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Marcellini A, Swieboda D, Guedan A, et al., 2017, Modulation of pro-inflammatory and anti-viral responses in BEAS2B cells by glucocorticoid agonists, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Wong E, Dhariwal J, Cuthbertson L, et al., 2017, An imbalanced airway microbiota correlates with greater peak flow decline in virus-induced asthma exacerbations, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Hellings PW, Fokkens WJ, Bachert C, et al., 2017, Positioning the principles of precision medicine in care pathways for allergic rhinitis and chronic rhinosinusitis - A EUFOREA-ARIA-EPOS-AIRWAYS ICP statement, Allergy, Vol: 72, Pages: 1297-1305, ISSN: 0105-4538
Precision medicine (PM) is increasingly recognized as the way forward for optimizing patient care. Introduced in the field of oncology, it is now considered of major interest in other medical domains like allergy and chronic airway diseases, which face an urgent need to improve the level of disease control, enhance patient satisfaction and increase effectiveness of preventive interventions. The combination of personalized care, prediction of treatment success, prevention of disease and patient participation in the elaboration of the treatment plan is expected to substantially improve the therapeutic approach for individuals suffering from chronic disabling conditions. Given the emerging data on the impact of patient stratification on treatment outcomes, European and American regulatory bodies support the principles of PM and its potential advantage over current treatment strategies. The aim of the current document was to propose a consensus on the position and gradual implementation of the principles of PM within existing adult treatment algorithms for allergic rhinitis (AR) and chronic rhinosinusitis (CRS). At the time of diagnosis, prediction of success of the initiated treatment and patient participation in the decision of the treatment plan can be implemented. The second‐level approach ideally involves strategies to prevent progression of disease, in addition to prediction of success of therapy, and patient participation in the long‐term therapeutic strategy. Endotype‐driven treatment is part of a personalized approach and should be positioned at the tertiary level of care, given the efforts needed for its implementation and the high cost of molecular diagnosis and biological treatment.
Upton N, Jackson DJ, Nikonova AA, et al., 2017, Rhinovirus induction of fractalkine (CX3CL1) in airway and peripheral blood mononuclear cells in asthma, PLoS ONE, Vol: 12, ISSN: 1932-6203
Rhinovirus infection is associated with the majority of asthma exacerbations. The role of fractalkine in anti-viral (type 1) and pathogenic (type 2) responses to rhinovirus infection in allergic asthma is unknown. To determine whether (1) fractalkine is produced in airway cells and in peripheral blood leucocytes, (2) rhinovirus infection increases production of fractalkine and (3) levels of fractalkine differ in asthmatic compared to non-asthmatic subjects. Fractalkine protein and mRNA levels were measured in bronchoalveolar lavage (BAL) cells and peripheral blood mononuclear cells (PBMCs) from non-asthmatic controls (n = 15) and mild allergic asthmatic (n = 15) subjects. Protein levels of fractalkine were also measured in macrophages polarised ex vivo to give M1 (type 1) and M2 (type 2) macrophages and in BAL fluid obtained from mild (n = 11) and moderate (n = 14) allergic asthmatic and non-asthmatic control (n = 10) subjects pre and post in vivo rhinovirus infection. BAL cells produced significantly greater levels of fractalkine than PBMCs. Rhinovirus infection increased production of fractalkine by BAL cells from non-asthmatic controls (P<0.01) and in M1-polarised macrophages (P<0.05), but not in BAL cells from mild asthmatics or in M2 polarised macrophages. Rhinovirus induced fractalkine in PBMCs from asthmatic (P<0.001) and healthy control subjects (P<0.05). Trends towards induction of fractalkine in moderate asthmatic subjects during in vivo rhinovirus infection failed to reach statistical significance. Fractalkine may be involved in both immunopathological and anti-viral immune responses to rhinovirus infection. Further investigation into how fractalkine is regulated across different cell types and into the effect of stimulation including rhinovirus infection is warranted to better understand the precise role of this unique dual adhesion factor and chemokine in immune cell recruitment.
