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Conference paperBonvini SJ, Wortley MA, Adcock JJ, et al., 2018,
Oestradiol Triggers Airway Sensory Nerve Activation Via The TRPM3-P2X2/3 Ion Channel Axis
, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X -
Conference paperChen X, Bonvini SJ, Dubuis E, et al., 2018,
Cromoglycate Inhibits Airway Sensory Nerves Through an Impact on NADPHase: A Novel Understanding of Its Biological Activity?
, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X -
Journal articleHajian B, De Backer J, Vos W, et al., 2018,
Changes in ventilation-perfusion during and after an COPD exacerbation: an assessment using fluid dynamic modeling
, International Journal of Chronic Obstructive Pulmonary Disease, Vol: 13, Pages: 833-842, ISSN: 1176-9106Introduction: Severe exacerbations associated with chronic obstructive pulmonary disease (COPD) that require hospitalization significantly contribute to morbidity and mortality. Definitions for exacerbations are very broad, and it is unclear whether there is one predominant underlying mechanism that leads to them. Functional respiratory imaging (FRI) with modeling provides detailed information about airway resistance, hyperinflation, and ventilation-perfusion (V/Q) mismatch during and following an acute exacerbation. Materials and methods: Forty-two patients with COPD participating in a multicenter study were assessed by FRI, pulmonary function tests, and self-reported outcome measures during an acute exacerbation and following resolution. Arterial blood gasses and lung function parameters were measured. Results: A significant correlation was found between alveolar-arterial gradient and image-based V/Q (iV/Q), suggesting that iV/Q represents V/Q mismatch during an exacerbation (p<0.05). Conclusion: Recovery of an exacerbation is due to decreased (mainly distal) airway resistance (p<0.05). Improvement in patient-reported outcomes were also associated with decreased distal airway resistance (p<0.05), but not with forced expiratory volume. FRI is, therefore, a sensitive tool to describe changes in airway caliber, ventilation, and perfusion during and after exacerbation. On the basis of the fact that FRI increased distal airway resistance seems to be the main cause of an exacerbation, therapy should mainly focus on decreasing it during and after the acute event.
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Conference paperWortley MA, Adcock JJ, Dubuis ED, et al., 2018,
Key Role for TLR2 in Bacterial Activation of Airway Sensory Nerves
, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X -
Journal articleDemenais F, Margaritte-Jeannin P, Barnes KC, et al., 2017,
Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks
, Nature Genetics, Vol: 50, Pages: 42-53, ISSN: 1061-4036We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.
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Journal articleWang Z, Singh R, Miller BE, et al., 2017,
Sputum microbiome temporal variability and dysbiosis in chronic obstructive pulmonary disease exacerbations: an analysis of the COPDMAP study
, Thorax, Vol: 73, Pages: 331-338, ISSN: 1468-3296BACKGROUND: Recent studies suggest that lung microbiome dysbiosis, the disease associated disruption of the lung microbial community, might play a key role in chronic obstructive pulmonary disease (COPD) exacerbations. However, characterising temporal variability of the microbiome from large longitudinal COPD cohorts is needed to better understand this phenomenon. METHODS: We performed a 16S ribosomal RNA survey of microbiome on 716 sputum samples collected longitudinally at baseline and exacerbations from 281 subjects with COPD at three UK clinical centres as part of the COPDMAP consortium. RESULTS: The microbiome composition was similar among centres and between stable and exacerbations except for a small significant decrease of Veillonella at exacerbations. The abundance of Moraxella was negatively associated with bacterial alpha diversity. Microbiomes were distinct between exacerbations associated with bacteria versus eosinophilic airway inflammation. Dysbiosis at exacerbations, measured as significant within subject deviation of microbial composition relative to baseline, was present in 41% of exacerbations. Dysbiosis was associated with increased exacerbation severity indicated by a greater fall in forced expiratory volume in one second, forced vital capacity and a greater increase in CAT score, particularly in exacerbations with concurrent eosinophilic inflammation. There was a significant difference of temporal variability of microbial alpha and beta diversity among centres. The variation of beta diversity significantly decreased in those subjects with frequent historical exacerbations. CONCLUSIONS: Microbial dysbiosis is a feature of some exacerbations and its presence, especially in concert with eosinophilic inflammation, is associated with more severe exacerbations indicated by a greater fall in lung function. TRIAL REGISTRATION NUMBER: Results, NCT01620645.
