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Drysdale SB, Alcazar M, Wilson T, et al., 2016, Functional and genetic predisposition to rhinovirus lower respiratory tract infections in prematurely born infants, European Journal of Pediatrics, Vol: 175, Pages: 1943-1949, ISSN: 1432-1076
Term born infants are predisposed to human rhinovirus (HRV) lower respiratory tract infections (LRTI) by reduced neonatal lung function and genetic susceptibility. Our aim was to investigate whether prematurely born infants were similarly predisposed to HRV LRTIs or any other viral LRTIs. Infants born less than 36 weeks of gestational age were recruited. Prior to neonatal/maternity unit discharge, lung function (functional residual capacity by helium gas dilution and multiple breath washout, lung clearance index and compliance (Crs), and resistance (Rrs) of the respiratory system) was assessed and DNA samples assessed for eight single nucleotide polymorphisms (SNPs) in seven genes: ADAM33, IL10, MMP16 NFκB1A,SFTPC, VDR, and NOS2A. Infants were prospectively followed until 1 year corrected age. Nasopharyngeal aspirates (NPAs) were sent whenever an infant developed a LRTI and tested for 13 viruses. One hundred and thirty-nine infants were included in the analysis. Infants who developed HRV LRTIs had reduced Crs (1.6 versus 1.2 mL/cmH2O/kg, p = 0.044) at 36 weeks postmenstrual age. A SNP in the gene coding for the vitamin D receptor was associated with the development of HRV LRTIs and any viral LRTIs (p = 0.02). CONCLUSION: Prematurely born infants may have both a functional and genetic predisposition to HRV LRTIs. What is Known: • Term born infants are predisposed to rhinovirus lower respiratory tract (HRV LRTIs) infection by reduced neonatal lung function. • Term born infants requiring hospitalisation due to HRV bronchiolitis were more likely to have single nucleotide polymorphism (SNP) in the IL-10 gene. What is New: • Prematurely born infants who developed a HRV LRTI had lower C rs before maternity unit discharge. • A SNP in the gene coding for the vitamin D receptor was associated with the development of HRV LRTIs and overall respiratory viral LRTIs in prematurely born infants.
Glanville N, Peel TJ, Schröder A, et al., 2016, Tbet Deficiency Causes T Helper Cell Dependent Airways Eosinophilia and Mucus Hypersecretion in Response to Rhinovirus Infection, PLOS Pathogens, Vol: 12, ISSN: 1553-7366
Current understanding of adaptive immune, particularly T cell, responses to human rhinoviruses (RV) is limited. Memory T cells are thought to be of a primarily T helper 1 type, but both T helper 1 and T helper 2 memory cells have been described, and heightened T helper 2/ lessened T helper 1 responses have been associated with increased RV-induced asthma exacerbation severity. We examined the contribution of T helper 1 cells to RV-induced airways inflammation using mice deficient in the transcription factor T-Box Expressed In T Cells (Tbet), a critical controller of T helper 1 cell differentiation. Using flow cytometry we showed that Tbet deficient mice lacked the T helper 1 response of wild type mice and instead developed mixed T helper 2/T helper 17 responses to RV infection, evidenced by increased numbers of GATA binding protein 3 (GATA-3) and RAR-related orphan receptor gamma t (RORγt), and interleukin-13 and interleukin-17A expressing CD4+ T cells in the lung. Forkhead box P3 (FOXP3) and interleukin-10 expressing T cell numbers were unaffected. Tbet deficient mice also displayed deficiencies in lung Natural Killer, Natural Killer T cell and γδT cell responses, and serum neutralising antibody responses. Tbet deficient mice exhibited pronounced airways eosinophilia and mucus production in response to RV infection that, by utilising a CD4+ cell depleting antibody, were found to be T helper cell dependent. RV induction of T helper 2 and T helper 17 responses may therefore have an important role in directly driving features of allergic airways disease such as eosinophilia and mucus hypersecretion during asthma exacerbations.
