90 results found
Pinkerton JW, Adcock JJ, Zervas D, et al., 2021, PI3K gamma d Inhibitor, AZD8154, Demonstrates Improved Efficacious Profile Over PI3Kd Selective Inhibitor, GSK2269557, in a Rat Model of Asthma, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Miles J, Pinkerton JW, Bonvini SJ, et al., 2020, Modelling IPF-associated chronic cough: role for oxidative stress?, The 2020 ERS International Congress, Publisher: European Respiratory Society, Pages: 1-2, ISSN: 0903-1936
Introduction: Chronic cough is a key symptom that plagues the lives of IPF patients, indeed, it is often the reason the disease is initially diagnosed. The aim of this project was to develop a pre-clinical model of IPF-associated cough and compare the mediator profiles with clinical samples, to aid in the search for effective treatments.Methods: Male guinea pigs (around 325g) were intratracheally dosed with vehicle (saline) or bleomycin (6 USP/kg) and coughs were quantified through manual observation of in-cage video footage, by watching 4.5 hours a day, for 3 weeks. Lung tissue, bronchoalveolar lavage fluid (BALF) and blood was harvested from a parallel group of animals. These were used to assess the extent of fibrosis and measure mediator production (e.g. a marker of oxidative stress: 8-isoprostane). Human BALF was obtained from IPF patients and healthy controls.Results: Spontaneous coughing was recorded in guinea pigs given bleomycin, which was associated with an increase in lung fibrosis and BALF 8-isoprostane (a marker of oxidative stress). We noted similar increases in BALF 8-isoprostane levels in the clinical samples.Conclusions: We have developed a preclinical model to aid in the search for a treatment for IPF-associated coughing. Furthermore, initial data suggests that an increase in oxidative burden (a known trigger of coughing) could be an attractive target.
Wortley MA, Bonvini SJ, Adcock JJ, et al., 2020, EPAC drives the anti-tussive effect of EP4 receptors on airway sensory nerves, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Bonvini SJ, Birrell MA, Dubuis E, et al., 2020, Novel airway smooth muscle-mast cell interactions and a role for the TRPV4-ATP axis in non-atopic asthma, EUROPEAN RESPIRATORY JOURNAL, Vol: 56, ISSN: 0903-1936
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 EP4 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
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
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
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
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
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
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.
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
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
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
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.
Bonvini SJ, Adcock JJ, Dubuis E, et al., 2017, Trpm3: A Regulator Of Airway Sensory Nerves And Respiratory Reflexes Via Distinct Mechanisms, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Dubuis E, Wrench C, Dekkak B, et al., 2016, Central role of AC6 in beta 2 agonist induced relaxation of human airway smooth muscle, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Bonvini S, Arshad M, Wortley MA, et al., 2016, TRPM3: A regulator of airway sensory nerves and respiratory reflexes, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Robinson R, Birrell M, Wortley M, et al., 2016, Direct activation of sensory afferents by diesel exhaust particles can trigger respiratory symptoms, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Belvisi MG, 2016, Transient receptor potential cation channel, subfamily V, member 4 and airway, sensory afferent activation: role of adenosine triphosphate, Journal of Allergy and Clinical Immunology, Vol: 138, Pages: 249-261.e12, ISSN: 1097-6825
BackgroundSensory nerves innervating the airways play an important role in regulating various cardiopulmonary functions, maintaining homeostasis under healthy conditions and contributing to pathophysiology in disease states. Hypo-osmotic solutions elicit sensory reflexes, including cough, and are a potent stimulus for airway narrowing in asthmatic patients, but the mechanisms involved are not known. Transient receptor potential cation channel, subfamily V, member 4 (TRPV4) is widely expressed in the respiratory tract, but its role as a peripheral nociceptor has not been explored.ObjectiveWe hypothesized that TRPV4 is expressed on airway afferents and is a key osmosensor initiating reflex events in the lung.MethodsWe used guinea pig primary cells, tissue bioassay, in vivo electrophysiology, and a guinea pig conscious cough model to investigate a role for TRPV4 in mediating sensory nerve activation in vagal afferents and the possible downstream signaling mechanisms. Human vagus nerve was used to confirm key observations in animal tissues.ResultsHere we show TRPV4-induced activation of guinea pig airway–specific primary nodose ganglion cells. TRPV4 ligands and hypo-osmotic solutions caused depolarization of murine, guinea pig, and human vagus and firing of Aδ-fibers (not C-fibers), which was inhibited by TRPV4 and P2X3 receptor antagonists. Both antagonists blocked TRPV4-induced cough.ConclusionThis study identifies the TRPV4-ATP-P2X3 interaction as a key osmosensing pathway involved in airway sensory nerve reflexes. The absence of TRPV4-ATP–mediated effects on C-fibers indicates a distinct neurobiology for this ion channel and implicates TRPV4 as a novel therapeutic target for neuronal hyperresponsiveness in the airways and symptoms, such as cough.