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Journal articleLalas A, Nousias S, Kikidis D, et al., 2017,
Substance deposition assessment in obstructed pulmonary system through numerical characterization of airflow and inhaled particles attributes
, BMC Medical Informatics and Decision Making, Vol: 17, ISSN: 1472-6947BackgroundChronic obstructive pulmonary disease (COPD) and asthma are considered as the two most widespread obstructive lung diseases, whereas they affect more than 500 million people worldwide. Unfortunately, the requirement for detailed geometric models of the lungs in combination with the increased computational resources needed for the simulation of the breathing did not allow great progress to be made in the past for the better understanding of inflammatory diseases of the airways through detailed modelling approaches. In this context, computational fluid dynamics (CFD) simulations accompanied by fluid particle tracing (FPT) analysis of the inhaled ambient particles are deemed critical for lung function assessment. Also they enable the understanding of particle depositions on the airways of patients, since these accumulations may affect or lead to inflammations. In this direction, the current study conducts an initial investigation for the better comprehension of particle deposition within the lungs. More specifically, accurate models of the airways obstructions that relate to pulmonary disease are developed and a thorough assessment of the airflow behavior together with identification of the effects of inhaled particle properties, such as size and density, is conducted. Our approach presents a first step towards an effective personalization of pulmonary treatment in regards to the geometric characteristics of the lungs and the in depth understanding of airflows within the airways.MethodsA geometry processing technique involving contraction algorithms is established and used to employ the different respiratory arrangements associated with lung related diseases that exhibit airways obstructions. Apart from the normal lung case, two categories of obstructed cases are examined, i.e. models with obstructions in both lungs and models with narrowings in the right lung only. Precise assumptions regarding airflow and deposition fraction (DF) over various sections of th
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Journal articleKemp P, Connolly, Paul R, et al., 2017,
miR-424-5p reduces ribosomal RNA and protein synthesis in muscle wasting
, Journal of Cachexia, Sarcopenia and Muscle, Vol: 9, Pages: 400-416, ISSN: 2190-6009Background: A loss of muscle mass occurs as a consequence of a range of chronic and acute diseases as well as in older age. This wasting results from an imbalance of protein synthesis and degradation with a reduction in synthesis and resistance to anabolic stimulation often reported features. Ribosomes are required for protein synthesis so changes in the control of ribosome synthesis is a potential contributor to muscle wasting. MicroRNAs (miRNAs) are known regulators of muscle phenotype and have been shown to modulate components of the protein synthetic pathway. One miRNA that is predicted to target a number of components of protein synthetic pathway is miR-424-5p, which is elevated in the quadriceps of patients with chronic obstructive pulmonary disease (COPD).Methods: Targets of miR-424-5p were identified by Ago2 pull-down and the effects of the miRNA on RNA and protein expression were determined by qPCR and western blotting in muscle cells in vitro. Protein synthesis was determined by puromycin incorporation in vitro. The miRNA was over-expressed in the tibialis anterior muscle of mice by electroporation and the effects quantified. Finally, quadriceps expression of the miRNA was determined by qPCR in patients with COPD, intensive care unit acquired weakness (ICUAW), and in patients undergoing aortic surgery as well as in individuals from the Hertfordshire Sarcopenia Study.Results: Pull-down assays showed that miR-424-5p bound to mRNAs encoding proteins associated with muscle protein synthesis. The most highly enriched mRNAs encoded proteins required for the Pol I RNA pre-initiation complex (PIC) required for rRNA transcription, (PolR1A and Upstream binding transcription factor, UBTF). In vitro, miR-424-5p reduced expression of these RNAs, reduced rRNA levels and inhibited protein synthesis. In mice, over-expression of miR-322 (rodent miR-424 orthologue) caused fibre atrophy and reduced UBTF expression and rRNA levels. In humans elevated miR-424-5p as
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Journal articleSinharay R, Gong J, Barratt B, et al., 2017,
Respiratory and cardiovascular responses to walking down a traffic-polluted road compared with walking in a traffic-free area in participants aged 60 years and older with chronic lung or heart disease and age-matched healthy controls: a randomised, crossover study