da Silva J, Hilzendeger C, Moermans C, et al., 2016, Raised interferon β, type 3 interferon and interferon stimulated genes - evidence of innate immune activation in neutrophilic asthma., Clinical & Experimental Allergy, Vol: 47, Pages: 313-323, ISSN: 0954-7894
BACKGROUND: Interferons play an important role in innate immunity. Previous studies report deficiency in virus-induction of interferon (IFN)-α, -β and -λ in bronchial epithelial and bronchial lavage cells in atopic asthmatics. It is now recognized that asthma is a heterogeneous disease comprising different inflammatory phenotypes, some of which may involve innate immune activation in the absence of overt infection. OBJECTIVE: The aim of the study was investigate if the severity of asthma or a specific cellular sputum pattern may be linked to evidence of innate immune activation. METHODS: Here we investigate the expression of IFN-β, IFN-λ1 (IL-29), IFN-λ2/3 (IL-28A/B) and the interferon-stimulated genes (ISGs) myxovirus resistance 1 (Mx1), oligoadenylate synthetase (OAS) and viperin in unstimulated sputum cells in 57 asthmatics (including 16 mild, 19 moderate and 22 severe asthma patients) and compared them with 19 healthy subjects. RESULTS: We observed increased expression of IFN-β, IFN-λ1/IL-29, OAS and viperin in asthmatic compared to healthy subjects while IL-28 was not expressed in any group. The overexpression was restricted to neutrophilic asthmatics (sputum neutrophils ≥ 76%) while eosinophilic asthmatics (sputum eosinophils ≥ 3%) did not differ from healthy subjects or even showed a lower expression of Mx1. No difference in interferon or ISG expression was seen according to clinical asthma severity. CONCLUSION AND CLINICAL RELEVANCE: Neutrophilic, but not eosinophilic, asthmatics display overexpression of IFN-β, IFN-λ1/IL-29 and ISGs in their sputum cells that may reflect ongoing innate immune activation. This article is protected by copyright. All rights reserved.
Webber J, Tregonning J, Trujillo-Torralbo M-B, et al., 2016, Airway glucose in COPD exacerbations, ERS London, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Cameron A, Dhariwal J, Johnston S, et al., 2016, LATE-BREAKING ABSTRACT: Airway recruitment and anti-viral function of dendritic cells in asthmatic patients during RV-16 infection, ERS Conference London, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Mallia P, Trujillo-Torralbo M-B, Dhariwal J, et al., 2016, Safety of research bronchoscopy in asthma and COPD, ERS London, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Strong K, McErlean P, Dhariwal J, et al., 2016, The role of suppressor of cytokine signalling 1 (SOCS1) in virus-induced asthma exacerbations, ERS London, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Singanayagam A, Glanville N, James P, et al., 2016, Fluticasone propionate alters the respiratory tract microbiota and has dose-related effects on anti-bacterial host defence, ERS Conference London, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Bousquet J, Farrell J, Crooks G, et al., 2016, 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: 6, ISSN: 2045-7022
Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) focuses on the integrated care of chronic diseases. Area 5 (Care Pathways) was initiated using chronic respiratory diseases as a model. The chronic respiratory disease action plan includes (1) AIRWAYS integrated care pathways (ICPs), (2) the joint initiative between the Reference site MACVIA-LR (Contre les MAladies Chroniques pour un VIeillissement Actif) and ARIA (Allergic Rhinitis and its Impact on Asthma), (3) Commitments for Action to the European Innovation Partnership on Active and Healthy Ageing and the AIRWAYS ICPs network. It is deployed in collaboration with the World Health Organization Global Alliance against Chronic Respiratory Diseases (GARD). The European Innovation Partnership on Active and Healthy Ageing has proposed a 5-step framework for developing an individual scaling up strategy: (1) what to scale up: (1-a) databases of good practices, (1-b) assessment of viability of the scaling up of good practices, (1-c) classification of good practices for local replication and (2) how to scale up: (2-a) facilitating partnerships for scaling up, (2-b) implementation of key success factors and lessons learnt, including emerging technologies for individualised and predictive medicine. This strategy has already been applied to the chronic respiratory disease action plan of the European Innovation Partnership on Active and Healthy Ageing.
