulatory effect. In conclusion, toxicity of CuO NPs is driven by ROS in human and mussel cells. Mussel cells respond to CuO NP exposure by triggering an array of defensive mechanisms.

  • Journal article
    Patel S, Kon S, Nolan C, Barker R, Simonds A, Morrell M, Man WDet al., 2018,

    The Epworth sleepiness scale: minimum clinically important difference in obstructive sleep apnea

    , American Journal of Respiratory and Critical Care Medicine, Vol: 197, Pages: 961-961, ISSN: 1073-449X
  • Journal article
    Brill A-K, Pickersgill R, Moghal M, Morrell MJ, Simonds AKet al., 2018,

    Mask pressure effects on the nasal bridge during short-term noninvasive ventilation

    , ERJ Open Research, Vol: 4, ISSN: 2312-0541

    The aim of this study was to assess the influence of different masks, ventilator settings and body positions on the pressure exerted on the nasal bridge by the mask and subjective comfort during noninvasive ventilation (NIV). We measured the pressure over the nasal bridge in 20 healthy participants receiving NIV via four different NIV masks (three oronasal masks, one nasal mask) at three different ventilator settings and in the seated or supine position. Objective pressure measurements were obtained with an I-Scan pressure-mapping system. Subjective comfort of the mask fit was assessed with a visual analogue scale. The masks exerted mean pressures between 47.6±29 mmHg and 91.9±42.4 mmHg on the nasal bridge. In the supine position, the pressure was lower in all masks (57.1±31.9 mmHg supine, 63.9±37.3 mmHg seated; p<0.001). With oronasal masks, a change of inspiratory positive airway pressure (IPAP) did not influence the objective pressure over the nasal bridge. Subjective discomfort was associated with higher IPAP and positively correlated with the pressure on the skin. Objective measurement of pressure on the skin during mask fitting might be helpful for mask selection. Mask fitting in the supine position should be considered in the clinical routine.

  • Journal article
    Krauskopf J, Caiment F, van Veldhoven K, Chadeau-Hyam M, Sinharay R, Chung KF, Cullinan P, Collins P, de Kok TM, Kelly F, Vermeulen R, Vineis P, Kleinjans JCet al., 2018,

    The human circulating miRNome reflects multiple organ disease risks in association with short-term exposure to traffic-related air pollution

    , Environment International, Vol: 113, Pages: 26-34, ISSN: 0160-4120

    Traffic-related air pollution is a complex mixture of particulate matter (PM) and gaseous pollutants, such as nitrogen dioxide (NO2). PM exposure contributes to the pathogenesis of many diseases including several types of cancer, as well as pulmonary, cardiovascular and neurodegenerative diseases. Also exposure to NO2 has been related to increased cardiovascular mortality. In search of an early diagnostic biomarker for improved air pollution-associated health risk assessment, recent human studies have shown that certain circulating miRNAs are altered upon exposure to traffic-related air pollutants. Here, we present for the first time a global analysis of the circulating miRNA genome in an experimental cross-over study of a human population exposed to traffic-related air pollution. By utilizing next-generation sequencing technology and detailed real-time exposure measurements we identified 54 circulating miRNAs to be dose- and pollutant species-dependently associated with PM10, PM2.5, black carbon, ultrafine particles and NO2 already after 2 h of exposure. Bioinformatics analysis suggests that these circulating miRNAs actually reflect the adverse consequences of traffic pollution-induced toxicity in target tissues including the lung, heart, kidney and brain. This study shows the strong potential of circulating miRNAs as novel biomarkers for environmental health risk assessment.

