Publications
411 results found
Almeida-Oliveira AR, Aquino JCJ, Abbasi A, et al., 2019, Effects of Aerobic Exercise on Molecular Aspects of Asthma: Involvement of SOCS-JAK-STAT, EXERCISE IMMUNOLOGY REVIEW, Vol: 25, Pages: 98-110, ISSN: 1077-5552
Miles JHA, Dubuis E, Bonvini SJ, et al., 2019, Monitoring Cough in a Preclinical Guinea Pig Model of Idiopathic Pulmonary Fibrosis, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Wortley MA, Bonvini SJ, Adcock JJ, et al., 2019, Agonism of EP<sub>4</sub> Receptors Expressed on Airway Sensory Nerves Inhibits Cough, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Chen X, Bonvini SJ, Dubuis ED, et al., 2019, Cromoglycate Inhibits Oxidative Stress Triggered Airway Sensory Nerves Through Its Actions on the Ion Channel TRPV2: A New Insight into Biological Mechanism of Action, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Wortley M, Bonvini SJ, Flajolet PLM, et al., 2018, The anti-tussive effects of an inhaled LABA are maintained after chronic treatment, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 3
Chen X, Bonvini SJ, Dubuis E, et al., 2018, Characterisation of TRPA1 activation on sensory nerves, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Bolaji JA, Adcock JJ, Sandstrom T, et al., 2018, Biodiesel: is it any safer to use?, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Flajolet P, De Alba J, Raemdonck K, et al., 2018, Characterisation of a chronic preclinical model of allergic asthma, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Belvisi MG, Baker K, Malloy N, et al., 2018, Modelling the asthma phenotype: impact of cigarette smoke exposure, Respiratory Research, Vol: 19, ISSN: 1465-9921
BackgroundAsthmatics that are exposed to inhaled pollutants such as cigarette smoke (CS) have increased symptom severity. Approximately 25% of adult asthmatics are thought to be active smokers and many sufferers, especially in the third world, are exposed to high levels of inhaled pollutants. The mechanism by which CS or other airborne pollutants alter the disease phenotype and the effectiveness of treatment in asthma is not known. The aim of this study was to determine the impact of CS exposure on the phenotype and treatment sensitivity of rodent models of allergic asthma.MethodsModels of allergic asthma were configured that mimicked aspects of the asthma phenotype and the effect of CS exposure investigated. In some experiments, treatment with gold standard asthma therapies was investigated and end-points such as airway cellular burden, late asthmatic response (LAR) and airway hyper-Reactivity (AHR) assessed.ResultsCS co-exposure caused an increase in the LAR but interestingly attenuated the AHR. The effectiveness of LABA, LAMA and glucocorticoid treatment on LAR appeared to be retained in the CS-exposed model system. The eosinophilia or lymphocyte burden was not altered by CS co-exposure, nor did CS appear to alter the effectiveness of glucocorticoid treatment. Steroids, however failed to reduce the neutrophilic inflammation in sensitized mice exposed to CS.ConclusionsThese model data have certain parallels with clinical findings in asthmatics, where CS exposure did not impact the anti-inflammatory efficacy of steroids but attenuated AHR and enhanced symptoms such as the bronchospasm associated with the LAR. These model systems may be utilised to investigate how CS and other airborne pollutants impact the asthma phenotype; providing the opportunity to identify novel targets.
