{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T09:57:09Z","timestamp":1791280629889,"version":"4.1.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2016,6,1]],"date-time":"2016-06-01T00:00:00Z","timestamp":1464739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/K020293\/1"],"award-info":[{"award-number":["MR\/K020293\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Medical Research Council Clinician Scientist Award","award":["G0701918"],"award-info":[{"award-number":["G0701918"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,6,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                    <jats:p>Clinical trial registered with www.clinicaltrials.gov (NCT 01297790).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201508-1602oc","type":"journal-article","created":{"date-parts":[[2016,1,7]],"date-time":"2016-01-07T17:34:33Z","timestamp":1452188073000},"page":"1364-1372","source":"Crossref","is-referenced-by-count":111,"title":["Neurophenotypes in Airway Diseases: Insights from Translational Cough Studies"],"prefix":"10.1093","volume":"193","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1652-4370","authenticated-orcid":false,"given":"Maria G.","family":"Belvisi","sequence":"first","affiliation":[{"name":"Respiratory Pharmacology Group, Division of Airway Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Birrell","sequence":"additional","affiliation":[{"name":"Respiratory Pharmacology Group, Division of Airway Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saifudin","family":"Khalid","sequence":"additional","affiliation":[{"name":"Centre for Respiratory and Allergy, University of Manchester, University Hospital of South Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Wortley","sequence":"additional","affiliation":[{"name":"Respiratory Pharmacology Group, Division of Airway Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Dockry","sequence":"additional","affiliation":[{"name":"Centre for Respiratory and Allergy, University of Manchester, University Hospital of South Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Coote","sequence":"additional","affiliation":[{"name":"Respiratory Pharmacology Group, Division of Airway Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom"},{"name":"Respiratory Diseases, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberley","family":"Holt","sequence":"additional","affiliation":[{"name":"Centre for Respiratory and Allergy, University of Manchester, University Hospital of South Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Dubuis","sequence":"additional","affiliation":[{"name":"Respiratory Pharmacology Group, Division of Airway Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Kelsall","sequence":"additional","affiliation":[{"name":"Centre for Respiratory and Allergy, University of Manchester, University Hospital of South Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah A.","family":"Maher","sequence":"additional","affiliation":[{"name":"Respiratory Pharmacology Group, Division of Airway Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Bonvini","sequence":"additional","affiliation":[{"name":"Respiratory Pharmacology Group, Division of Airway Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Woodcock","sequence":"additional","affiliation":[{"name":"Centre for Respiratory and Allergy, University of Manchester, University Hospital of South Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8837-4928","authenticated-orcid":false,"given":"Jaclyn A.","family":"Smith","sequence":"additional","affiliation":[{"name":"Centre for Respiratory and Allergy, University of Manchester, University Hospital of South Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,6,15]]},"reference":[{"key":"2026032100070367500_bib1","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1136\/thx.2006.060087","article-title":"Cough in the community: a cross sectional survey and the relationship to gastrointestinal symptoms","volume":"61","author":"Ford","year":"2006","journal-title":"Thorax"},{"key":"2026032100070367500_bib2","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1183\/09031936.01.00098701","article-title":"Determinants of cough in young adults participating in the European Community Respiratory Health Survey","volume":"18","author":"Janson","year":"2001","journal-title":"Eur Respir J"},{"key":"2026032100070367500_bib3","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1164\/rccm.201211-2000OC","article-title":"Predictors of objective cough frequency in chronic obstructive pulmonary disease","volume":"187","author":"Sumner","year":"2013","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100070367500_bib4","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1136\/thoraxjnl-2011-201443","article-title":"Transient receptor potential channels mediate the tussive response to prostaglandin E2 and bradykinin","volume":"67","author":"Grace","year":"2012","journal-title":"Thorax"},{"key":"2026032100070367500_bib5","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1124\/jpet.102.043422","article-title":"A role for TRPV1 in bradykinin-induced excitation of vagal airway afferent nerve terminals","volume":"304","author":"Carr","year":"2003","journal-title":"J Pharmacol Exp Ther"},{"key":"2026032100070367500_bib6","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1113\/jphysiol.2003.054890","article-title":"Activation of bronchopulmonary vagal afferent nerves with bradykinin, acid and vanilloid receptor agonists in wild-type and TRPV1-\/- mice","volume":"555","author":"Kollarik","year":"2004","journal-title":"J