Haldar K, Bafadhel M, Lau K, et al., 2017, Microbiome balance in sputum determined by PCR stratifies COPD exacerbations and shows potential for selective use of antibiotics, PLOS ONE, Vol: 12, ISSN: 1932-6203
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- Citations: 23
Farne HA, Johnston SL, 2017, Immune mechanisms of respiratory viral infections in asthma., Current Opinion in Immunology, Vol: 48, Pages: 31-37, ISSN: 0952-7915
The more severe pathology respiratory viral infections produce in asthma sufferers is a result of a dysregulated immune response. Excess type 2 inflammation is a well-described feature of virally induced asthma exacerbations, with growing evidence that production of antiviral interferons may also be impaired. However, the mechanisms underlying these are little understood. This review summarizes the current understanding and recent discoveries of the cellular and molecular events that follow viral infections in asthma. In particular, we discuss differences in viral sensing and intracellular signalling pathways upstream of interferon induction in asthma, and the role of epithelial-derived cytokines in orchestrating type 2 immunopathology, including type 2 innate lymhpoid cells (ILC2s).
Edwards MR, Walton RP, Jackson DJ, et al., 2017, The potential of anti-infectives and immunomodulators as therapies for asthma and asthma exacerbations., Allergy, Vol: 73, Pages: 50-63, ISSN: 0105-4538
Asthma is responsible for approximately 25,000 deaths annually in Europe despite available medicines that maintain asthma control and reduce asthma exacerbations. Better treatments are urgently needed for the control of chronic asthma and reduction in asthma exacerbations, the major cause of asthma mortality. Much research spanning >20 years shows a strong association between microorganisms including pathogens in asthma onset, severity and exacerbation, yet with the exception of antibiotics, few treatments are available that specifically target the offending pathogens. Recent insights into the microbiome suggest that modulating commensal organisms within the gut or lung may also be a possible way to treat/prevent asthma. The European Academy of Allergy & Clinical Immunology Task Force on Anti-infectives in Asthma was initiated to investigate the potential of anti-infectives and immunomodulators in asthma. This review provides a concise summary of the current literature and aimed to identify and address key questions that concern the use of anti-infectives and both microbe- and host-based immunomodulators and their feasibility for use in asthma.
Vasileiou E, Sheikh A, Butler C, et al., 2017, Effectiveness of influenza vaccines in asthma: a systematic review and meta-analysis, Clinical Infectious Diseases, Vol: 65, Pages: 1388-1395, ISSN: 1058-4838
There is uncertainty about the effectiveness of influenza vaccination in people with asthma and its impact on asthma outcomes, which may contribute to the sub-optimal vaccination rates in people with asthma. This systematic review and meta-analysis involved searching 12 international databases for randomized controlled trials (RCTs) and high quality quasi-experimental and epidemiological studies (1970 to 2016). The risk of bias was low for three included RCTs. The quality of three included observational studies was moderate. The quality of evidence was very low for all study outcomes. Pooled vaccine effectiveness in 1,825 people with asthma from two test-negative design case-control studies was 45% (95% CI 31 to 56) for laboratory-confirmed influenza. Pooled efficacy of live vaccines in reducing influenza was 81% (95% CI 33 to 94). Live vaccine reduced febrile illness by 72% (95% CI 20 to 90). Influenza vaccine prevented 59-78% of asthma attacks leading to emergency visits and/or hospitalizations. For people with asthma influenza vaccination may be effective in both reducing influenza infection and asthma attacks.
