Publications

Journal article

Peiró T, Patel DF, Akthar S, Gregory LG, Pyle CJ, Harker JA, Birrell MA, LLoyd CM, Snelgrove RJet al., 2017,

Neutrophils drive alveolar macrophage IL-1β release during respiratory viral infection

, Thorax, Vol: 73, Pages: 546-556, ISSN: 1468-3296

Background Alveolar macrophages are sentinels of the airways that must exhibit immune restraint to innocuous antigens but elicit a robust inflammatory response to pathogenic threats. How distinction between these dichotomous functions is controlled is poorly defined.Neutrophils are the first responders to infection, and we hypothesised that they may free alveolar macrophages from their hyporesponsive state, promoting their activation. Activation of the inflammasome and interleukin (IL)-1β release is a key early inflammatory event that must be tightly regulated. Thus, the role of neutrophils in defining inflammasome activation in the alveolar macrophage was assessed.Methods Mice were infected with the X31 strain of influenza virus and the role of neutrophils in alveolar macrophage activation established through administration of a neutrophil-depleting (1A8) antibody.Results Influenza elicited a robust IL-1β release that correlated (r=0.6849; p<0.001) with neutrophil infiltrate and was ablated by neutrophil depletion. Alveolar macrophages were shown to be the prominent source of IL-1β during influenza infection, and virus triggered the expression of Nod-like receptor protein 3 (NLRP3) inflammasome and pro-IL-1β in these cells. However, subsequent activation of the inflammasome complex and release of mature IL-1β from alveolar macrophages were critically dependent on the provision of a secondary signal, in the form of antimicrobial peptide mCRAMP, from infiltrating neutrophils.Conclusions Neutrophils are critical for the activation of the NLRP3 inflammasome in alveolar macrophages during respiratory viral infection. Accordingly, we rationalise that neutrophils are recruited to the lung to confront a viable pathogenic threat and subsequently commit alveolar macrophages to a pro-inflammatory phenotype to combat infection.

Journal article

Bonini M, Usmani OS, 2017,

Novel methods for device and adherence monitoring in asthma.

, Current Opinion in Pulmonary Medicine, Vol: 24, Pages: 63-69, ISSN: 1070-5287

PURPOSE OF REVIEW: The article aims to provide an updated and evidence-based review of the innovative electronic health interventions to monitor and improve inhaler technique and adherence to recommended therapy in asthma. RECENT FINDINGS: Out of the 290 articles identified by the search strategy, 23 manuscripts fulfilled the review inclusion criteria. Included studies mainly addressed m-health, electronic reminders, telemedicine, and inhaler tracker interventions. Investigations were performed both in adults and children. Remarkably, the majority of studies were performed in the most recent years, showing a progressively increasing interest for this field. Existing findings appear to be of moderate-high quality. A significant number of papers, however, were published in scientific journals with a low impact factor (<2). Furthermore, extremely high heterogeneity was found in the considered study endpoints. Collected evidence supports a relevant role for e-health in monitoring and improving inhaler use and treatment adherence in asthma. The patients' acceptance and satisfaction towards assessed interventions were also found to be positive. SUMMARY: E-health represents a highly valuable tool for achieving optimal and personalized asthma management. Unanimously agreed and adopted standards for conducting trials and reporting results on e-health in asthma are however needed to fully understand its real added value.

Journal article

Dal Negro RW, Wedzicha JA, Iversen M, Fontana G, Page C, Cicero AF, Pozzi E, Calverley PMAet al., 2017,

Effect of erdosteine on the rate and duration of COPD exacerbations: the RESTORE study

