{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T05:07:27Z","timestamp":1789967247707,"version":"4.0.1"},"reference-count":57,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2016,11,5]],"date-time":"2016-11-05T00:00:00Z","timestamp":1478304000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Transient Receptor Potential Ankyrin 1 (TRPA1) ion channel is expressed abundantly on the C fibers that innervate almost entire respiratory tract starting from oral cavity and oropharynx, conducting airways in the trachea, bronchi, terminal bronchioles, respiratory bronchioles and upto alveolar ducts and alveoli. Functional presence of TRPA1 on non-neuronal cells got recognized recently. TRPA1 plays a well-recognized role of \u201cchemosensor\u201d, detecting presence of exogenous irritants and endogenous pro-inflammatory mediators that are implicated in airway inflammation and sensory symptoms like chronic cough, asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis and cystic fibrosis. TRPA1 can remain activated chronically due to elevated levels and continued presence of such endogenous ligands and pro-inflammatory mediators. Several selective TRPA1 antagonists have been tested in animal models of respiratory disease and their performance is very promising. Although there is no TRPA1 antagonist in advanced clinical trials or approved on market yet to treat respiratory diseases, however, limited but promising evidences available so far indicate likelihood that targeting TRPA1 may present a new therapy in treatment of respiratory diseases in near future. This review will focus on in vitro, animal and human evidences that strengthen the proposed role of TRPA1 in modulation of specific airway sensory responses and also on preclinical and clinical progress of selected TRPA1 antagonists.<\/jats:p>","DOI":"10.3390\/ph9040070","type":"journal-article","created":{"date-parts":[[2016,11,7]],"date-time":"2016-11-07T10:36:50Z","timestamp":1478515010000},"page":"70","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Blocking TRPA1 in Respiratory Disorders: Does It Hold a Promise?"],"prefix":"10.3390","volume":"9","author":[{"given":"Indranil","family":"Mukhopadhyay","sequence":"first","affiliation":[{"name":"Biological Research, Glenmark Research Centre, Glenmark Pharmaceuticals Ltd. Navi Mumbai, Maharashtra 400709, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhay","family":"Kulkarni","sequence":"additional","affiliation":[{"name":"Biological Research, Glenmark Research Centre, Glenmark Pharmaceuticals Ltd. Navi Mumbai, Maharashtra 400709, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neelima","family":"Khairatkar-Joshi","sequence":"additional","affiliation":[{"name":"Biological Research, Glenmark Research Centre, Glenmark Pharmaceuticals Ltd. Navi Mumbai, Maharashtra 400709, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2016,11,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7325","DOI":"10.1074\/jbc.274.11.7325","article-title":"An ankyrin-like protein with transmembrane domains is specifically lost after oncogenic transformation of human fibroblasts","volume":"274","author":"Jaquemar","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Kunert-Keil, C., Bisping, F., Kr\u00fcger, J., and Brinkmeier, H. (2006). Tissue-specific expression of TRP channel genes in the mouse and its variation in three different mouse strains. BMC Genom., 7.","DOI":"10.1186\/1471-2164-7-159"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1113\/jphysiol.2007.148379","article-title":"Expression and function of the ion channel TRPA1 in vagal afferent nerves innervating mouse lungs","volume":"586","author":"Nassenstein","year":"2008","journal-title":"J. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1016\/j.cell.2006.02.023","article-title":"TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents","volume":"124","author":"Bautista","year":"2006","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"13519","DOI":"10.1073\/pnas.0705923104","article-title":"4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1","volume":"104","author":"Trevisani","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1172\/JCI34192","article-title":"TRPA1 is a major oxidant sensor in murine airway sensory neurons","volume":"118","author":"Bessac","year":"2008","journal-title":"J. Clin. Invest."},{"key":"ref_7","first-page":"2574","article-title":"Cigarette smoke-induced neurogenic inflammation is mediated by \u03b1,\u03b2-unsaturated aldehydes and the TRPA1 receptor in rodents","volume":"118","author":"Campi","year":"2008","journal-title":"J. Clin. Invest."