Toussaint M, Jackson DJ, Swieboda D, et al., 2017, Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation, Nature Medicine, Vol: 23, Pages: 681-691, ISSN: 1078-8956
Respiratory viral infections represent the most common cause of allergic asthma exacerbations. Amplification of the type-2 immune response is strongly implicated in asthma exacerbation, but how virus infection boosts type-2 responses is poorly understood. We report a significant correlation between the release of host double-stranded DNA (dsDNA) following rhinovirus infection and the exacerbation of type-2 allergic inflammation in humans. In a mouse model of allergic airway hypersensitivity, we show that rhinovirus infection triggers dsDNA release associated with the formation of neutrophil extracellular traps (NETs), known as NETosis. We further demonstrate that inhibiting NETosis by blocking neutrophil elastase or by degrading NETs with DNase protects mice from type-2 immunopathology. Furthermore, the injection of mouse genomic DNA alone is sufficient to recapitulate many features of rhinovirus-induced type-2 immune responses and asthma pathology. Thus, NETosis and its associated extracellular dsDNA contribute to the pathogenesis and may represent potential therapeutic targets of rhinovirus-induced asthma exacerbations.
Prakash R, Hallett IC, Wong SF, et al., 2017, Cell separation in kiwifruit without development of a specialised detachment zone, BMC PLANT BIOLOGY, Vol: 17, ISSN: 1471-2229
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- Citations: 8
Papadopoulos NG, Androutsopoulou A, Akdis C, et al., 2017, Asthma research in Europe: a transformative agenda for innovation and competitiveness, European Respiratory Journal, Vol: 49, ISSN: 0903-1936
Asthma is highly prevalent, often starting in infancy and persisting throughout life, and is associated with high morbidity and burden. It is a major global health challenge with growing impact, affecting more than 300 million people worldwide and at least 10% of all Europeans [1]. Furthermore, it is the most prevalent long-term condition in children [2]. Approximately 5–10% of asthma cases are so severe that current treatments do not work, and over five million people in the European Union (EU) fall into this category.People with asthma live at risk of life-threatening asthma attacks, leading to at least 500 000 hospitalisations worldwide each year [3]. A European study estimated that unscheduled care and rescue medication accounted for 47% of the total cost-per-patient in infants, 45% in children and 56% in adults [4]. This results in high socio-economic impact, estimated at more than €70 billion annually [1]. This includes the costs of direct primary and hospital healthcare (estimated to be close to €20 billion per annum), costs due to lost productivity (€14 billion) [1], and the monetised value of disability-adjusted life-years (DALYs) lost (over €38 billion) [1]. Close to 1 million DALYs are lost due to asthma in Europe every year [5].Despite the fact that the direct and indirect costs of asthma are substantial and continue to rise, asthma remains under-prioritised in the EU research agenda. Only 0.5% of the Seventh Framework Programme (FP7) health research budget was devoted to asthma and chronic obstructive pulmonary disease (COPD) (€30 million) [5]. In comparison, some 5.4 times this amount (over €163 million) was spent on cardiovascular conditions and some 20.6 times (over €618 million) on brain research.Asthma, with its high global prevalence and an associated multi-billion global market for treatments, plus its historical underfunding and the demand for new treatments and diagnostics, represents an enormous opportu
Toussaint M, Swieboda D, Guedan A, et al., 2017, NETosis and associated host DNA orchestrate rhinovirus-induced type 2 allergic asthma exacerbation, Nature Medicine, ISSN: 1546-170X
Respiratory viral infections represent the most common cause of allergic asthma exacerbations. Amplification of type 2 immunity is strongly implicated in asthma exacerbation, but how virus infection boosts type 2 responses during exacerbation is poorly understood. We report a significant correlation between release of host double stranded DNA (dsDNA) following rhinovirus infection and exacerbation of type 2 allergic inflammation and disease severity in patients. In a mouse model, we show that rhinovirus infection triggers neutrophil extracellular traps (NETs) formation and host dsDNA release. We further demonstrate that inhibiting NETosis by blocking neutrophil elastase or degrading NETs with DNase protects mice from type 2 allergic asthma exacerbations. Furthermore, injection of host dsDNA alone is sufficient to recapitulate many features of rhinovirus-induced type 2 immune responses and asthma pathology. Thus, NETosis and host dsDNA contribute to exacerbation pathogenesis and may represent potential targets for novel treatments of rhinovirus-induced asthma exacerbations.