, European Respiratory Journal, Vol: 50, ISSN: 0903-1936

Oxidative stress contributes to chronic obstructive pulmonary disease (COPD) exacerbations and antioxidants can decrease exacerbation rates, although we lack data about the effect of such drugs on exacerbation duration.The RESTORE (Reducing Exacerbations and Symptoms by Treatment with ORal Erdosteine in COPD) study was a prospective randomised, double-blind, placebo-controlled study, enrolling patients aged 40–80 years with Global Initiative for Chronic Obstructive Lung Disease stage II/III. Patients received erdosteine 300 mg twice daily or placebo added to usual COPD therapy for 12 months. The primary outcome was the number of acute exacerbations during the study.In the pre-specified intention-to-treat population of 445 patients (74% male; mean age 64.8 years, forced expiratory volume in 1 s 51.8% predicted) erdosteine reduced the exacerbation rate by 19.4% (0.91 versus. 1.13 exacerbations·patient−1·year−1 for erdosteine and placebo, respectively; p=0.01), due to an effect on mild events; the reduction in the rate of mild exacerbations was 57.1% (0.23 versus 0.54 exacerbations·patient−1·year−1 for erdosteine and placebo, respectively; p=0.002). No significant difference was observed in the rate of moderate and severe exacerbations (0.68 versus 0.59 exacerbations·patient−1·year−1 for erdosteine and placebo, respectively; p=0.054) despite a trend in favour of the comparison group. Erdosteine decreased the exacerbation duration irrespective of event severity by 24.6% (9.55 versus 12.63 days for erdosteine and placebo, respectively; p=0.023). Erdosteine significantly improved subject and physician subjective severity scores (p=0.022 and p=0.048, respectively), and reduced the use of reliever medication (p<0.001), but did not affect the St George's Respiratory Questionnaire score or the time to first exacerbation.In patients with COPD, erdosteine can reduce both the rate and duration

Journal article

Jamaati H, Mortaz E, Pajouhi Z, Folkerts G, Movassaghi M, Moloudizargari M, Adcock IM, Garssen Jet al., 2017,

Nitric Oxide in the Pathogenesis and Treatment of Tuberculosis

, Frontiers in Microbiology, Vol: 8, ISSN: 1664-302X

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is globally known as one of the most important human pathogens. Mtb is estimated to infect nearly one third of the world's population with many subjects having a latent infection. Thus, from an estimated 2 billion people infected with Mtb, less than 10% may develop symptomatic TB. This indicates that the host immune system may constrain pathogen replication in most infected individuals. On entering the lungs of the host, Mtb initially encounters resident alveolar macrophages which can engulf and subsequently eliminate intracellular microbes via a plethora of bactericidal mechanisms including the generation of free radicals such as reactive oxygen and nitrogen species. Nitric oxide (NO), a key anti-mycobacterial molecule, is detected in the exhaled breath of patients infected with Mtb. Recent knowledge regarding the regulatory role of NO in airway function and Mtb proliferation paves the way of exploiting the beneficial effects of this molecule for the treatment of airway diseases. Here, we discuss the importance of NO in the pathogenesis of TB, the diagnostic use of exhaled and urinary NO in Mtb infection and the potential of NO-based treatments.

Journal article

Smyth E, Solomon A, Birrell MA, Smallwood MJ, Winyard PG, Tetley TD, Emerson Met al., 2017,

Effects of diesel exhaust particles on coagulation.

, British Journal of Pharmacology, Vol: 174, Pages: 4200-4200, ISSN: 1476-5381

Journal article

Singh D, Corradi M, Spinola M, Papi A, Usmani OS, Scuri M, Petruzzelli S, Vestbo Jet al., 2017,

Triple therapy in COPD: new evidence with the extrafine fixed combination of beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide

, International Journal of Chronic Obstructive Pulmonary Disease, Vol: 12, Pages: 2917-2928, ISSN: 1176-9106

The goals of COPD therapy are to prevent and control symptoms, reduce the frequency and severity of exacerbations, and improve exercise tolerance. The triple combination therapy of inhaled corticosteroids (ICSs), long-acting beta2 agonists (LABAs), and long-acting muscarinic antagonists (LAMAs) has become an option for maintenance treatment of COPD and as a “step-up” therapy from single or double combination treatments. There is evidence that triple combination ICS/LABA/LAMA with different inhalers improves lung function, symptoms, and health status and reduces exacerbations. A new triple fixed-dose combination of extrafine beclomethasone dipropionate (100 µg/puff)/formoterol fumarate (6 µg/puff)/glycopyrronium bromide (12.5 µg/puff) has been developed as a hydrofluoroalkane pressurized metered dose inhaler. Two large pivotal studies showed that this extrafine fixed ICS/LABA/LAMA triple combination is superior to fixed ICS/LABA combined therapy and also superior to the LAMA tiotropium in terms of lung function and exacerbation prevention in COPD patients at risk of exacerbation. This review considers the new information provided by these clinical trials of extrafine triple therapy and the implications for the clinical management of COPD patients.