, Lancet, Vol: 391, Pages: 339-349, ISSN: 0140-6736BackgroundLong-term exposure to pollution can lead to an increase in the rate of decline of lung function, especially in older individuals and in those with chronic obstructive pulmonary disease (COPD), whereas shorter-term exposure at higher pollution levels has been implicated in causing excess deaths from ischaemic heart disease and exacerbations of COPD. We aimed to assess the effects on respiratory and cardiovascular responses of walking down a busy street with high levels of pollution compared with walking in a traffic-free area with lower pollution levels in older adults.MethodsIn this randomised, crossover study, we recruited men and women aged 60 years and older with angiographically proven stable ischaemic heart disease or stage 2 Global initiative for Obstructive Lung Disease (GOLD) COPD who had been clinically stable for 6 months, and age-matched healthy volunteers. Individuals with ischaemic heart disease or COPD were recruited from existing databases or outpatient respiratory and cardiology clinics at the Royal Brompton & Harefield NHS Foundation Trust and age-matched healthy volunteers using advertising and existing databases. All participants had abstained from smoking for at least 12 months and medications were taken as recommended by participants' doctors during the study. Participants were randomly assigned by drawing numbered disks at random from a bag to do a 2 h walk either along a commercial street in London (Oxford Street) or in an urban park (Hyde Park). Baseline measurements of participants were taken before the walk in the hospital laboratory. During each walk session, black carbon, particulate matter (PM) concentrations, ultrafine particles, and nitrogen dioxide (NO2) concentrations were measured.FindingsBetween October, 2012, and June, 2014, we screened 135 participants, of whom 40 healthy volunteers, 40 individuals with COPD, and 39 with ischaemic heart disease were recruited. Concentrations of black carbon, NO2, PM10, PM2.5, and ul
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Conference paperWortley MA, Dubuis ED, Bonvini SJ, et al., 2017,
BACTERIA CAN TRIGGER AIRWAY SENSORY NERVES VIA THE ACTIVATION OF TLR2
, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A1-A1, ISSN: 0040-6376- Author Web Link
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- Citations: 1
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Conference paperMullegama R, Pavlidis S, Chung KF, et al., 2017,
CLINICAL AND TRANSCRIPTOMIC PROFILES OF SEVERE ASTHMATICS WITH HIGH OR LOW EXPRESSION OF THE GLUCOCORTICOID RECEPTOR AND IMPORTIN-7
, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A40-A41, ISSN: 0040-6376 -
Conference paperFinney LJ, Belchamber K, Kemp S, et al., 2017,
HUMAN RHINOVIRUS IMPAIRS PHAGOCYTOSIS OF HAEMOPHILUS INFLUENZAE IN ALVEOLAR MACROPHAGES IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE
, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A112-A112, ISSN: 0040-6376- Author Web Link
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- Citations: 1
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Conference paperBonini M, Usmani O, Pacini A, et al., 2017,
MARKED SMALL AIRWAY DYSFUNCTION AND CONSEQUENT AIR-TRAPPING CHARACTERISE CHRONIC HYPERSENSITIVITY PNEUMONITIS (CHP) BUT NOT IDIOPATHIC PULMONARY FIBROSIS (IPF)
, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A34-A35, ISSN: 0040-6376 -
Conference paperBonvini SJ, Wortley MA, Adcock JJ, et al., 2017,
OESTROGEN: AN ENDOGENOUS AGONIST FOR TRPM3 TRIGGERED SENSORY NERVE ACTIVATION IN THE AIRWAY?
, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A1-A1, ISSN: 0040-6376 -
Journal articleLo C-Y, Michaeloudes C, Bhavsar PK, et al., 2017,
Reduced suppressive effect of beta(2)-adrenoceptor agonist on fibrocyte function in severe asthma
, RESPIRATORY RESEARCH, Vol: 18, ISSN: 1465-993XBackgroundPatients with severe asthma have increased airway remodelling and elevated numbers of circulating fibrocytes with enhanced myofibroblastic differentiation capacity, despite being treated with high doses of corticosteroids, and long acting β2-adrenergic receptor (AR) agonists (LABAs). We determined the effect of β2-AR agonists, alone or in combination with corticosteroids, on fibrocyte function.MethodsNon-adherent non-T cells from peripheral blood mononuclear cells isolated from healthy subjects and patients with non-severe or severe asthma were treated with the β2-AR agonist, salmeterol, in the presence or absence of the corticosteroid dexamethasone. The number of fibrocytes (collagen I+/CD45+ cells) and differentiating fibrocytes (α-smooth muscle actin+ cells), and the expression of CC chemokine receptor 7 and of β2-AR were determined using flow cytometry. The role of cyclic adenosine monophosphate (cAMP) was elucidated using the cAMP analogue 8-bromoadenosine 3′,5′-cyclic monophosphate (8-Br-cAMP) and the phosphodiesterase type IV (PDE4) inhibitor, rolipram.ResultsSalmeterol reduced the proliferation, myofibroblastic differentiation and CCR7 expression of fibrocytes from healthy subjects and non-severe asthma patients. Fibrocytes from severe asthma patients had a lower baseline surface β2-AR expression and were relatively insensitive to salmeterol but not to 8-Br-cAMP or rolipram. Dexamethasone increased β2-AR expression and enhanced the inhibitory effect of salmeterol on severe asthma fibrocyte differentiation.ConclusionsFibrocytes from patients with severe asthma are relatively insensitive to the inhibitory effects of salmeterol, an effect which is reversed by combination with corticosteroids.