Edwards MR, Saglani S, Schwarze J, et al., 2017, Addressing unmet needs in understanding asthma mechanisms: From the European Asthma Research and Innovation Partnership (EARIP) Work Package (WP)2 collaborators, European Respiratory Journal, Vol: 49, ISSN: 1399-3003
Asthma is a heterogeneous, complex disease with clinical phenotypes that incorporate persistent symptoms and acute exacerbations. It affects many millions of Europeans throughout their education and working lives and puts a heavy cost on European productivity. There is a wide spectrum of disease severity and control. Therapeutic advances have been slow despite greater understanding of basic mechanisms and the lack of satisfactory preventative and disease modifying management for asthma constitutes a significant unmet clinical need. Preventing, treating and ultimately curing asthma requires co-ordinated research and innovation across Europe. The European Asthma Research and Innovation Partnership (EARIP) is an FP7-funded programme which has taken a co-ordinated and integrated approach to analysing the future of asthma research and development. This report aims to identify the mechanistic areas in which investment is required to bring about significant improvements in asthma outcomes.
Johnston SL, Mansur A, Chauhan A, 2017, Incorrect Conclusions Concerning Antibiotics and Asthma Exacerbation, JAMA INTERNAL MEDICINE, Vol: 177, Pages: 598-598, ISSN: 2168-6106
Tunstall T, Kon OM, Bartlett N, et al., 2017, A Comprehensive Evaluation of Nasal and Bronchial Cytokines and Chemokines Following Experimental Rhinovirus Infection in Allergic Asthma: Increased Interferons (IFN-γ and IFN-λ) and Type 2 Inflammation (IL-5 and IL-13), EBioMedicine, Vol: 19, Pages: 128-138, ISSN: 2352-3964
BackgroundRhinovirus infection is a major cause of asthma exacerbations.ObjectivesWe studied nasal and bronchial mucosal inflammatory responses during experimental rhinovirus-induced asthma exacerbations.MethodsWe used nasosorption on days 0, 2–5 and 7 and bronchosorption at baseline and day 4 to sample mucosal lining fluid to investigate airway mucosal responses to rhinovirus infection in patients with allergic asthma (n = 28) and healthy non-atopic controls (n = 11), by using a synthetic absorptive matrix and measuring levels of 34 cytokines and chemokines using a sensitive multiplex assay.ResultsFollowing rhinovirus infection asthmatics developed more upper and lower respiratory symptoms and lower peak expiratory flows compared to controls (all P < 0.05). Asthmatics also developed higher nasal lining fluid levels of an anti-viral pathway (including IFN-γ, IFN-λ/IL-29, CXCL11/ITAC, CXCL10/IP10 and IL-15) and a type 2 inflammatory pathway (IL-4, IL-5, IL-13, CCL17/TARC, CCL11/eotaxin, CCL26/eotaxin-3) (area under curve day 0–7, all P < 0.05). Nasal IL-5 and IL-13 were higher in asthmatics at day 0 (P < 0.01) and levels increased by days 3 and 4 (P < 0.01). A hierarchical correlation matrix of 24 nasal lining fluid cytokine and chemokine levels over 7 days demonstrated expression of distinct interferon-related and type 2 pathways in asthmatics. In asthmatics IFN-γ, CXCL10/IP10, CXCL11/ITAC, IL-15 and IL-5 increased in bronchial lining fluid following viral infection (all P < 0.05).ConclusionsPrecision sampling of mucosal lining fluid identifies robust interferon and type 2 responses in the upper and lower airways of asthmatics during an asthma exacerbation. Nasosorption and bronchosorption have potential to define asthma endotypes in stable disease and at exacerbation.