  • Journal article
    Botelho D, Leo BF, Massa C, Sarkar S, Tetley T, Chung KF, Chen S, Ryan MP, Porter A, Atochina-Vasserman EN, Zhang J, Schwander S, Gow AJet al., 2018,

    Exposure to silver nanospheres leads to altered respiratory mechanics and delayed immune response in an in vivo Murine model

    , Frontiers in Pharmacology, Vol: 9, ISSN: 1663-9812

    Here we examine the organ level toxicology of both carbon black (CB) and silver nanoparticles (AgNP). We aim to determine metal-specific effects to respiratory function, inflammation and potential interactions with lung lining fluid (LLF). C57Bl6/J male mice were intratracheally instilled with saline (control), low (0.05 μg/g) or high (0.5 μg/g) doses of either AgNP or CB 15 nm nanospheres. Lung histology, cytology, surfactant composition and function, inflammatory gene expression, and pulmonary function were measured at 1, 3, and 7 days post-exposure. Acutely, high dose CB resulted in an inflammatory response, increased neutrophilia and cytokine production, without alteration in surfactant composition or respiratory mechanics. Low dose CB had no effect. Neither low nor high dose AgNPs resulted in an acute inflammatory response, but there was an increase in work of breathing. Three days post-exposure with CB, a persistent neutrophilia was noted. High dose AgNP resulted in an elevated number of macrophages and invasion of lymphocytes. Additionally, AgNP treated mice displayed increased expression of IL1B, IL6, CCL2, and IL10. However, there were no significant changes in respiratory mechanics. At day 7, inflammation had resolved in AgNP-treated mice, but tissue stiffness and resistance were significantly decreased, which was accompanied by an increase in surfactant protein D (SP-D) content. These data demonstrate that the presence of metal alters the response of the lung to nanoparticle exposure. AgNP-surfactant interactions may alter respiratory function and result in a delayed immune response, potentially due to modified airway epithelial cell function.

  • Journal article
    Gutowska-Owsiak D, de La Serna JB, Fritzsche M, Naeem A, Podobas EI, Leeming M, Colin-York H, O'Shaughnessy R, Eggeling C, Ogg GSet al., 2018,

    Orchestrated control of filaggrin-actin scaffolds underpins cornification

    , Cell Death and Disease, Vol: 9, ISSN: 2041-4889

    Epidermal stratification critically depends on keratinocyte differentiation and programmed death by cornification, leading to formation of a protective skin barrier. Cornification is dynamically controlled by the protein filaggrin, rapidly released from keratohyalin granules (KHGs). However, the mechanisms of cornification largely remain elusive, partly due to limitations of the observation techniques employed to study filaggrin organization in keratinocytes. Moreover, while the abundance of keratins within KHGs has been well described, it is not clear whether actin also contributes to their formation or fate. We employed advanced (super-resolution) microscopy to examine filaggrin organization and dynamics in skin and human keratinocytes during differentiation. We found that filaggrin organization depends on the cytoplasmic actin cytoskeleton, including the role for α- and β-actin scaffolds. Filaggrin-containing KHGs displayed high mobility and migrated toward the nucleus during differentiation. Pharmacological disruption targeting actin networks resulted in granule disintegration and accelerated cornification. We identified the role of AKT serine/threonine kinase 1 (AKT1), which controls binding preference and function of heat shock protein B1 (HspB1), facilitating the switch from actin stabilization to filaggrin processing. Our results suggest an extended model of cornification in which filaggrin utilizes actins to effectively control keratinocyte differentiation and death, promoting epidermal stratification and formation of a fully functional skin barrier.

  • Journal article
    Andersson C, Bonvini SJ, Horvath P, Marquez E, Satia I, Kirkham P, Schleich F, Idzko M, Gosens R, Lopez-Campos JL, Bossios A, Usmani O, Spanevello A, Adcock IM, Mathioudakis AGet al., 2018,

    Research highlights from the 2017 ERS International Congress: airway diseases in focus

    , ERJ Open Research, Vol: 4, ISSN: 2312-0541

    For another year, high-quality research studies from around the world transformed the annual ERS International Congress into a vivid platform to discuss trending research topics, to produce new research questions and to further push the boundaries of respiratory medicine and science. This article reviews only some of the high-quality research studies on asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis and chronic cough that were presented during the congress through the Airway Diseases Assembly (ERS Assembly 5) and places them into the context of current knowledge and research challenges.