Porter JD, Watson J, Groves H, et al., 2016, Identification of novel macrolides with antibacterial, anti-inflammatory and type I and III IFN-augmenting activity in airway epithelium, Journal of Antimicrobial Chemotherapy, Vol: 71, Pages: 2767-2781, ISSN: 1460-2091
Background Exacerbations of asthma and COPD are triggered by rhinoviruses. Uncontrolled inflammatory pathways, pathogenic bacterial burden and impaired antiviral immunity are thought to be important factors in disease severity and duration. Macrolides including azithromycin are often used to treat the above diseases, but exhibit variable levels of efficacy. Inhaled corticosteroids are also readily used in treatment, but may lack specificity. Ideally, new treatment alternatives should suppress unwanted inflammation, but spare beneficial antiviral immunity.Methods In the present study, we screened 225 novel macrolides and tested them for enhanced antiviral activity against rhinovirus, as well as anti-inflammatory activity and activity against Gram-positive and Gram-negative bacteria. Primary bronchial epithelial cells were grown from 10 asthmatic individuals and the effects of macrolides on rhinovirus replication were also examined. Another 30 structurally similar macrolides were also examined.Results The oleandomycin derivative Mac5, compared with azithromycin, showed superior induction (up to 5-fold, EC50 = 5–11 μM) of rhinovirus-induced type I IFNβ, type III IFNλ1 and type III IFNλ2/3 mRNA and the IFN-stimulated genes viperin and MxA, yet had no effect on IL-6 and IL-8 mRNA. Mac5 also suppressed rhinovirus replication at 48 h, proving antiviral activity. Mac5 showed antibacterial activity against Gram-positive Streptococcus pneumoniae; however, it did not have any antibacterial properties compared with azithromycin when used against Gram-negative Escherichia coli (as a model organism) and also the respiratory pathogens Pseudomonas aeruginosa and non-typeable Haemophilus influenzae. Further non-toxic Mac5 derivatives were identified with various anti-inflammatory, antiviral and antibacterial activities.Conclusions The data support the idea that macrolides have antiviral properties through a mechanism that is yet to be ascertained. We also
Johnston SL, 2016, IFN deficiency in asthma attacks. Is restoring toll-like receptor-7 expression a new treatment approach in severe asthma?, American Journal of Respiratory and Critical Care Medicine, Vol: 194, Pages: 1-3, ISSN: 1535-4970
Lan F, Wane XD, Nauwynck HJ, et al., 2016, Th2 biased upper airway inflammation is associated with an impaired response to viral infection with Herpes simplex virus 1, Rhinology, Vol: 54, Pages: 141-149, ISSN: 0300-0729
Hilzendeger C, da Silva J, Henket M, et al., 2016, Reduced sputum expression of interferon-stimulated genes in severe COPD, International Journal of Chronic Obstructive Pulmonary Disease, Vol: 11, Pages: 1485-1494, ISSN: 1176-9106
BACKGROUND: Exacerbations of COPD are frequent and commonly triggered by respiratory tract infections. The purpose of our study was to investigate innate immunity in stable COPD patients. METHODS: Induced sputum was collected from 51 stable consecutive COPD patients recruited from the COPD Clinic of CHU Liege and 35 healthy subjects. Expression of interferons beta (IFN-β) and lambda1 (IL-29), IFN-stimulated genes (ISGs) MxA, OAS, and viperin were measured in total sputum cells by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The presence of Picornaviruses was assessed by RT-PCR, while potential pathogenic microorganisms (PPM) were identified by sputum bacteriology. RESULTS: Expression of IL-29 was found in 16 of 51 COPD patients (31%) and in nine of 35 healthy subjects (26%), while IFN-β was detected in six of 51 COPD patients (12%) and in two of 35 healthy subjects (6%). ISGs were easily detectable in both groups. In the whole group of COPD patients, OAS expression was decreased (P<0.05), while that of viperin was increased (P<0.01) compared to healthy subjects. No difference was found with respect to MxA. COPD patients from group D of Global Initiative for Chronic Obstructive Lung Disease (GOLD) had reduced expression of all three ISGs (P<0.01 for MxA, P<0.05 for OAS, and P<0.01 for viperin) as compared to those of group B patients. Picornaviruses were detected in eight of 51 (16%) COPD patients vs four of 33 (12%) healthy subjects, while PPM were detected in seven of 39 (18%) COPD patients and associated with raised sputum neutrophil counts. IFN-β expression was raised when either picornavirus or PPM were detected (P=0.06), but no difference was seen regarding IL-29 or ISGs. CONCLUSION: ISGs expression was reduced in severe COPD that may favor exacerbation and contribute to disease progress by altering response to infection.