Petrova NV, Emelyanova AG, Gorbunov EA, et al., 2017, Efficacy of novel antibody-based drugs against rhinovirus infection: In vitro and in vivo results, ANTIVIRAL RESEARCH, Vol: 142, Pages: 185-192, ISSN: 0166-3542
Guedan A, Swieboda D, Charles M, et al., 2017, Investigation of the Role of Protein Kinase D in Human Rhinovirus Replication, Journal of Virology, Vol: 91, ISSN: 0022-538X
Picornavirus replication is known to cause extensive remodeling of Golgi and endoplasmic reticulum membranes, and a number of the host proteins involved in the viral replication complex have been identified, including oxysterol binding protein (OSBP) and phosphatidylinositol 4-kinase III beta (PI4KB). Since both OSBP and PI4KB are substrates for protein kinase D (PKD) and PKD is known to be involved in the control of Golgi membrane vesicular and lipid transport, we hypothesized that PKD played a role in viral replication. We present multiple lines of evidence in support of this hypothesis. First, infection of HeLa cells with human rhinovirus (HRV) induced the phosphorylation of PKD. Second, PKD inhibitors reduced HRV genome replication, protein expression, and titers in a concentration-dependent fashion and also blocked the replication of poliovirus (PV) and foot-and-mouth disease virus (FMDV) in a variety of cells. Third, HRV replication was significantly reduced in HeLa cells overexpressing wild-type and mutant forms of PKD1. Fourth, HRV genome replication was reduced in HAP1 cells in which the PKD1 gene was knocked out by clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9. Although we have not identified the molecular mechanism through which PKD regulates viral replication, our data suggest that this is not due to enhanced interferon signaling or an inhibition of clathrin-mediated endocytosis, and PKD inhibitors do not need to be present during viral uptake. Our data show for the first time that targeting PKD with small molecules can inhibit the replication of HRV, PV, and FMDV, and therefore, PKD may represent a novel antiviral target for drug discovery.
Bousquet J, Farrell J, Crooks G, et al., 2017, Erratum to: Scaling up strategies of the chronic respiratory disease programme of the European Innovation Partnership on Active and Healthy Ageing (Action Plan B3: Area 5), CLINICAL AND TRANSLATIONAL ALLERGY, Vol: 7, ISSN: 2045-7022
Bright PD, Gompels M, Donati M, et al., 2017, Successful oral treatment of Ganciclovir resistant cytomegalovirus with Maribavir in the context of primary immunodeficiency: First case report and review, JOURNAL OF CLINICAL VIROLOGY, Vol: 87, Pages: 12-16, ISSN: 1386-6532
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- Citations: 7
Dhariwal J, Cameron A, Trujillo-Torralbo MB, et al., 2017, Mucosal type 2 innate lymphoid cells are a key component of the allergic response to aeroallergen, American Journal of Respiratory and Critical Care Medicine, Vol: 195, Pages: 1586-1596, ISSN: 1535-4970
RATIONALE: Newly characterised type 2 innate lymphoid cells display potent type 2 effector functionality, however their contribution to allergic airways inflammation and asthma is poorly understood. Mucosal biopsy used to characterise the airway mucosa is invasive, poorly tolerated and does not allow sequential sampling. OBJECTIVES: To assess the role of type 2 innate lymphoid cells during nasal allergen challenge in subjects with allergic rhinitis, using novel non-invasive methodology. METHODS: We used a human experimental allergen challenge model, with flow cytometric analysis of nasal curettage samples, to assess the recruitment of type 2 innate lymphoid cells and granulocytes to the upper airways of atopic and healthy subjects following allergen provocation. Soluble mediators in the nasal lining fluid were measured using nasosorption. MEASUREMENTS AND MAIN RESULTS: Following allergen challenge, atopic subjects displayed rapid induction of upper airway symptoms, an enrichment of type 2 innate lymphoid cells, eosinophils and neutrophils, along with increased production of interleukin-5, prostaglandin D2, and eosinophil and T-helper type 2 cell chemokines compared to healthy subjects. The most pronounced type 2 innate lymphoid cell recruitment was observed in patients with elevated serum IgE and airway eosinophilia. CONCLUSIONS: The rapid recruitment of type 2 innate lymphoid cells to the upper airways of allergic rhinitis patients, and their association with key type 2 mediators, highlights their likely important role in the early allergic response to aeroallergen in the airways. The novel methodology described herein enables the analysis of rare cell populations from non-invasive, serial tissue sampling.