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"8784","DOI":"10.1073\/pnas.0711038105","article-title":"General anesthetics activate a nociceptive ion channel to enhance pain and inflammation","volume":"105","author":"Matta","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1111\/j.1476-5381.2009.00438.x","article-title":"Transient receptor potential ankyrin receptor 1 is a novel target for pro-tussive agents","volume":"158","author":"Gatti","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/nchembio.146","article-title":"Zinc activates damage-sensing TRPA1 ion channels","volume":"5","author":"Hu","year":"2009","journal-title":"Nat. Chem. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1124\/mol.108.054445","article-title":"Nitrooleic acid, an endogenous product of nitrative stress, activates nociceptive sensory nerves via the direct activation of TRPA1","volume":"75","author":"Ghatta","year":"2009","journal-title":"Mol. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4052","DOI":"10.1523\/JNEUROSCI.0013-05.2005","article-title":"Nociceptor and hair cell transducer properties of TRPA1, a channel for pain and hearing","volume":"25","author":"Nagata","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"350","DOI":"10.3109\/10799893.2011.602413","article-title":"Expression of functional TRPA1 receptor on human lung fibroblast and epithelial cells","volume":"31","author":"Mukhopadhyay","year":"2011","journal-title":"J. Recept. Signal Transduct."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Nassini, R., Pedretti, P., Moretto, N., Fusi, C., Carnini, C., Facchinetti, F., Viscomi, A.R., Pisano, A.R., Stokesberry, S., and Brunmark, C. (2012). Transient receptor potential ankyrin 1 channel localized to non-neuronal airway cells promotes non-neurogenic inflammation. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0042454"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.cbi.2013.08.012","article-title":"Functional expression of the transient receptor potential channel TRPA1, a sensor for toxic lung inhalants, in pulmonary epithelial cells","volume":"206","author":"Demmel","year":"2013","journal-title":"Chem. Biol. Interact."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Mihara, S., and Shibamoto, T. (2015). The role of flavor and fragrance chemicals in TRPA1 (transient receptor potential cation channel, member A1) activity associated with allergies. Allergy Asthma Clin. Immunol., 11.","DOI":"10.1186\/s13223-015-0074-0"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"L812","DOI":"10.1152\/ajplung.00164.2015","article-title":"Cigarette smoke has sensory effects through nicotinic and TRPA1 but not TRPV1 receptors on the isolated mouse trachea and larynx","volume":"309","author":"Kichko","year":"2015","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1021\/tx400024h","article-title":"Activation of transient receptor potential ankyrin-1 (TRPA1) in lung cells by wood smoke particulate material","volume":"26","author":"Shapiro","year":"2013","journal-title":"Chem. Res. Toxicol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.pupt.2013.02.007","article-title":"Pre-clinical studies in cough research: Role of Transient Receptor Potential (TRP) channels","volume":"26","author":"Grace","year":"2013","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_20","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":"ref_21","doi-asserted-by":"crossref","first-page":"28621","DOI":"10.1038\/srep28621","article-title":"Systemic desensitization through TRPA1 channels by capsazepine and mustard oil\u2014A novel strategy against inflammation and pain","volume":"6","author":"Kistner","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Mukhopadhyay, I., Kulkarni, A., Aranake, S., Karnik, P., Shetty, M., Thorat, S., Ghosh, I., Wale, D., Bhosale, V., and Khairatkar-Joshi, N. (2014). Transient receptor potential ankyrin 1 receptor activation in vitro and in vivo by pro-tussive agents: GRC 17536 as a promising anti-tussive therapeutic. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0097005"},{"key":"ref_23","first-page":"PA3948","article-title":"Pharmacological profile of a novel, potent and oral TRPA1 antagonist. Characterization in a preclinical model of induced cough","volume":"46","author":"Aparici","year":"2015","journal-title":"Eur. Respir. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.otc.2009.11.012","article-title":"Afferent nerves regulating the cough reflex: Mechanisms and mediators of cough in disease","volume":"43","author":"Canning","year":"2010","journal-title":"Otolaryngol. Clin. North Am."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1124\/pr.111.004622","article-title":"Dual Role of Toll-Like Receptors in Asthma and Chronic Obstructive Pulmonary Disease","volume":"64","author":"Bezemer","year":"2012","journal-title":"Pharmacol. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1186\/1743-422X-10-135","article-title":"Comparative expression of Toll-like receptors and inflammatory cytokines in pigs infected with different virulent porcine reproductive and respiratory syndrome virus isolates","volume":"10","author":"Zhang","year":"2013","journal-title":"J. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6417","DOI":"10.4049\/jimmunol.1001241","article-title":"Painful pathways induced by TLR stimulation of dorsal root ganglion neurons","volume":"186","author":"Qi","year":"2011","journal-title":"J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1378\/chest.10-3327","article-title":"Transient receptor potential A1 channels: Insights into cough and airway inflammatory disease","volume":"140","author":"Belvisi","year":"2011","journal-title":"Chest"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1745-9974-9-8","article-title":"Molecular signaling and targets from itch: Lessons for cough","volume":"9","author":"Lavinka","year":"2013","journal-title":"Cough"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"9099","DOI":"10.1073\/pnas.0900591106","article-title":"A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma","volume":"106","author":"Caceres","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"71","DOI":"10.2174\/1877381801002030071","article-title":"The rising role of TRPA1 in asthma","volume":"2","author":"Facchinetti","year":"2010","journal-title":"Open Drug Discov. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1136\/thoraxjnl-2011-200365","article-title":"A role for sensory nerves in the late asthmatic response","volume":"67","author":"Raemdonck","year":"2012","journal-title":"Thorax"},{"key":"ref_33","first-page":"E5645","article-title":"GRC 17536, a novel, selective TRPA1 antagonist for potential treatment of respiratory disorders","volume":"36","author":"Anupindi","year":"2010","journal-title":"Eur. Respir. J."},{"key":"ref_34","unstructured":"Camino, D., Chong, J.A., Hayward, N.J., Monsen, J., Moran, M.M., Curtis, R., Murphy, C., Mortin, L.I., and Abraham, W.M. (2012, January 12\u201314). Effects of blocking TRPA1 in a sheep model of asthma. Proceedings of the International Workshop on Transient Receptor Potential Channels, a TRiP to Spain, Valencia, Spain."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1016\/S0140-6736(08)61445-2","article-title":"Association between paracetamol use in infancy and childhood, and risk of asthma, rhinoconjunctivitis, and eczema in children aged 6\u20137 years: Analysis from phase three of the ISAAC programme","volume":"372","author":"Beasley","year":"2008","journal-title":"Lancet"},{"key":"ref_36","first-page":"4904","article-title":"Acetaminophen, via its reactive metabolite N-acetyl-pbenzo-quinoneimine and transient receptor potential ankyrin-1 stimulation, causes neurogenic inflammation in the airways and other tissues in rodents","volume":"24","author":"Nassini","year":"2010","journal-title":"FASEB J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1136\/thx.2006.061457","article-title":"Biomass fuels are the probable risk factor for chronic obstructive pulmonary disease in rural South China","volume":"62","author":"Liu","year":"2007","journal-title":"Thorax"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1165\/rcmb.2007-0130OC","article-title":"\u03b1,\u03b2-Unsaturated aldehydes in cigarette smoke release inflammatory mediators from human macrophages","volume":"37","author":"Facchinetti","year":"2007","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Lin, A.H., Liu, M.H., Ko, H.K., Perng, D.W., Lee, T.S., and Kou, Y.R. (2015). Lung epithelial TRPA1 transduces the extracellular ROS into transcriptional regulation of lung inflammation induced by cigarette smoke: The role of influxed Ca2+. Mediat. Inflamm., 2015.","DOI":"10.1155\/2015\/148367"},{"key":"ref_40","unstructured":"Dupont, L.L., Alpizar, Y.A., Brusselle, G.G., Bracke, K.R., Talavera, K., Joos, G.F., and Maes, T. (2014, January 16\u201321). Expression of transient receptor potential (TRP) channels in a murine model of cigarette smoke exposure. Proceedings of the C34. Insights into COPD Pathogenesis from Pre-Clinical Studies, San Diego, CA, USA."