Physiol"},{"key":"2026032100070367500_bib7","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1113\/jphysiol.1996.sp021234","article-title":"Immunomodulation of afferent neurons in guinea-pig isolated airway","volume":"491","author":"Riccio","year":"1996","journal-title":"J Physiol"},{"key":"2026032100070367500_bib8","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1152\/jappl.1995.79.4.1082","article-title":"Capsazepine inhibits cough induced by capsaicin and citric acid but not by hypertonic saline in guinea pigs","volume":"79","author":"Lalloo","year":"1995","journal-title":"J Appl Physiol (1985)"},{"key":"2026032100070367500_bib9","doi-asserted-by":"crossref","first-page":"e97005","DOI":"10.1371\/journal.pone.0097005","article-title":"Transient receptor potential ankyrin 1 receptor activation in vitro and in vivo by pro-tussive agents: GRC 17536 as a promising anti-tussive therapeutic","volume":"9","author":"Mukhopadhyay","year":"2014","journal-title":"PLoS One"},{"key":"2026032100070367500_bib10","doi-asserted-by":"crossref","first-page":"R454","DOI":"10.1152\/ajpregu.00862.2005","article-title":"Mechanistic studies of acid-evoked coughing in anesthetized guinea pigs","volume":"291","author":"Canning","year":"2006","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"2026032100070367500_bib11","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1164\/ajrccm.159.1.9804030","article-title":"Protective effects of inhaled PGE2 on allergen-induced airway responses and airway inflammation","volume":"159","author":"Gauvreau","year":"1999","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100070367500_bib12","doi-asserted-by":"crossref","first-page":"S139","DOI":"10.1136\/thoraxjnl-2011-201054b.139","article-title":"Cough responses to tussive agents in health and disease [abstract]","volume":"66","author":"Khalid","year":"2011","journal-title":"Thorax"},{"key":"2026032100070367500_bib13","first-page":"A3565","article-title":"Changes in vagal afferent responses and cough reflex sensitivity to PGE2 in smokers and COPD patients and in a guinea pig cigarette-smoke exposure model [abstract]","volume":"185","author":"Wortley","year":"2012","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100070367500_bib14","doi-asserted-by":"crossref","first-page":"A131","DOI":"10.1136\/thoraxjnl-2012-202678.220","article-title":"Validation of the VitaloJAK 24hour ambulatory cough monitor [abstract]","volume":"67","author":"McGuinness","year":"2012","journal-title":"Thorax"},{"key":"2026032100070367500_bib15","doi-asserted-by":"crossref","first-page":"94","DOI":"10.4103\/0976-500X.72351","article-title":"Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research","volume":"1","author":"Kilkenny","year":"2010","journal-title":"J Pharmacol Pharmacother"},{"key":"2026032100070367500_bib16","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.jaci.2013.12.003","article-title":"Tiotropium modulates transient receptor potential V1 (TRPV1) in airway sensory nerves: a beneficial off-target effect?","volume":"133","author":"Birrell","year":"2014","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100070367500_bib17","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1016\/j.jaci.2013.11.017","article-title":"Theophylline inhibits the cough reflex through a novel mechanism of action","volume":"133","author":"Dubuis","year":"2014","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100070367500_bib18","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1164\/rccm.200903-0388OC","article-title":"Prostaglandin E2 mediates cough via the EP3 receptor: implications for future disease therapy","volume":"180","author":"Maher","year":"2009","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100070367500_bib19","first-page":"Unit 12.15","article-title":"Harvesting, isolation, and functional assessment of primary vagal ganglia cells","volume":"62","author":"Dubuis","year":"2013","journal-title":"Curr Protoc Pharmacol"},{"key":"2026032100070367500_bib20","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1164\/rccm.200905-0665OC","article-title":"TRPA1 agonists evoke coughing in guinea pig and human volunteers","volume":"180","author":"Birrell","year":"2009","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100070367500_bib21","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/S0012-3692(15)51851-5","article-title":"Cough in COPD: correlation of objective monitoring with cough challenge and subjective assessments","volume":"130","author":"Smith","year":"2006","journal-title":"Chest"},{"key":"2026032100070367500_bib22","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.jaci.2005.09.055","article-title":"Effect of codeine on objective measurement of cough in chronic obstructive pulmonary disease","volume":"117","author":"Smith","year":"2006","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100070367500_bib23","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1016\/j.jaci.2008.08.029","article-title":"A comparison of objective and subjective measures of cough in asthma","volume":"122","author":"Marsden","year":"2008","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100070367500_bib24","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.pupt.2006.12.001","article-title":"Animal models of cough: literature review and presentation of a novel cigarette smoke-enhanced cough model in the guinea-pig","volume":"20","author":"Lewis","year":"2007","journal-title":"Pulm Pharmacol Ther"},{"key":"2026032100070367500_bib25","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/S0034-5687(01)00193-1","article-title":"Chronic tobacco smoke exposure increases cough to capsaicin in awake