, Volume 186, Supplement 1, pp 88–93 | Cite as

Irritant-Induced Chronic Cough: Irritant-Induced TRPpathy

  • Stuart M. BrooksEmail author


This article expands the author’s presentation at the First American Cough Conference in New York City, June 8–9, 2007. The results of a scientific literature search and application of personal research findings are included. A new hypothesis to explain irritant-induced cough as a being a dysfunction of the transient receptor potential vanilloid 1 (TRPV1) cation channels located in pulmonary excitable cells is presented. The TRPV1 cation channels regulate cellular transmembrane voltage by raising intracellular Ca2+ and Na+ concentrations and depolarizing sensory nerve cells containing C-fibers. The discussion centers on the “capsaicin receptor” (TRPV1) and another important ion channel, TRPA1. The author reviews results of published scientific investigations to support his contention that neural events, initiated by TRPV1 ion channels, lead to a cascade of alterations that progress to a cough endpoint. A potential mechanism to explain chronic cough in conditions where there is repeated or severe irritant-induced airway epithelial injury (e.g., RADS) is through persistent TRPV1 channel activation (e.g., TRPV1pathy) with accumulation of inflammatory mediators, tachykinins, and the release of neurotrophins leading to persistent cough and airway inflammation. The significance of the hypothesis is that, if proven, it may provide new therapeutic approaches for the treatment of chronic cough.