Saunders P, Czyzyk P, Sen S, et al., 2018, Measuring Cough and Its Impact on Quality of Life in Fibrotic Lung Disease, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Bolaji J, Bonvini SJ, Adcock JJ, et al., 2018, Cleaning Agent Surfactant, 4-Octylphenol, Activates Airway Sensory Nerves and Triggers Respiratory Symptoms: Role in Occupational Asthma?, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Bonvini 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
Wortley 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
Chen 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
Ma J, Bonvini SJ, Dubuis E, et al., 2018, Investigation into the Mechanisms Driving Hypo-Osmotic Stress-Triggered Activation of Airway Sensory Nerves, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Wortley 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
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- Citations: 1
Bonvini 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
Rodrigues Brandao-Rangel MA, Lacerda Bachi AL, Oliveira-Junior MC, et al., 2017, Exercise inhibits the effects of smoke-induced COPD involving modulation of STAT3, Oxidative Medicine and Cellular Longevity, Vol: 2017, ISSN: 1942-0900
Purpose. Evaluate the participation of STAT3 in the effects of aerobic exercise (AE) in a model of smoke-induced COPD.Methods.C57Bl/6 male mice were divided into control, Exe, COPD, and COPD+Exe groups. Smoke were administered during 90 days.Treadmill aerobic training begun on day 61 until day 90. Pulmonary inflammation, systemic inflammation, the level of lungemphysema, and the airway remodeling were evaluated. Analysis of integral and phosphorylated expression of STAT3 by airwayepithelial cells, peribronchial leukocytes, and parenchymal leukocytes was performed.Results. AE inhibited smoke-inducedaccumulation of total cells (p<0001), lymphocytes (p<0001), and neutrophils (p<0001) in BAL, as well as BAL levels of IL-1β(p<0001), CXCL1 (p<0001), IL-17 (p<0001), and TNF-α(p<005), while increased the levels of IL-10 (p<0001). AEalso inhibited smoke-induced increases in total leukocytes (p<0001), neutrophils (p<005), lymphocytes (p<0001), andmonocytes (p<001) in blood, as well as serum levels of IL-1β(p<001), CXCL1 (p<001), IL-17 (p<005), and TNF-α(p<001), while increased the levels of IL-10 (p<0001). AE reduced smoke-induced emphysema (p<0001) and collagenfiber accumulation in the airways (p<0001). AE reduced smoke-induced STAT3 and phospho-STAT3 expression in airwayepithelial cells (p<0001), peribronchial leukocytes (p<0001), and parenchymal leukocytes (p<0001).Conclusions.AEreduces smoke-induced COPD phenotype involving STAT3.
Wortley MA, Adcock JJ, Dubuis ED, et 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.
Wortley M, Dubuis E, Maher S, et al., 2017, TRPM3, P2X2 and P2X3 expression patterns in single airway sensory nerves, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Bolaji JA, Bonvini SJ, Wortley MA, et al., 2017, Phthalates trigger respiratory reflexes, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 1
Bonvini S, Dubuis E, Adcock J, et al., 2017, Activation of transient receptor potential (TRP) channels by hypoosmolar solution: an endogenous mechanism of ATP release and afferent nerve activation, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 1
Rangel M, Renno AS, Oliveira-Junior MC, et al., 2017, Involvement of STAT-3 in the Beneficial Effects of Aerobic Exercise in a Model of Smoke-Induced COPD, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Belvisi MG, Birrell MA, 2017, The emerging role of transient receptor potential channels in chronic lung disease, EUROPEAN RESPIRATORY JOURNAL, Vol: 50, ISSN: 0903-1936
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- Citations: 41
Paschalaki KE, Zampetaki A, Baker JR, et al., 2017, Downregulation of MicroRNA-126 Augments DNA Damage Response in Cigarette Smokers and COPD Patients., Am J Respir Crit Care Med
Belvisi MG, Smith JA, 2017, ATP and cough reflex hypersensitivity: a confusion of goals?, European Respiratory Journal, Vol: 50, ISSN: 0903-1936
Bonvini SJ, Belvisi MG, 2017, Cough and airway disease: the role of ion channels, Pulmonary Pharmacology and Therapeutics, Vol: 47, Pages: 21-28, ISSN: 1094-5539
Cough is the most common reason for patients to visit a primary care physician, yet it remains an unmet medical need. It can be idiopathic in nature but can also be a troublesome symptom across chronic lung diseases such as asthma, COPD and idiopathic pulmonary fibrosis (IPF). Chronic cough affects up to 12% of the population and yet there are no safe and effective therapies. The cough reflex is regulated by vagal, sensory afferent nerves which innervate the airway. The Transient Receptor Potential (TRP) family of ion channels are expressed on sensory nerve terminals, and when activated can evoke cough. This review focuses on the role of 4 TRP channels; TRP Vannilloid 1 (TRPV1), TRP Ankyrin 1 (TRPA1), TRP Vannilloid 4 (TRPV4) and TRP Melastatin 8 (TRPM8) and the purinergic P2X3 receptor and their possible role in chronic cough. We conclude that these ion channels, given their expression profile and their role in the activation of sensory afferents and the cough reflex, may represent excellent therapeutic targets for the treatment of respiratory symptoms in chronic lung disease.