Journal article

Kemp P, paul R, lee J, donaldson AV, connolly M, sharif M, natanek SA, rosendahl U, polkey M, griffiths Met al., 2017,

miR-422a suppresses SMAD4 protein expression and promotes resistance to muscle loss

, Journal of Cachexia Sarcopenia and Muscle, Vol: 9, Pages: 119-128, ISSN: 2190-5991

BackgroundLoss of muscle mass and strength are important sequelae of chronic disease, but the response of individuals is remarkably variable, suggesting important genetic and epigenetic modulators of muscle homeostasis. Such factors are likely to modify the activity of pathways that regulate wasting, but to date, few such factors have been identified.MethodsThe effect of miR-422a on SMAD4 expression and transforming growth factor (TGF)-β signalling were determined by western blotting and luciferase assay. miRNA expression was determined by qPCR in plasma and muscle biopsy samples from a cross-sectional study of patients with chronic obstructive pulmonary disease (COPD) and a longitudinal study of patients undergoing aortic surgery, who were subsequently admitted to the intensive care unit (ICU).ResultsmiR-422a was identified, by a screen, as a microRNA that was present in the plasma of patients with COPD and negatively associated with muscle strength as well as being readily detectable in the muscle of patients. In vitro, miR-422a suppressed SMAD4 expression and inhibited TGF-beta and bone morphogenetic protein-dependent luciferase activity in muscle cells. In male patients with COPD and those undergoing aortic surgery and on the ICU, a model of ICU-associated muscle weakness, quadriceps expression of miR-422a was positively associated with muscle strength (maximal voluntary contraction r = 0.59, P < 0.001 and r = 0.51, P = 0.004, for COPD and aortic surgery, respectively). Furthermore, pre-surgery levels of miR-422a were inversely associated with the amount of muscle that would be lost in the first post-operative week (r = −0.57, P < 0.001).ConclusionsThese data suggest that differences in miR-422a expression contribute to the susceptibility to muscle wasting associated with chronic and acute disease and that at least part of this activity may be mediated by reduced TGF-beta signalling in skeletal muscle.

Journal article

Edwards MR, Strong K, Cameron A, Walton RP, Jackson DJ, Johnston SLet al., 2017,

Viral infections in allergy and immunology: How allergic inflammation influences viral infections and illness

, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 140, Pages: 909-920, ISSN: 0091-6749

Viral respiratory tract infections are associated with asthma inception in early life and asthma exacerbations in older children and adults. Although how viruses influence asthma inception is poorly understood, much research has focused on the host response to respiratory viruses and how viruses can promote; or how the host response is affected by subsequent allergen sensitization and exposure. This review focuses on the innate interferon-mediated host response to respiratory viruses and discusses and summarizes the available evidence that this response is impaired or suboptimal. In addition, the ability of respiratory viruses to act in a synergistic or additive manner with TH2 pathways will be discussed. In this review we argue that these 2 outcomes are likely linked and discuss the available evidence that shows reciprocal negative regulation between innate interferons and TH2 mediators. With the renewed interest in anti-TH2 biologics, we propose a rationale for why they are particularly successful in controlling asthma exacerbations and suggest ways in which future clinical studies could be used to find direct evidence for this hypothesis.

Journal article

Bewley MA, Preston JA, Mohasin M, Marriott HM, Budd RC, Swales J, Collini P, Greaves DR, Craig RW, Brightling CE, Donnelly LE, Barnes PJ, Singh D, Shapiro SD, Whyte MKB, Dockrell DHet al., 2017,

Impaired Mitochondrial Microbicidal Responses in Chronic Obstructive Pulmonary Disease Macrophages

, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 196, Pages: 845-855, ISSN: 1073-449X

Journal article

Bucks RS, Olaithe M, Rosenzweig I, Morrell MJet al., 2017,

Reviewing the relationship between OSA and cognition: Where do we go from here?

