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  • Journal article
    Belvisi MG, 2016,

    Transient receptor potential cation channel subfamily V member 4 (TRPV4) and airway, sensory afferent activation: role of adenosine triphosphate (ATP)

    , 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.

  • Journal article
    Belvisi MG, Birrell MA, Khalid S, Wortley MA, Dockry R, Coote J, Holt K, Dubuis E, Kelsall A, Maher SA, Bonvini S, Woodcock A, Smith JAet 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.

  • Journal article
    Birrell MA, Maher SA, Dekkak B, Jones V, Wong S, Brook P, Belvisi MGet al., 2015,

    Anti-inflammatory effects of PGE(2) in the lung: role of the EP4 receptor subtype

    , Thorax, Vol: 70, Pages: 740-747, ISSN: 0040-6376

    Background Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases of the airway. Current treatment options (long acting β-adrenoceptor agonists and glucocorticosteroids) are not optimal as they are only effective in certain patient groups and safety concerns exist regarding both compound classes. Therefore, novel bronchodilator and anti-inflammatory strategies are being pursued. Prostaglandin E2 (PGE2) is an arachidonic acid-derived eicosanoid produced by the lung which acts on four different G-protein coupled receptors (EP1–4) to cause an array of beneficial and deleterious effects. The aim of this study was to identify the EP receptor mediating the anti-inflammatory actions of PGE2 in the lung using a range of cell-based assays and in vivo models.Methods and results It was demonstrated in three distinct model systems (innate stimulus, lipopolysaccharide (LPS); allergic response, ovalbumin (OVA); inhaled pollutant, cigarette smoke) that mice missing functional EP4 (Ptger4−/−) receptors had higher levels of airway inflammation, suggesting that endogenous PGE2 was suppressing inflammation via EP4 receptor activation. Cell-based assay systems (murine and human monocytes/alveolar macrophages) demonstrated that PGE2 inhibited cytokine release from LPS-stimulated cells and that this was mimicked by an EP4 (but not EP1–3) receptor agonist and inhibited by an EP4 receptor antagonist. The anti-inflammatory effect occurred at the transcriptional level and was via the adenylyl cyclase/cAMP/ cAMP-dependent protein kinase (PKA) axis.Conclusion This study demonstrates that EP4 receptor activation is responsible for the anti-inflammatory activity of PGE2 in a range of disease relevant models and, as such, could represent a novel therapeutic target for chronic airway inflammatory conditions.

  • Journal article
    Baxter M, Eltom S, Dekkak B, Yew-Booth L, Dubuis ED, Maher SA, Belvisi MG, Birrell MAet al., 2014,

    Role of transient receptor potential and pannexin channels in cigarette smoke-triggered ATP release in the lung

    , THORAX, Vol: 69, Pages: 1080-1089, ISSN: 0040-6376
  • Journal article
    Raemdonck K, de Alba J, Birrell MA, Grace M, Maher SA, Irvin CG, Fozard JR, O'Byrne PM, Belvisi MGet al., 2012,

    A role for sensory nerves in the late asthmatic response

    , THORAX, Vol: 67, Pages: 19-25, ISSN: 0040-6376
  • Journal article
    Birrell MA, Belvisi MG, Grace M, Sadofsky L, Faruqi S, Hele DJ, Maher SA, Freund-Michel V, Morice AHet al., 2009,

    TRPA1 Agonists Evoke Coughing in Guinea Pig and Human Volunteers

    , AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 180, Pages: 1042-1047, ISSN: 1073-449X

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