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  • 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
    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.

  • 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
    Garcia E, Bernardino de la Serna J, 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
  • 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, Bernardino de la Serna J, 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
    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
    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
    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
    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.

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