Johnston S, Carpio J, Panuto J, et al., 2017, Spiritus: A Phase 2b Trial To Assess The Efficacy And Safety Of Vapendavir In Moderate And Severe Asthmatics With Rhinovirus Upper Respiratory Tract Infection, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Singanayagam A, Ritchie AI, Johnston SL, 2017, Role of microbiome in the pathophysiology and disease course of asthma, Current Opinion in Pulmonary Medicine, Vol: 23, Pages: 41-47, ISSN: 1070-5287
Purpose of review: The emergence of next-generation 16S rRNA sequencing techniques has facilitated a more detailed study of the body's microbiota and led to renewed interest in the association between microbial exposure and asthma inception. In this review, we evaluate the evidence that the respiratory tract and intestinal microbiota contribute to asthma pathogenesis and progression.Recent findings: Human studies have revealed associations between the presence of potentially pathogenic bacteria in the respiratory tract in early life and subsequent risk of allergic sensitization and asthma. Similarly, alterations in the intestinal microbiota of neonates have also been shown to precede the development of asthma. Emerging evidence suggests that the lung microbiota is dysregulated in asthma with specific changes in bacterial diversity and community composition according to severity and phenotype. Studies using germ-free mice have been invaluable in moving our understanding from correlation to causation by demonstrating a mechanistic link between the neonatal microbiota and the development of allergic airway inflammation.Summary: An expanding body of literature supports the hypothesis that early life microbial exposures and bacterial communities within the lung and/or intestine play an important role in shaping early immunological development. Perturbations in the microbiota may promote immune defects associated with the development of asthma and allergic sensitization.
Bousquet J, Bewick M, Cano A, et al., 2017, Building bridges for innovation in ageing: Synergies between action groups of the EIP on AHA, Journal of Nutrition, Health and Aging, Vol: 21, Pages: 92-104, ISSN: 1279-7707
The Strategic Implementation Plan of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) proposed six Action Groups. After almost three years of activity, many achievements have been obtained through commitments or collaborative work of the Action Groups. However, they have often worked in silos and, consequently, synergies between Action Groups have been proposed to strengthen the triple win of the EIP on AHA. The paper presents the methodology and current status of the Task Force on EIP on AHA synergies. Synergies are in line with the Action Groups’ new Renovated Action Plan (2016-2018) to ensure that their future objectives are coherent and fully connected. The outcomes and impact of synergies are using the Monitoring and Assessment Framework for the EIP on AHA (MAFEIP). Eight proposals for synergies have been approved by the Task Force: Five cross-cutting synergies which can be used for all current and future synergies as they consider overarching domains (appropriate polypharmacy, citizen empowerment, teaching and coaching on AHA, deployment of synergies to EU regions, Responsible Research and Innovation), and three cross-cutting synergies focussing on current Action Group activities (falls, frailty, integrated care and chronic respiratory diseases).
Bousquet J, Hellings PW, Agache I, et al., 2016, ARIA 2016: Care pathways implementing emerging technologies for predictive medicine in rhinitis and asthma across the life cycle, Clinical and Translational Allergy, Vol: 6, ISSN: 2045-7022
The Allergic Rhinitis and its Impact on Asthma (ARIA) initiative commenced during a World Health Organization workshop in 1999. The initial goals were (1) to propose a new allergic rhinitis classification, (2) to promote the concept of multi-morbidity in asthma and rhinitis and (3) to develop guidelines with all stakeholders that could be used globally for all countries and populations. ARIA—disseminated and implemented in over 70 countries globally—is now focusing on the implementation of emerging technologies for individualized and predictive medicine. MASK [MACVIA (Contre les Maladies Chroniques pour un Vieillissement Actif)-ARIA Sentinel NetworK] uses mobile technology to develop care pathways for the management of rhinitis and asthma by a multi-disciplinary group and by patients themselves. An app (Android and iOS) is available in 20 countries and 15 languages. It uses a visual analogue scale to assess symptom control and work productivity as well as a clinical decision support system. It is associated with an inter-operable tablet for physicians and other health care professionals. The scaling up strategy uses the recommendations of the European Innovation Partnership on Active and Healthy Ageing. The aim of the novel ARIA approach is to provide an active and healthy life to rhinitis sufferers, whatever their age, sex or socio-economic status, in order to reduce health and social inequalities incurred by the disease.