Aab A, Wirz O, van de Veen W, et al., 2016, Human rhinoviruses enter and induce proliferation of B lymphocytes, Allergy, Vol: 72, Pages: 232-243, ISSN: 1398-9995
BACKGROUND: Human rhinoviruses (HRV) are one of the main causes of virus induced asthma exacerbations. Infiltration of B lymphocytes into the subepithelial tissue of the lungs has been demonstrated during rhinovirus infection in allergic individuals. However, the mechanisms through which HRVs modulate the immune responses of monocytes and lymphocytes are not yet well described. OBJECTIVE: To study the dynamics of virus uptake by monocytes and lymphocytes, and the ability of HRVs to induce activation of in vitro cultured human peripheral blood mononuclear cells. METHODS: Flow cytometry was used for the enumeration and characterization of lymphocytes. Proliferation was estimated using (3) H-thymidine or CFSE labelling and ICAM-1 blocking. We used bead based multiplex assays and quantitative PCR for cytokine quantification. HRV accumulation and replication inside B lymphocytes was detected by a combination of in situ hybridation (ISH), immunofluorescence and with PCR for positive strand and negative strand viral RNA. Cell images were acquired with imaging flow cytometry. RESULTS: By means of imaging flow cytometry, we demonstrate a strong and quick binding of HRV types 16 and 1B to monocytes, and slower interaction of these HRVs with CD4+ T cells, CD8+ T cells and CD19+ B cells. Importantly, we show that HRVs induce the proliferation of B cells while addition of anti-ICAM-1-antibody partially reduces this proliferation for HRV16. We prove with ISH that HRVs can enter B cells, form their viral replication centers and the newly formed virions are able to infect HeLa cells. In addition, we demonstrate that similarly to epithelial cells, HRVs induce the production of pro-inflammatory cytokines in PBMCs. CONCLUSION: Our results demonstrate for the first time that HRVs enter and form viral replication centers in B lymphocytes and induce the proliferation of B cells. Newly formed virions have the capacity to infect other cells (HeLa). These findings indicate that the regulati
Jha A, Jarvis H, Fraser C, et al., 2016, Respiratory Syncytial Virus, SARS, MERS and other Viral Lung Infections, Editors: Hui, Rossi, Johnston, Publisher: European Respiratory Society, Pages: 84-109, ISBN: 978-1-84984-069-9
RSV infection has an estimated global incidence of 33 million cases in children <5 years of age, with 10% requiring hospital admission and up to 199 000 dying of the disease. There is growing evidence that severe infantile RSV bronchiolitis, a condition characterised by an inflammatory reaction to the virus, is associated with later childhood wheeze in somevulnerable children; however, a direct causal relationship with asthma has not yet been established. RSV infection is also increasingly recognised as a cause of morbidity and mortality in those with underlying airway disease, the immunocompromised and frail elderlypersons. Novel molecular-based diagnostic tools are becoming established, but treatment remains largely supportive, with palivizumab the only licensed agent currently available for passive prophylaxis of selected pre-term infants. While effective treatments remain elusive,there is optimism about the testing of novel antiviral drugs and the development of vaccines that may induce long-lasting immunity without the risk of disease augmentation.