Belvisi MG, Birrell MA, Khalid S, et al., 2016, Neurophenotypes in airway diseases: insights from translational cough studies, American Journal of Respiratory and Critical Care Medicine, Vol: 193, Pages: 1364-1372, ISSN: 1535-4970
Rationale: Most airway diseases, including chronic obstructive pulmonary disease (COPD), are associated with excessive coughing. The extent to which this may be a consequence of increased activation of vagal afferents by pathology in the airways (e.g. inflammatory mediators, excessive mucus) or an altered neuronal phenotype is unknown. Understanding whether respiratory diseases are associated with dysfunction of airway sensory nerves has the potential to identify novel therapeutic targets. Objectives: To assess the changes in cough responses to a range of inhaled irritants in COPD, and model these in animals to investigate the underlying mechanisms. Methods: Cough responses to inhaled stimuli in patients with COPD, healthy smokers, refractory chronic cough, asthma and healthy volunteers were assessed and compared with vagus/airway nerve and cough responses in a cigarette smoke (CS) exposure guinea-pig model. Measurements and Main Results: Patients with COPD had heightened cough responses to capsaicin but reduced responses to PGE2 compared with healthy volunteers. Furthermore, the different patient groups all exhibited different patterns of modulation of cough responses. Consistent with these findings, capsaicin caused a greater number of coughs in CS-exposed guinea-pigs than in controls; similar increased responses were observed in ex-vivo vagus nerve and neuron cell bodies in the vagal ganglia. However, responses to PGE2 were decreased by CS-exposure. Conclusions: CS exposure is capable of inducing responses consistent with phenotypic switching in airway sensory nerves comparable to the cough responses observed in patients with COPD. Moreover, the differing profiles of cough responses support the concept of disease-specific neuro-phenotypes in airway disease.
Raemdonck K, Baker K, Dale N, et al., 2016, CD4(+) and CD8(+) T cells play a central role in a HDM driven model of allergic asthma., Respiratory Research, Vol: 17, ISSN: 1465-993X
BACKGROUND: The incidence of asthma is increasing at an alarming rate and while the current available therapies are effective in the majority of patients they fail to adequately control symptoms at the more severe end of the disease spectrum. In the search to understand disease pathogenesis and find effective therapies animal models are often employed. As exposure to house dust mite (HDM) has a causative link, it is thought of as the allergen of choice for modelling asthma. The objective was to develop a HDM driven model of asthmatic sensitisation and characterise the role of key allergic effector cells/mediators. METHODS: Mice were sensitised with low doses of HDM and then subsequently challenged. Cellular inflammation, IgE and airway responsiveness (AHR) was assessed in wild type mice or CD4(+)/CD8(+) T cells, B cells or IgE knock out mice. RESULTS: Only those mice sensitised with HDM responded to subsequent low dose topical challenge. Similar to the classical ovalbumin model, there was no requirement for systemic alum sensitisation. Characterisation of the role of effector cells demonstrated that the allergic cellular inflammation and AHR was dependent on CD4(+) and CD8(+) T cells but not B cells or IgE. Finally, we show that this model, unlike the classic OVA model, appears to be resistant to developing tolerance. CONCLUSIONS: This CD4(+)/CD8(+) T cell dependent, HDM driven model of allergic asthma exhibits key features of asthma. Furthermore, we suggest that the ability to repeat challenge with HDM means this model is amenable to studies exploring the effect of therapeutic dosing in chronic, established disease.
Robinson RK, Birrell MA, Wortley MA, et al., 2016, Diesel Activates Airway Sensory Nerves To Initiate Respiratory Symptoms, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Wortley MA, Dubuis E, Bonvini SJ, et al., 2016, Making Sense Of Sensory Nerves: An In Vitro Characterisation Of Gene Expression Profiles Of Airway-Innervating Guinea-Pig Airway Neurons Using Single-Cell Analysis, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Wortley M, Adcock J, Dubuis E, et al., 2015, Anti-tussive effects of FAAH inhibition: The role of endocannabinoids and downstream signalling pathways in the inhibition of vagal sensory nerve activation, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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