Naveed SU, Clements D, Jackson DJ, et al., 2016, MMP-1 activation contributes to airway smooth muscle growth and asthma severity, American Journal of Respiratory and Critical Care Medicine, Vol: 195, Pages: 1000-1009, ISSN: 1535-4970
INTRODUCTION: Matrix metalloproteinase-1 and mast cells are present in the airways of people with asthma. We hypothesised that matrix metalloproteinase-1 could be activated by mast cells and increase asthma severity. METHODS: Patients with stable asthma and healthy controls underwent spirometry, methacholine challenge, bronchoscopy and their airway smooth muscle cells were grown in culture. A second asthma group and controls had symptom scores, spirometry and bronchoalveolar lavage before and after rhinovirus-induced asthma exacerbations. Extra-cellular matrix was prepared from decellularised airway smooth muscle cultures. Matrix metalloproteinase-1 protein and activity were assessed. RESULTS: Airway smooth muscle cells generated pro-matrix metalloproteinase-1 which was proteolytically activated by mast cell tryptase. Airway smooth muscle treated with activated mast cell supernatants produced extra-cellular matrix which enhanced subsequent airway smooth muscle growth by 1.5 fold (p<0.05) which was dependent on matrix metalloproteinase-1 activation. In asthma, airway pro-matrix metalloproteinase-1 was 5.4 fold higher than control subjects (p=0.002). Mast cell numbers were associated with airway smooth muscle proliferation and matrix metalloproteinase-1 protein associated with bronchial hyper-responsiveness. During exacerbations, matrix metalloproteinase-1 activity increased and was associated with fall in FEV1 and worsening asthma symptoms. CONCLUSIONS: Matrix metalloproteinase-1 is activated by mast cell tryptase resulting in a pro-proliferative extra-cellular matrix. In asthma, mast cells are associated with airway smooth muscle growth, matrix metalloproteinase-1 levels are associated with bronchial hyper-responsiveness and matrix metalloproteinase-1 activation with exacerbation severity. Our findings suggest that airway smooth muscle/mast cell interactions contribute to asthma severity by transiently increasing matrix metalloproteinase activation, airway smooth
Wong EHC, Dhariwal J, Cuthbertson L, et al., 2016, THE AIRWAY MICROBIOTA IN HUMAN RHINOVIRUS INDUCED ASTHMA EXACERBATION, THORAX, Vol: 71, Pages: A218-A218, ISSN: 0040-6376
Telcian AG, Zdrenghea MT, Edwards MR, et al., 2016, Vitamin D increases the antiviral activity of bronchial epithelial cells in vitro, Antiviral Research, Vol: 137, Pages: 93-101, ISSN: 1872-9096
BACKGROUND: By modulating the antiviral immune response via vitamin D receptor, the active form of vitamin D (1,25-dihydroxyvitamin D, calcitriol) could play a central role in protection against respiratory virus infections. This in vitro study tested the hypothesis that respiratory viruses modulate vitamin D receptor expression in human bronchial epithelial cells and this modulation affects the antiviral response to exogenous vitamin D. METHODS: Human primary bronchial epithelial cells were infected with rhinoviruses and respiratory syncytial virus in the presence or absence of vitamin D. Expression of vitamin D receptor, 1α-hydroxylase (1α(OH)ase), 24-hydroxylase (24(OH)ase), innate interferons, interferon stimulated genes and cathelicidin were measured by quantitative polymerase chain reaction. The antiviral effect of vitamin D on rhinovirus replication was determined by measurement of virus load. A direct inactivation assay was used to determine the antiviral activity of cathelicidin. RESULTS: Both RV and RSV decreased vitamin D receptor and 24(OH)ase and, in addition, RSV increased 1α(OH)ase expression in epithelial cells. Vitamin D decreased rhinovirus replication and release, and increased rhinovirus-induced interferon stimulated genes and cathelicidin. Furthermore, cathelicidin had direct anti-rhinovirus activity. CONCLUSIONS: Despite lower vitamin D receptor levels in rhinovirus-infected epithelial cells, exogenous vitamin D increased antiviral defences most likely via cathelicidin and innate interferon pathways.