, RESPIROLOGY, Vol: 22, Pages: 1253-1261, ISSN: 1323-7799

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Citations: 77

Journal article

Wortley MA, Adcock JJ, Dubuis ED, Maher SA, Bonvini SJ, Delescluse I, Kinloch R, McMurray G, Perros-Huguet C, Papakosta M, Birrell MA, Belvisi MGet al., 2017,

Targeting fatty acid amide hydrolase as a therapeutic strategy for antitussive therapy

, European Respiratory Journal, Vol: 50, Pages: 1-11, ISSN: 0903-1936

Cough is the most common reason to visit a primary care physician, yet it remains an unmet medical need. Fatty acid amide hydrolase (FAAH) is an enzyme that breaks down endocannabinoids, and inhibition of FAAH produces analgesic and anti-inflammatory effects. Cannabinoids inhibit vagal sensory nerve activation and the cough reflex, so it was hypothesised that FAAH inhibition would produce antitussive activity via elevation of endocannabinoids.Primary vagal ganglia neurons, tissue bioassay, in vivo electrophysiology and a conscious guinea pig cough model were utilised to investigate a role for fatty acid amides in modulating sensory nerve activation in vagal afferents.FAAH inhibition produced antitussive activity in guinea pigs with concomitant plasma elevation of the fatty acid amides N-arachidonoylethanolamide (anandamide), palmitoylethanolamide, N-oleoylethanolamide and linoleoylethanolamide. Palmitoylethanolamide inhibited tussive stimulus-induced activation of guinea pig airway innervating vagal ganglia neurons, depolarisation of guinea pig and human vagus, and firing of C-fibre afferents. These effects were mediated via a cannabinoid CB2/Gi/o-coupled pathway and activation of protein phosphatase 2A, resulting in increased calcium sensitivity of calcium-activated potassium channels.These findings identify FAAH inhibition as a target for the development of novel, antitussive agents without the undesirable side-effects of direct cannabinoid receptor agonists.

Journal article

Li X, Michaeloudes C, Zhang Y, Wiegman CH, Adcock IM, Lian Q, Mak JCW, Bhavsar PK, Chung KFet al., 2017,

Mesenchymal stem cells alleviate oxidative stress-induced mitochondrial dysfunction in the airways.

, Journal of Allergy and Clinical Immunology, Vol: 141, Pages: 1634-1645.e5, ISSN: 0091-6749

BACKGROUND: Oxidative stress-induced mitochondrial dysfunction may contribute to inflammation and remodeling in chronic obstructive pulmonary disease (COPD). Mesenchymal stem cells (MSCs) protect against lung damage in animal models of COPD. It is unknown whether these effects occur through attenuating mitochondrial dysfunction in airway cells. OBJECTIVE: To examine the effect of induced-pluripotent stem cell-derived MSCs (iPSC-MSCs) on oxidative stress-induce mitochondrial dysfunction in human airway smooth muscle cells (ASMCs) in vitro and in mouse lungs in vivo. METHODS: ASMCs were co-cultured with iPSC-MSCs in the presence of cigarette smoke medium (CSM), and mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm) and apoptosis were measured. Conditioned media from iPSC-MSCs and trans-well co-cultures were used to detect any paracrine effects. The effect of systemic injection of iPSC-MSCs on airway inflammation and hyper-responsiveness in ozone-exposed mice was also investigated. RESULTS: Co-culture of iPSC-MSCs with ASMCs attenuated CSM-induced mitochondrial ROS, apoptosis and ΔΨm loss in ASMCs. iPSC-MSC-conditioned media or trans-well co-cultures with iPSC-MSCs reduced CSM-induced mitochondrial ROS but not ΔΨm or apoptosis in ASMCs. Mitochondrial transfer from iPSC-MSCs to ASMCs was observed after direct co-culture and was enhanced by CSM. iPSC-MSCs attenuated ozone-induced mitochondrial dysfunction, airway hyper-responsiveness and inflammation in mouse lungs. CONCLUSION: iPSC-MSCs offered protection against oxidative stress-induced mitochondrial dysfunction in human ASMCs and in mouse lungs, whilst reducing airway inflammation and hyper-responsiveness. These effects are, at least partly, dependent on cell-cell contact that allows for mitochondrial transfer, and paracrine regulation. Therefore, iPSC-MSCs show promise as a therapy for oxidative stress-dependent lung diseases such as COPD.

Journal article

Wedzicha JA, Calverley PMA, Albert RK, Anzueto A, Criner GJ, Hurst JR, Miravitlles M, Papi A, Rabe KF, Rigau D, Sliwinski P, Tonia T, Vestbo J, Wilson KC, Krishnan JAet al., 2017,

Prevention of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline

, EUROPEAN RESPIRATORY JOURNAL, Vol: 50, ISSN: 0903-1936

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Citations: 102

Conference paper

Dean L, Chen S, Shaffer M, Thorley A, Tetley Tet al., 2017,