guinea pigs","volume":"126","author":"Bergren","year":"2001","journal-title":"Respir Physiol"},{"key":"2026032100070367500_bib26","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1111\/j.1748-1716.1991.tb09105.x","article-title":"Hyperresponsiveness to tussive stimuli in cigarette smoke-exposed guinea-pigs: a role for capsaicin-sensitive, calcitonin gene-related peptide-containing nerves","volume":"141","author":"Karlsson","year":"1991","journal-title":"Acta Physiol Scand"},{"key":"2026032100070367500_bib27","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1164\/rccm.200308-1139OC","article-title":"Passive smoke effects on cough and airways in young guinea pigs: role of brainstem substance P","volume":"169","author":"Joad","year":"2004","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100070367500_bib28","doi-asserted-by":"crossref","first-page":"S23","DOI":"10.1007\/s00408-009-9191-1","article-title":"Effect of smoking on cough reflex sensitivity: basic and preclinical studies","volume":"188","author":"Lee","year":"2010","journal-title":"Lung"},{"key":"2026032100070367500_bib29","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1136\/thorax.58.7.585","article-title":"Exhaled leukotrienes and prostaglandins in COPD","volume":"58","author":"Montuschi","year":"2003","journal-title":"Thorax"},{"key":"2026032100070367500_bib30","doi-asserted-by":"crossref","first-page":"L261","DOI":"10.1152\/ajplung.90593.2008","article-title":"Chronic obstructive pulmonary disease and neutrophil infiltration: role of cigarette smoke and cyclooxygenase products","volume":"298","author":"Profita","year":"2010","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026032100070367500_bib31","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1111\/j.1440-1843.2008.01365.x","article-title":"Enhanced levels of prostaglandin E2 and matrix metalloproteinase-2 correlate with the severity of airflow limitation in stable COPD","volume":"13","author":"Chen","year":"2008","journal-title":"Respirology"},{"key":"2026032100070367500_bib32","doi-asserted-by":"crossref","first-page":"L941","DOI":"10.1152\/ajplung.00366.2011","article-title":"TRPV1 induction in airway vagal low-threshold mechanosensory neurons by allergen challenge and neurotrophic factors","volume":"302","author":"Lieu","year":"2012","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026032100070367500_bib33","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1152\/jappl.1998.85.5.1847","article-title":"Effects of airway inflammation on cough response in the guinea pig","volume":"85","author":"Xiang","year":"1998","journal-title":"J Appl Physiol (1985)"},{"key":"2026032100070367500_bib34","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1046\/j.1365-2222.2001.00989.x","article-title":"Characterization of increased cough sensitivity after antigen challenge in guinea pigs","volume":"31","author":"Liu","year":"2001","journal-title":"Clin Exp Allergy"},{"key":"2026032100070367500_bib35","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1136\/thorax.58.1.19","article-title":"Cough receptor sensitivity to capsaicin does not change after allergen bronchoprovocation in allergic asthma","volume":"58","author":"Minoguchi","year":"2003","journal-title":"Thorax"},{"key":"2026032100070367500_bib36","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1136\/thorax.55.8.643","article-title":"Capsaicin responsiveness and cough in asthma and chronic obstructive pulmonary disease","volume":"55","author":"Doherty","year":"2000","journal-title":"Thorax"},{"key":"2026032100070367500_bib37","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1016\/j.rmed.2008.11.010","article-title":"Capsaicin cough sensitivity in smokers with and without airflow obstruction","volume":"103","author":"Blanc","year":"2009","journal-title":"Respir Med"},{"key":"2026032100070367500_bib38","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1016\/j.jaci.2013.04.042","article-title":"Pharmacodynamic modeling of cough responses to capsaicin inhalation calls into question the utility of the C5 end point","volume":"132","author":"Hilton","year":"2013","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100070367500_bib39","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1164\/ajrccm\/140.1.137","article-title":"Sensitivity of the human cough reflex: effect of inflammatory mediators prostaglandin E2, bradykinin, and histamine","volume":"140","author":"Choudry","year":"1989","journal-title":"Am Rev Respir Dis"},{"key":"2026032100070367500_bib40","first-page":"176","article-title":"Bradykinin-induced bronchoconstriction in humans. Mode of action","volume":"135","author":"Fuller","year":"1987","journal-title":"Am Rev Respir Dis"}],"container-title":["American Journal of Respiratory and Critical Care Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/193\/12\/1364\/67256189\/ajrccm_193_12_1364.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/193\/12\/1364\/67256189\/ajrccm_193_12_1364.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T04:07:11Z","timestamp":1774066031000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrccm\/article\/193\/12\/1364\/8508988"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,6]]},"references-count":40,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2016,6,15]]},"published-print":{"date-parts":[[2016,6,15]]}},"URL":"https:\/\/doi.org\/10.1164\/rccm.201508-1602oc","relation":{},"ISSN":["1073-449X","1535-4970"],"issn-type":[{"value":"1073-449X","type":"print"},{"value":"1535-4970","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,6]]},"published":{"date-parts":[[2016,6]]}}}