Lin L, Belgrave D, Bakhsoliani E, et al., 2016, Phenotyping immune responses In asthma and respiratory infections, American Thoracic Society 2016 International Conference, Publisher: American Thoracic Society, ISSN: 1535-4970
Bousquet J, Schünemann HJ, Hellings PW, et al., 2016, MACVIA clinical decision algorithm in adolescents and adults with allergic rhinitis, Journal of Allergy and Clinical Immunology, Vol: 138, Pages: 367-374.e2, ISSN: 1097-6825
The selection of pharmacotherapy for patients with allergic rhinitis (AR) depends on several factors, including age, prominent symptoms, symptom severity, control of AR, patient preferences, and cost. Allergen exposure and the resulting symptoms vary, and treatment adjustment is required. Clinical decision support systems (CDSSs) might be beneficial for the assessment of disease control. CDSSs should be based on the best evidence and algorithms to aid patients and health care professionals to jointly determine treatment and its step-up or step-down strategy depending on AR control. Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon (MACVIA-LR [fighting chronic diseases for active and healthy ageing]), one of the reference sites of the European Innovation Partnership on Active and Healthy Ageing, has initiated an allergy sentinel network (the MACVIA-ARIA Sentinel Network). A CDSS is currently being developed to optimize AR control. An algorithm developed by consensus is presented in this article. This algorithm should be confirmed by appropriate trials.
Singanayagam A, Johnston SL, 2016, Smoke and viruses-a hindrance to relaxing the airways?, Clinical Science, Vol: 130, Pages: 839-841, ISSN: 1470-8736
Inhaled β2-adrenoceptor agonists are a mainstay of therapy for airways diseases and are almost universally prescribed for patients with asthma or chronic obstructive pulmonary disease (COPD). Very few studies have evaluated the efficacy of these commonly used therapies during acute disease exacerbations which are frequently triggered by viral infection. In this edition of Clinical Science, Donovan et al. assess the ex vivo effects of the most commonly used short-acting β2-agonist salbutamol on small airway reactivity using precision cut lung slices (PCLS) from a mouse model of virus-induced exacerbation of COPD. They demonstrate that combined challenge with cigarette smoke and influenza infection in mice markedly impairs salbutamol-mediated airway relaxation. The findings of the present study suggest that cigarette smoke and respiratory virus infection may intefere with the ability of commonly prescribed therapies to effectively bronchodilate the airways.
Bønnelykke K, Vissing NH, Sevelsted A, et al., 2016, Reply, Journal of Allergy and Clinical Immunology, Vol: 170, Pages: 916-917, ISSN: 1097-6825
Reply to: Minna Lukkarinen, Tuomas Jartti, The first rhinovirus-wheeze acts as a marker for later asthma in high-risk children, Journal of Allergy and Clinical Immunology
Bartlett N, Singanayagam A, Johnston S, 2016, INHALED CORTICOSTEROIDS SUPPRESS INNATE AND ADAPTIVE ANTI-VIRAL IMMUNE RESPONSES IN THE AIRWAYS, RESPIROLOGY, Vol: 21, Pages: 34-34, ISSN: 1323-7799
Bousquet J, Barbara C, Bateman E, et al., 2016, AIRWAYS-ICPs (European Innovation Partnership on Active and Healthy Ageing) from concept to implementation, European Respiratory Journal, Vol: 47, Pages: 1028-1033, ISSN: 0903-1936
Wang Z, Bafadhel M, Haldar K, et al., 2016, Lung microbiome dynamics in COPD exacerbations, European Respiratory Journal, Vol: 47, Pages: 1082-1092, ISSN: 1399-3003
Increasing evidence suggests that the lung microbiome plays an important role in chronic obstructive pulmonary disease (COPD) severity. However, the dynamics of the lung microbiome during COPD exacerbations and its potential role in disease aetiology remain poorly understood.We completed a longitudinal 16S ribosomal RNA survey of the lung microbiome on 476 sputum samples collected from 87 subjects with COPD at four visits defined as stable state, exacerbation, 2 weeks post-therapy and 6 weeks recovery.Our analysis revealed a dynamic lung microbiota where changes appeared to be associated with exacerbation events and indicative of specific exacerbation phenotypes. Antibiotic and steroid treatments appear to have differential effects on the lung microbiome. We depict a microbial interaction network for the lung microbiome and suggest that perturbation of a few bacterial operational taxonomic units, in particularHaemophilusspp., could greatly impact the overall microbial community structure. Furthermore, several serum and sputum biomarkers, in particular sputum interleukin-8, appear to be highly correlated with the structure and diversity of the microbiome.Our study furthers the understanding of lung microbiome dynamics in COPD patients and highlights its potential as a biomarker, and possibly a target, for future respiratory therapeutics.