  • Journal article
    Yanagisawa S, Baker JR, Vuppusetty C, Koga T, Colley T, Fenwick P, Donnelly LE, Barnes PJ, Ito Ket al., 2018,

    The dynamic shuttling of SIRT1 between cytoplasm and nuclei in bronchial epithelial cells by single and repeated cigarette smoke exposure

    , PLoS ONE, Vol: 13, ISSN: 1932-6203

    SIRT1 (silent information regulator 2 homolog 1) is a crucial cellular survival protein especially in oxidative stress environments, and has been thought to locate within the nuclei, but also known to shuttle between cytoplasm and nuclei in some cell types. Here, we show for the first time the dynamics of SIRT1 in the presence of single or concurrent cigarette smoke extract (CSE) exposure in human bronchial epithelial cells (HBEC). In BEAS-2B HBEC or primary HBEC, SIRT1 was localized predominantly in cytoplasm, and the CSE (3%) induced nuclear translocation of SIRT1 from cytoplasm in the presence of L-buthionine sulfoximine (an irreversible inhibitor of γ-glutamylcystein synthetase), mainly through the activation of phosphatidylinositol 3-kinase (PI3K) α subunit. This SIRT1 nuclear shuttling was associated with FOXO3a nuclear translocation and the strong induction of several anti-oxidant genes including superoxide dismutase (SOD) 2 and 3; therefore seemed to be an adaptive response. When BEAS-2B cells were pretreated with repeated exposure to a lower concentration of CSE (0.3%), the CSE-induced SIRT1 shuttling and resultant SOD2/3 mRNA induction were significantly impaired. Thus, this result offers a useful cell model to mimic the impaired anti-oxidant capacity in cigarette smoking-associated lung disease such as chronic obstructive pulmonary disease.

  • Journal article
    Santos AM, Ponjavic A, Fritzsche M, Fernandes RA, de la Serna JB, Wilcock MJ, Schneider F, Urbancic I, McColl J, Anzilotti C, Ganzinger KA, Assmann M, Depoil D, Cornal RJ, Dustin ML, Klenerman D, Davis SJ, Eggeling C, Lee SFet al., 2018,

    Capturing resting T cells: the perils of PLL

    , NATURE IMMUNOLOGY, Vol: 19, Pages: 203-205, ISSN: 1529-2908
  • Journal article
    Cowie MR, Woehrle H, Wegscheider K, Vettorazzi E, Lezius S, Koenig W, Weidemann F, Smith G, Angermann C, d'Ortho M-P, Erdmann E, Levy P, Simonds AK, Somers VK, Zannad F, Teschler Het al., 2018,

    Adaptive servo-ventilation for central sleep apnoea in systolic heart failure: results of the major substudy of SERVE-HF

    , European Journal of Heart Failure, Vol: 20, Pages: 536-544, ISSN: 1388-9842

    AIMS: The SERVE-HF trial investigated the impact of treating central sleep apnoea (CSA) with adaptive servo-ventilation (ASV) in patients with systolic heart failure. A preplanned substudy was conducted to provide insight into mechanistic changes underlying the observed effects of ASV, including assessment of changes in left ventricular function, ventricular remodelling, and cardiac, renal and inflammatory biomarkers. METHODS AND RESULTS: In a subset of the 1325 randomised patients, echocardiography, cardiac magnetic resonance imaging (cMRI) and biomarker analysis were performed at baseline, and 3 and 12 months. In secondary analyses, data for patients with baseline and 12-month values were evaluated; 312 patients participated in the substudy. The primary endpoint, change in echocardiographically determined left ventricular ejection fraction from baseline to 12 months, did not differ significantly between the ASV and the control groups. There were also no significant between-group differences for changes in left ventricular dimensions, wall thickness, diastolic function or right ventricular dimensions and ejection fraction (echocardiography), and on cMRI (in small patient numbers). Plasma N-terminal pro B-type natriuretic peptide concentration decreased in both groups, and values were similar at 12 months. There were no significant between-group differences in changes in cardiac, renal and systemic inflammation biomarkers. CONCLUSION: In patients with systolic heart failure and CSA, addition of ASV to guideline-based medical management had no statistically significant effect on cardiac structure and function, or on cardiac biomarkers, renal function and systemic inflammation over 12 months. The increased cardiovascular mortality reported in SERVE-HF may not be related to adverse remodelling or worsening heart failure.