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Journal articleGarcia E, Bernardino de la Serna J, 2017,
Dissecting single–cell molecular spatiotemporal mobility and clustering at Focal Adhesions in polarised cells by fluorescence fluctuation spectroscopy methods
<jats:title>Abstract</jats:title><jats:p>Quantitative fluorescence fluctuation spectroscopy from optical microscopy datasets is a very powerful tool to resolve multiple spatiotemporal cellular and subcellular processes at the molecular level. In particular, raster image correlation spectroscopy (RICS) and number and brightness analyses (N&B) yield molecular mobility and clustering dynamic information extracted from real-time cellular processes. This quantitative information can be inferred in a highly flexibly and detailed manner, i.e. 1) at the localisation level: from full-frame datasets and multiple regions of interest within; and 2) at the temporal level: not only from full-frame and multiple regions, but also intermediate temporal events. Here we build on previous research in deciphering the molecular dynamics of paxillin, a main component of focal adhesions. Cells use focal adhesions to attach to the extracellular matrix and interact with their local environment. Through focal adhesions and other adhesion structures, cells sense their local environment and respond accordingly; due to this continuous communication, these structures can be highly dynamic depending on the extracellular characteristics. By using a previously well-characterised model like paxillin, we examine powerful sensitivity characteristics and some limitations of RICS and N&B analyses. We show that cells upon contact to different surfaces show differential self-assembly dynamics in terms of molecular diffusion and oligomerisation. In addition, single-cell studies show that these dynamics change gradually following an antero-posterior gradient.</jats:p>
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Journal articleBelchamber KBR, Donnelly LE, 2017,
Correcting the "Wandering" Neutrophil with Statins A Novel Antiaging Strategy?
, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 196, Pages: 1243-1244, ISSN: 1073-449X -
Journal articleSreedharan S, Gill MR, Garcia E, et al., 2017,
Multimodal super-resolution optical microscopy using a transition-metal-based probe provides unprecedented capabilities for imaging both nuclear chromatin and mitochondria
, Journal of the American Chemical Society, Vol: 139, Pages: 15907-15913, ISSN: 0002-7863Detailed studies on the live cell uptake properties of a dinuclear membrane-permeable RuII cell probe show that, at low concentrations, the complex localizes and images mitochondria. At concentrations above ∼20 μM, the complex images nuclear DNA. Because the complex is extremely photostable, has a large Stokes shift, and displays intrinsic subcellular targeting, its compatibility with super-resolution techniques was investigated. It was found to be very well suited to image mitochondria and nuclear chromatin in two color, 2C-SIM, and STED and 3D-STED, both in fixed and live cells. In particular, due to its vastly improved photostability compared to that of conventional SR probes, it can provide images of nuclear DNA at unprecedented resolution.
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Journal articleToussaint M, Jackson DJ, Swieboda D, et al., 2017,
Corrigendum: Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation.
, Nat Med, Vol: 23, Pages: 1384-1384This corrects the article DOI: 10.1038/nm.4332.
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Journal articleMichaeloudes C, Bhavsar PK, Mumby S, et al., 2017,
Dealing with Stress: Defective Metabolic Adaptation in Chronic Obstructive Pulmonary Disease Pathogenesis
, Annals of the American Thoracic Society, Vol: 14, Pages: S374-S382, ISSN: 2329-6933The mitochondrion is the main site of energy production and ahub of key signaling pathways. It is also central in stress-adaptiveresponse due to its dynamic morphology and ability to interactwith other organelles. In response to stress, mitochondria fuseinto networks to increase bioenergetic efficiency and protectagainst oxidative damage. Mitochondrial damage triggerssegregation of damaged mitochondria from the mitochondrialnetwork through fission and their proteolytic degradation bymitophagy. Post-translational modifications of themitochondrial proteome and nuclear cross-talk lead toreprogramming of metabolic gene expression to maintain energyproduction and redox balance. Chronic obstructive pulmonarydisease (COPD) is caused by chronic exposure to oxidativestress arising from inhaled irritants, such as cigarette smoke.Impaired mitochondrial structure and function, due tooxidative stress–induced damage, may play a key role incausing COPD. Deregulated metabolic adaptation maycontribute to the development and persistence of mitochondrialdysfunction in COPD. We discuss the evidence for deregulatedmetabolic adaptation and highlight important areas forinvestigation that will allow the identification of moleculartargets for protecting the COPD lung from the effects ofdysfunctional mitochondria.
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