Hewitt R, Farne H, Ritchie A, et al., 2016, The role of viral infections in exacerbations of chronic obstructive pulmonary disease and asthma, Therapeutic Advances in Respiratory Disease, Vol: 10, Pages: 158-174, ISSN: 1753-4666
Asthma and chronic obstructive pulmonary disease (COPD) are major causes of global morbidity and mortality worldwide. The clinical course of both asthma and COPD are punctuated by the occurrence of exacerbations, acute events characterized by increased symptoms and airflow obstruction. Exacerbations contribute most of the morbidity, mortality and excess healthcare costs associated with both asthma and COPD. COPD and asthma exacerbations are frequently associated with respiratory virus infections and this has led to an intense research focus into the mechanisms of virus-induced exacerbations over the past decade. Current therapies are effective in reducing chronic symptoms but are less effective in preventing exacerbations, particularly in COPD. Understanding the mechanisms of virus-induced exacerbation will lead to the development of new targeted therapies that can reduce the burden of virus-induced exacerbations. In this review we discuss current knowledge of virus-induced exacerbations of asthma and COPD with a particular focus on mechanisms, human studies, virus–bacteria interactions and therapeutic advances.
Jozwik A, Habibi MS, Paras A, et al., 2016, Erratum: RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection, Nature Communications, Vol: 7, ISSN: 2041-1723
Ritchie AI, Jackson DJ, Edwards MR, et al., 2016, Airway epithelial orchestration of innate immune function in response to virus infection. A focus on asthma, Annals of the American Thoracic Society, Vol: 13 Suppl 1, Pages: S55-S63, ISSN: 2329-6933
Heaney LG, Djukanovic R, Woodcock A, et al., 2016, Research in progress: Medical Research Council United Kingdom Refractory Asthma Stratification Programme (RASP-UK), Thorax, Vol: 71, Pages: 187-189, ISSN: 0040-6376
The UK Refractory Asthma Stratification Programme (RASP-UK) will explore novel biomarker stratification strategies in severe asthma to improve clinical management and accelerate development of new therapies. Prior asthma mechanistic studies have not stratified on inflammatory phenotype and the understanding of pathophysiological mechanisms in asthma without Type 2 cytokine inflammation is limited. RASP-UK will objectively assess adherence to corticosteroids (CS) and examine a novel composite biomarker strategy to optimise CS dose; this will also address what proportion of patients with severe asthma have persistent symptoms without eosinophilic airways inflammation after progressive CS withdrawal. There will be interactive partnership with the pharmaceutical industry to facilitate access to stratified populations for novel therapeutic studies.
Edwards MR, Facchinetti F, Civelli M, et al., 2016, Anti-inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus-inducible cytokines, Pharmacology Research and Perspectives, Vol: 4, ISSN: 2052-1707
Respiratory virus infections precipitate asthma and chronic obstructive pulmonary disease (COPD) exacerbations, with most exacerbations due to rhinovirus infection. Both asthma and COPD exacerbations are not well controlled by steroid therapies, and there is a much research interest in finding improved therapies or combinations of therapies for controlling exacerbations. CHF6001 is a new, inhaled highly potent and selective phosphodiesterase type 4 (PDE4) inhibitor. Using in vitro human bronchial epithelial cells (BEAS-2B), we investigated the potential anti-inflammatory effects of CHF6001 on rhinovirus (RV1B)-induced cytokines. Cytokine mRNA was measured by real-time PCR, while protein release was measured by ELISA. CHF6001 was used in a 7-point dose–response curve (1000–0.001 nmol/L) as a 1.5-h pretreatment prior to infection in comparison with roflumilast. Both roflumilast and CHF6001 reduced RV1B-induced IL-8, IL-29, IP-10, and RANTES mRNA and protein in a concentration-dependent manner. Generally, CHF6001 was 13- to 16-fold more potent (subnanomolar EC50 values) than roflumilast at reducing IL-8, IL-29, IP-10, and RANTES mRNA and protein release, but had similar efficacies. In combination with the steroid fluticasone propionate (1 nmol/L), CHF6001 had additive effects, significantly reducing RV-induced cytokines when compared with steroid or CHF6001 alone. Combined low-dose steroid and low-dose CHF6001 had a similar efficacy as high-dose steroid or CHF6001 alone, indicating the combination had steroid and PDE4 inhibitor sparing effects. Overall results indicate that PDE4 inhibitors have anti-inflammatory activity against virus-induced inflammatory mediators and that CHF6001 is more potent than roflumilast.