Johnston SL, Szigeti M, Cross M, et al., 2016, Azithromycin for acute exacerbations of asthma. The AZALEA randomized clinical trial, JAMA Internal Medicine, Vol: 176, Pages: 1630-1637, ISSN: 2168-6106
Importance Guidelines recommend against antibiotic use to treat asthma attacks. A study with telithromycin reported benefit, but adverse reactions limit its use.Objective To determine whether azithromycin added to standard care for asthma attacks in adults results in clinical benefit.Design, Setting, and Participants The Azithromycin Against Placebo in Exacerbations of Asthma (AZALEA) randomized, double-blind, placebo-controlled clinical trial, a United Kingdom–based multicenter study in adults requesting emergency care for acute asthma exacerbations, ran from September 2011 to April 2014. Adults with a history of asthma for more than 6 months were recruited within 48 hours of presentation to medical care with an acute deterioration in asthma control requiring a course of oral and/or systemic corticosteroids.Interventions Azithromycin 500 mg daily or matched placebo for 3 days.Main Outcomes and Measures The primary outcome was diary card symptom score 10 days after randomization, with a hypothesized treatment effect size of −0.3. Secondary outcomes were diary card symptom score, quality-of-life questionnaires, and lung function changes, all between exacerbation and day 10, and time to a 50% reduction in symptom score.Results Of 4582 patients screened at 31 centers, 199 of a planned 380 were randomized within 48 hours of presentation. The major reason for nonrecruitment was receipt of antibiotics (2044 [44.6%] screened patients). Median time from presentation to drug administration was 22 hours (interquartile range, 14-28 hours). Exacerbation characteristics were well balanced across treatment arms and centers. The primary outcome asthma symptom scores were mean (SD), 4.14 (1.38) at exacerbation and 2.09 (1.71) at 10 days for the azithromycin group and 4.18 (1.48) and 2.20 (1.51) for the placebo group, respectively. Using multilevel modeling, there was no significant difference in symptom scores between azithromycin and placebo at day 10 (difference
Farne H, Jackson DJ, Johnston SL, 2016, Are emerging PGD2 antagonists a promising therapy class for treating asthma?, Expert Opinion on Emerging Drugs, Vol: 21, Pages: 359-364, ISSN: 1744-7623
Zdrenghea MT, Makrinioti H, Bagacean C, et al., 2016, Vitamin D modulation of innate immune responses to respiratory viral infections, Reviews in Medical Virology, Vol: 27, ISSN: 1099-1654
Vitamin D, in addition to its classical functions in bone homeostasis, has a modulatory and regulatory role in multiple processes, including host defense, inflammation, immunity, and epithelial repair. Patients with respiratory disease are frequently deficient in vitamin D, implying that supplementation might provide significant benefit to these patients. Respiratory viral infections are common and are the main trigger of acute exacerbations and hospitalization in children and adults with asthma and other airways diseases. Respiratory monocytes/macrophages and epithelial cells constitutively express the vitamin D receptor. Vitamin D, acting through this receptor, may be important in protection against respiratory infections. Whether the in vitro findings can be translated into a substantial in vivo benefit still remains uncertain. Here we review the in vitro data on the role of vitamin D in antiviral innate immunity, the data concerning the deficient levels of vitamin D in lung diseases, and the in vivo role of supplementation as protection against respiratory viral infections in healthy individuals and in patients with chronic respiratory diseases. Finally, we suggest ways of improving the effectiveness of vitamin D as an adjuvant in the prevention and treatment of acute respiratory infections.
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