Belvisi MG, Birrell MA, Wortley MA, et al., 2017, XEN-D0501, a novel TRPV1 antagonist, does not reduce cough in refractory cough patients, American Journal of Respiratory and Critical Care Medicine, Vol: 196, Pages: 1255-1263, ISSN: 1073-449X
RATIONALE: Heightened cough responses to inhaled capsaicin, a TRPV1 agonist, are characteristic of patients with chronic cough. However, previously a TRPV1 antagonist (SB-705498) failed to improve spontaneous cough frequency in these patients despite small reductions in capsaicin-evoked cough. OBJECTIVES: XEN-D0501 (potent TRPV1 antagonist) was compared with SB-705498 in pre-clinical studies to establish whether an improved efficacy profile would support a further clinical trial of XEN-D0501 in refractory chronic cough. METHODS: XEN-D0501 and SB-705498 were profiled against capsaicin in a sensory nerve activation assay and in vivo potency established against capsaicin-induced cough in the guinea pig. Twenty patients with refractory chronic cough participated in a double-blind, randomised, placebo-controlled, crossover study evaluating the effect of 14 days XEN-D0501 (oral, 4mg bd) versus placebo on awake cough frequency (primary outcome), capsaicin-evoked cough and patient reported outcomes. MEASUREMENTS AND MAIN RESULTS: XEN-D0501 was more efficacious and 1000-fold more potent than SB-705498 at inhibiting capsaicin-induced depolarization of guinea pig and human isolated vagus. In vivo, XEN-D0501 completely inhibited capsaicin-induced cough whereas 100-times more SB-705498 was required to achieve the same effect. In patients, XEN-D0501 substantially reduced maximal cough responses to capsaicin (mean change from baseline XEN-D0501 -19.3(±16.4) coughs vs. placebo -1.8(±5.8), p<0.0001), but not spontaneous awake cough frequency (mean change from baseline XEN-D0501 6.7c/h(±16.9) vs. placebo 0.4c/h(±13.7), p =0.41). CONCLUSIONS: XEN-D0501 demonstrated superior efficacy and potency in pre-clinical and clinical capsaicin challenge studies; despite this improved pharmacodynamic profile, spontaneous cough frequency did not improve, ruling out TRPV1 as an effective therapeutic target for refractory cough. Clinical trial registration available ww
Robinson RK, Birrell MA, Adcock JJ, et al., 2017, Mechanistic link between diesel exhaust particles and respiratory reflexes, Journal of Allergy and Clinical Immunology, Vol: 141, Pages: 1074-1084.e9, ISSN: 1097-6825
BackgroundDiesel exhaust particles (DEPs) are a major component of particulate matter in Europe's largest cities, and epidemiologic evidence links exposure with respiratory symptoms and asthma exacerbations. Respiratory reflexes are responsible for symptoms and are regulated by vagal afferent nerves, which innervate the airway. It is not known how DEP exposure activates airway afferents to elicit symptoms, such as cough and bronchospasm.ObjectiveWe sought to identify the mechanisms involved in activation of airway sensory afferents by DEPs.MethodsIn this study we use in vitro and in vivo electrophysiologic techniques, including a unique model that assesses depolarization (a marker of sensory nerve activation) of human vagus.ResultsWe demonstrate a direct interaction between DEP and airway C-fiber afferents. In anesthetized guinea pigs intratracheal administration of DEPs activated airway C-fibers. The organic extract (DEP-OE) and not the cleaned particles evoked depolarization of guinea pig and human vagus, and this was inhibited by a transient receptor potential ankyrin-1 antagonist and the antioxidant N-acetyl cysteine. Polycyclic aromatic hydrocarbons, major constituents of DEPs, were implicated in this process through activation of the aryl hydrocarbon receptor and subsequent mitochondrial reactive oxygen species production, which is known to activate transient receptor potential ankyrin-1 on nociceptive C-fibers.ConclusionsThis study provides the first mechanistic insights into how exposure to urban air pollution leads to activation of guinea pig and human sensory nerves, which are responsible for respiratory symptoms. Mechanistic information will enable the development of appropriate therapeutic interventions and mitigation strategies for those susceptible subjects who are most at risk.
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.
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