James AJ, Reinius LE, Verhoek M, et al., 2016, Increased YKL-40 and Chitotriosidase in Asthma and Chronic Obstructive Pulmonary Disease, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 193, Pages: 131-142, ISSN: 1073-449X
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Williams GR, Kubajewska I, Glanville NS, et al., 2016, The potential for a protective vaccine for rhinovirus infections., Expert Review of Vaccines, Vol: 15, Pages: 569-571, ISSN: 1744-8395
Rhinovirus (RV) infections impose a major disease burden as they cause around three out offour common colds and are responsible for the majority of acute exacerbations of chronicobstructive pulmonary disease (COPD) and asthma [1, 2]. RVs therefore are associated withan enormous economic cost in missed work or school and medical attention. Prophylacticvaccination against infection is arguably the most effective medical intervention everdeveloped, and has proven enormously effective in protecting against a large number ofdiseases. However, at the present time no effective vaccine exists for RVs. This is largelydue to the existence of 100 serotyped antigenically distinct RV strains - such variabilitymeans that a vaccine designed to elicit immune responses against a particular RV is unlikelyto be able to provide protection against the full range of virus subtypes successfully [3]. Infact, this phenomenon was observed as early as 1965 when immunising with formalininactivated whole RV and is confirmed by the knowledge that the immunity induced followingRV infection does not significantly protect from future infection by different RV serotypes [4].More sophisticated attempts at immunisation with multiple inactivated RV serotypes alsofailed to induce significant cross-serotype protection [5]. Thus, an effective cross-serotyperesponsive RV vaccine has remained elusive. The relatively recent description of a newclade of RV types (RV-C) has increased the number of identified strains/serotypes to ~160[6]. Perhaps the quest for a RV vaccine has been dismissed as too difficult or evenimpossible, but new developments suggest that it may be feasible to generate a significantbreadth of immune protection.
Russell KE, Chung KF, Clarke CJ, et al., 2016, The MIF Antagonist ISO-1 Attenuates Corticosteroid-Insensitive Inflammation and Airways Hyperresponsiveness in an Ozone-Induced Model of COPD., PLOS One, Vol: 11, ISSN: 1932-6203
INTRODUCTION: Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine associated with acute and chronic inflammatory disorders and corticosteroid insensitivity. Its expression in the airways of patients with chronic obstructive pulmonary disease (COPD), a relatively steroid insensitive inflammatory disease is unclear, however. METHODS: Sputum, bronchoalveolar lavage (BAL) macrophages and serum were obtained from non-smokers, smokers and COPD patients. To mimic oxidative stress-induced COPD, mice were exposed to ozone for six-weeks and treated with ISO-1, a MIF inhibitor, and/or dexamethasone before each exposure. BAL fluid and lung tissue were collected after the final exposure. Airway hyperresponsiveness (AHR) and lung function were measured using whole body plethysmography. HIF-1α binding to the Mif promoter was determined by Chromatin Immunoprecipitation assays. RESULTS: MIF levels in sputum and BAL macrophages from COPD patients were higher than those from non-smokers, with healthy smokers having intermediate levels. MIF expression correlated with that of HIF-1α in all patients groups and in ozone-exposed mice. BAL cell counts, cytokine mRNA and protein expression in lungs and BAL, including MIF, were elevated in ozone-exposed mice and had increased AHR. Dexamethasone had no effect on these parameters in the mouse but ISO-1 attenuated cell recruitment, cytokine release and AHR. CONCLUSION: MIF and HIF-1α levels are elevated in COPD BAL macrophages and inhibition of MIF function blocks corticosteroid-insensitive lung inflammation and AHR. Inhibition of MIF may provide a novel anti-inflammatory approach in COPD.
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