  • Journal article
    Polsek D, Gildeh N, Cash D, Winsky-Sommerer R, Williams SCR, Turkheimer F, Leschziner GD, Morrell MJ, Rosenzweig Iet al., 2018,

    Obstructive sleep apnoea and Alzheimer's disease: in search of shared pathomechanisms

    , Neuroscience and Biobehavioral Reviews, Vol: 86, Pages: 142-149, ISSN: 0149-7634

    Alzheimer’s disease (AD) is a significant public health concern. The incidence continues to rise, and it is set to be over one million in the UK by 2025. The processes involved in the pathogenesis of AD have been shown to overlap with those found in cognitive decline in patients with Obstructive Sleep Apnoea (OSA). Currently, the standard treatment for OSA is Continuous Positive Airway Pressure. Adherence to treatment can, however, be an issue, especially in patients with dementia. Also, not all patients respond adequately, necessitating the use of additional treatments. Based on the body of data, we here suggest that excessive and prolonged neuronal activity might contribute to genesis and acceleration of both AD and OSA in the absence of appropriately structured sleep. Further, we argue that external factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain, and further promote disease progression. If this hypothesis is proven in future studies, it could have far-reaching clinical translational implications, as well as implications for future treatment strategies in OSA.

  • Journal article
    Finkel RS, Mercuri E, Meyer OH, Simonds AK, Schroth MK, Graham RJ, Kirschner J, Iannaccone ST, Crawford TO, Woods S, Muntoni F, Wirth B, Montes J, Main M, Mazzone ES, Vitale M, Snyder B, Quijano-Roy S, Bertini E, Davis RH, Qian Y, Sejersen Tet al., 2018,

    Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics

    , NEUROMUSCULAR DISORDERS, Vol: 28, Pages: 197-207, ISSN: 0960-8966
  • Journal article
    Moskwa S, Piotrowski W, Marczak J, Pawelczyk M, Lewandowska-Polak A, Jarzebska M, Brauncajs M, Globinska A, Gorski P, Papadopoulos NG, Edwards MR, Johnston SL, Kowalski MLet al., 2018,

    Innate Immune Response to Viral Infections in Primary Bronchial Epithelial Cells is Modified by the Atopic Status of Asthmatic Patients

    , ALLERGY ASTHMA & IMMUNOLOGY RESEARCH, Vol: 10, Pages: 144-154, ISSN: 2092-7355

    PurposeIn order to gain an insight into determinants of reported variability in immune responses to respiratory viruses in human bronchial epithelial cells (HBECs) from asthmatics, the responses of HBEC to viral infections were evaluated in HBECs from phenotypically heterogeneous groups of asthmatics and in healthy controls.MethodsHBECs were obtained during bronchoscopy from 10 patients with asthma (6 atopic and 4 non-atopic) and from healthy controls (n=9) and grown as undifferentiated cultures. HBECs were infected with parainfluenza virus (PIV)-3 (MOI 0.1) and rhinovirus (RV)-1B (MOI 0.1), or treated with medium alone. The cell supernatants were harvested at 8, 24, and 48 hours. IFN-α, CXCL10 (IP-10), and RANTES (CCL5) were analyzed by using Cytometric Bead Array (CBA), and interferon (IFN)-β and IFN-λ1 by ELISA. Gene expression of IFNs, chemokines, and IFN-regulatory factors (IRF-3 and IRF-7) was determined by using quantitative PCR.ResultsPIV3 and RV1B infections increased IFN-λ1 mRNA expression in HBECs from asthmatics and healthy controls to a similar extent, and virus-induced IFN-λ1 expression correlated positively with IRF-7 expression. Following PIV3 infection, IP-10 protein release and mRNA expression were significantly higher in asthmatics compared to healthy controls (median 36.03-fold). No differences in the release or expression of RANTES, IFN-λ1 protein and mRNA, or IFN-α and IFN-β mRNA between asthmatics and healthy controls were observed. However, when asthmatics were divided according to their atopic status, HBECs from atopic asthmatics (n=6) generated significantly more IFN-λ1 protein and demonstrated higher IFN-α, IFN-β, and IRF-7 mRNA expressions in response to PIV3 compared to non-atopic asthmatics (n=4) and healthy controls (n=9). In response to RV1B infection, IFN-β mRNA expression was lower (12.39-fold at 24 hours and 19.37-fold at 48 hours) in non-atopic asthmatics com

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