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1378\/chest.08-2114","article-title":"Risk of COPD from exposure to biomass smoke: A metaanalysis","volume":"1381","author":"Hu","year":"2010","journal-title":"Chest"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1111\/j.1365-2222.2008.02935.x","article-title":"Clinical and immunologic findings of methylene Diphenyl diisocyanate-induced occupational asthma in a car upholstery factory","volume":"38","author":"Hur","year":"2008","journal-title":"Clin. Exp. Allergy"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3672","DOI":"10.3390\/ijerph8093672","article-title":"Environmental isocyanate-induced asthma: Morphologic and pathogenetic aspects of an increasing occupational disease","volume":"8","author":"Bartsch","year":"2011","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.4049\/jimmunol.179.3.1864","article-title":"Inhalation of toluene diisocyanate vapor induces allergic rhinitis in mice","volume":"179","author":"Johnson","year":"2007","journal-title":"J. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1165\/rcmb.2008-0292OC","article-title":"Transient receptor potential ankyrin 1 mediates toluene diisocyanate\u2013evoked respiratory irritation","volume":"40","author":"Kiros","year":"2009","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"AB52","DOI":"10.1016\/j.jaci.2010.12.218","article-title":"Nasal mucosal TRPA1 and TRPV1 levels in human rhinitis","volume":"127","author":"Tourangeau","year":"2011","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Prandini, P., De Logu, F., Fusi, C., Provezza, L., Nassini, R., Montagner, G., Materazzi, S., Munari, S., Gilioli, E., and Bezzerri, V. (2016). TRPA1 channels modulate inflammatory response in respiratory cells from cystic fibrosis patients. Am. J. Respir. Cell. Mol. Biol., 55.","DOI":"10.1165\/rcmb.2016-0089OC"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1007\/s00210-015-1088-3","article-title":"TRPA1 as drug target-Promise and challenges","volume":"388","author":"Chen","year":"2015","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3125","DOI":"10.1038\/ncomms4125","article-title":"TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins","volume":"5","author":"Meseguer","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_50","unstructured":"Tandon, M., Jain, S.M., Balamurugan, R., Koslowski, M., and Keohane, P. (2015, January 14\u201317). Treatment of pain associated with diabetic peripheral neuropathy with the novel TRPA1 antagonist GRC 17536 in patients with intact peripheral nerve function. Proceedings of the Fifth International Meeting of The Special Interest Group on Neuropathic Pain (NeuPSIG), Nice, France."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1016\/S0140-6736(12)60776-4","article-title":"Gabapentin for refractory chronic cough: A randomised, double-blind, placebo-controlled trial","volume":"380","author":"Ryan","year":"2012","journal-title":"Lancet"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.neuron.2006.03.042","article-title":"TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction","volume":"50","author":"Kwan","year":"2006","journal-title":"Neuron"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1016\/j.pain.2011.01.049","article-title":"Selective blockade of TRPA1 channel attenuates pathological pain without altering noxious cold sensation or body temperature regulation","volume":"152","author":"Chen","year":"2011","journal-title":"Pain"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4445","DOI":"10.1523\/JNEUROSCI.5387-13.2014","article-title":"Transient receptor potential channel ankyrin-1 is not a cold sensor for autonomic thermoregulation in rodents","volume":"34","author":"Garami","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_55","unstructured":"Curtis, R., Coleman, S., Camino, D.D., Hayward, N.J., Moran, M.M., and Bokesch, P. (2012, January 12\u201314). Transient Receptor Potential A1 (TRPA1) is not involved in thermoregulation in dogs and humans. Proceedings of the A Trip to Spain: International workshop on transient receptor potential channels, Valencia, Spain."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2393","DOI":"10.1172\/JCI25437","article-title":"TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury","volume":"115","author":"Obata","year":"2005","journal-title":"J. Clin. Invest."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e00052","DOI":"10.1002\/prp2.52","article-title":"Investigating the potential role of TRPA1 in locomotion and cardiovascular control during hypertension","volume":"2","author":"Bodkin","year":"2014","journal-title":"Pharmacol. Res. Perspect."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/9\/4\/70\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:34:51Z","timestamp":1760211291000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/9\/4\/70"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,11,5]]},"references-count":57,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2016,12]]}},"alternative-id":["ph9040070"],"URL":"https:\/\/doi.org\/10.3390\/ph9040070","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,11,5]]}}}