title: Neurophenotypes in Airway Diseases. Insights from Translational Cough Studies.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Patients with COPD had heightened cough responses to capsaicin but reduced responses to prostaglandin E2 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 control animals; similar increased responses were observed in ex vivo vagus nerve and neuron cell bodies in the vagal ganglia. However, responses to prostaglandin E2 were decreased by CS exposure.
  
  
  
  CS exposure is capable of inducing responses consistent with phenotypic switching in airway sensory nerves comparable with the cough responses observed in patients with COPD. Moreover, the differing profiles of cough responses support the concept of disease-specific neurophenotypes in airway disease. Clinical trial registered with www.clinicaltrials.gov (NCT 01297790).
authors.affiliation: 1 Respiratory Pharmacology Group, Division of Airway Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Maria G
authors.identifier: 0000-0003-1652-4370
authors.initials: MG
authors.lastname: Belvisi
authors.affiliation: 1 Respiratory Pharmacology Group, Division of Airway Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Birrell
authors.affiliation: 2 Centre for Respiratory and Allergy, University of Manchester, University Hospital of South Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom; and.
authors.forename: Saifudin
authors.initials: S
authors.lastname: Khalid
authors.affiliation: 1 Respiratory Pharmacology Group, Division of Airway Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Wortley
authors.affiliation: 2 Centre for Respiratory and Allergy, University of Manchester, University Hospital of South Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom; and.
authors.forename: Rachel
authors.initials: R
authors.lastname: Dockry
authors.affiliation: 1 Respiratory Pharmacology Group, Division of Airway Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom.|3 Respiratory Diseases, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
authors.forename: Julie
authors.initials: J
authors.lastname: Coote
authors.affiliation: 2 Centre for Respiratory and Allergy, University of Manchester, University Hospital of South Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom; and.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Holt
authors.affiliation: 1 Respiratory Pharmacology Group, Division of Airway Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Eric
authors.initials: E
authors.lastname: Dubuis
authors.affiliation: 2 Centre for Respiratory and Allergy, University of Manchester, University Hospital of South Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom; and.
authors.forename: Angela
authors.initials: A
authors.lastname: Kelsall
authors.affiliation: 1 Respiratory Pharmacology Group, Division of Airway Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Maher
authors.affiliation: 1 Respiratory Pharmacology Group, Division of Airway Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Sara
authors.initials: S
authors.lastname: Bonvini
authors.affiliation: 2 Centre for Respiratory and Allergy, University of Manchester, University Hospital of South Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom; and.
authors.forename: Ashley
authors.initials: A
authors.lastname: Woodcock
authors.affiliation: 2 Centre for Respiratory and Allergy, University of Manchester, University Hospital of South Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom; and.
authors.forename: Jaclyn A
authors.identifier: 0000-0001-8837-4928
authors.initials: JA
authors.lastname: Smith
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000368:Aged; D000818:Animals; D002211:Capsaicin / Q000008:administration & dosage; D003371:Cough; D015232:Dinoprostone / Q000008:administration & dosage; D004195:Disease Models, Animal; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology*; D012137:Respiratory System / Q000294:innervation* / Q000503:physiopathology*; D012906:Smoke; D014630:Vagus Nerve / Q000503:physiopathology
chemical_list: D012906:Smoke; D015232:Dinoprostone; D002211:Capsaicin
keywords: COPD; asthma; cough; guinea pig; vagus nerve