Cation channels TRPV1 proteins TRPpathies Capsaicin Chronic cough 


  1. 1.
    Online Medical Dictionary, Stedman’s Medical Dictionary, 27th ed. Baltimore: Lippincott Williams and Wilkins, 2007Google Scholar
  2. 2.
    Shusterman D (2004) Sequel of respiratory tract exposures to irritants. (PCCU) Pulmonary and critical care update. Lesson 2, Volume 15, December 31, 2004. Website:
  3. 3.
    Occupational Safety and Health Administration (OSHA) (1994) The OSHA hazard communication standard (HCS)Google Scholar
  4. 4.
    Safety, Environment Unit (2007) Glossary of Chemical Terms. Rehovot, Israel: Weizmann Institute of Science. Website:
  5. 5.
    Randle WM, Bussard ML (1993) Streamlining onion pungency analyses. Hort Sci 28:60Google Scholar
  6. 6.
    Brooks SM (2007) Inhalation airway injury: A spectrum of changes. Clin Pulm Med 14(6):330–337Google Scholar
  7. 7.
    Green BG, Schullery MT (2003) Stimulation of bitterness by capsaicin and menthol: differences between lingual areas innervated by the glossopharyngeal and chorda tympani nerves. Chem Senses 28:45–55PubMedCrossRefGoogle Scholar
  8. 8.
    Dicpinigaitis PV (2003) Short- and long-term reproducibility of capsaicin cough challenge testing. Pulm Pharmacol Ther 16:61–65PubMedCrossRefGoogle Scholar
  9. 9.
    Dicpinigaitis PV (2003) Cough reflex sensitivity in cigarette smokers. Chest 123:685–688PubMedCrossRefGoogle Scholar
  10. 10.
    Barber CM, Curran AD, Fishwick D (2003) Impaired cough reflex in patients with recurrent pneumonia. Thorax 58:645–646PubMedCrossRefGoogle Scholar
  11. 11.
    Kastelik JA, Thompson RH, Aziz I, Ojoo JC, Redington AE, Morice AH (2002) Sex-related differences in cough reflex sensitivity in patients with chronic cough. Am J Respir Crit Care Med 166:961–964PubMedCrossRefGoogle Scholar
  12. 12.
    Nieto L, deDiego A, Perpina M, et al. (2003) Cough reflex testing with inhaled capsaicin in the study of chronic cough. Respir Med 97:393–400PubMedCrossRefGoogle Scholar
  13. 13.
    Morice AH, Kastelik JA, Thompson R (2001) Cough challenge in the assessment of cough reflex. Br J Clin Pharmacol 52:365–375PubMedCrossRefGoogle Scholar
  14. 14.
    Dicpinigaitis PV (2001) Capsaicin responsiveness in asthma and COPD. Thorax 56:162–164PubMedCrossRefGoogle Scholar
  15. 15.
    Prescott J, Swain-Campbell N (2000) Responses to repeated oral irritation by capsaicin, cinnamaldehyde and ethanol in PROP tasters and non-tasters. Chem Senses 25:239–246PubMedCrossRefGoogle Scholar
  16. 16.
    Millqvist E (2000) Cough provocation with capsaicin is an objective way to test sensory hyperreactivity in patients with asthma-like symptoms. Allergy 55:546–550PubMedCrossRefGoogle Scholar
  17. 17.
    Doherty MJ, Mister R, Pearson MG, Calverley PM (2000) Capsaicin induced cough in cryptogenic fibrosing alveolitis. Thorax 55:1028–1032PubMedCrossRefGoogle Scholar
  18. 18.
    Hathaway TJ, Higenbottam TW, Morrison JF, Clelland CA, Wallwork J (1993) Effects of inhaled capsaicin in heart-lung transplant patients and asthmatic subjects. Am Rev Respir Dis 148:1233–1237PubMedGoogle Scholar
  19. 19.
    Midgren B, Hansson B, Karlsson J-A, Simonsson BG, Persson CG (1992) Capsaicin-induced cough in humans. Am Rev Respir Dis 146:347–351PubMedGoogle Scholar
  20. 20.
    Hansson L, Wollmer P, Dahlback M, Karlsson JA (1992) Regional sensitivity of human airways to capsaicin-induced cough. Amer Rev Respir Dis 145:1191–1195Google Scholar
  21. 21.
    Stjarne P, Lundblad L, Lundberg JM, Anggård A (1989) Capsaicin and nicotine-sensitive afferent neurones and nasal secretion in healthy human volunteers and in patients with vasomotor rhinitis. Br J Pharmacol 96:693–701PubMedGoogle Scholar
  22. 22.
    Szallasi A, Blumberg PM (1999) Vanilloid (Capsaicin) receptors and mechanisms. Pharmacol Rev 51:159–212PubMedGoogle Scholar
  23. 23.
    Huang C-L (2004) The transient receptor potential superfamily of ion channels. J Am Soc Nephrol 15:1690–1699PubMedCrossRefGoogle Scholar
  24. 24.
    Rohacs T, Nilius B (2007) Regulation of transient receptor potential (TRP) channels by phosphoinositides. Pflugers Arch 455:157–168PubMedCrossRefGoogle Scholar
  25. 25.
    Ramsey IS, Delling M, Clapham DE (2006) An introduction to TRP channels. Annu Rev Physiol 68:619–647PubMedCrossRefGoogle Scholar
  26. 26.
    Taylor-Clark T, Undem BJ (2006) Transduction mechanisms in airway sensory nerves. J Appl Physiol 101:950–959PubMedCrossRefGoogle Scholar
  27. 27.
    Nilius B, Voets T, Peters J (2005) TRP channels in disease. Sci STKE 295:1–9Google Scholar
  28. 28.
    Tatar M, Pecova R (1996) The effect of experimental gastroesophageal reflux on the cough reflex in anesthetized cats. Bratisl Lek Listy 97:284–288PubMedGoogle Scholar
  29. 29.
    Wong CH, Matai R, Morice AH (1999) Cough induced by low pH. Respir Med 93:58–61PubMedCrossRefGoogle Scholar
  30. 30.
    Clapham DE (2003) TRP channels as cellular sensors. Nature 426:517–524PubMedCrossRefGoogle Scholar
  31. 31.
    Mazzone SB, McLennan L, McGovern AE, Egan GF, Farrell MJ (2007) Representation of capsaicin-evoked urge to cough in the human brain using functional magnetic resonance imaging. Am J Respir Crit Care Med 176:327–332PubMedCrossRefGoogle Scholar
  32. 32.
    Canning BJ, Farmer DG, Mori N (2006) Mechanistic studies of acid-evoked coughing in anesthetized guinea pigs. Am J Physiol Regul Integr Comp Physiol 291:R454–R463PubMedGoogle Scholar
  33. 33.
    Groneberg DA, Niimi A, Dinh QT, Cosio B, Hew M, Fischer A, Chung KF (2004) Increased expression of transient receptor potential vanilloid-1 in airway nerves of chronic cough. Am J Respir Crit Care Med 170:1276–1280PubMedCrossRefGoogle Scholar
  34. 34.
    LeVan TD, Koh W-P, Lee H-P, Koh D, Yu MC, London SJ (2006) Vapor, dust, and smoke exposure in relation to adult-onset asthma and chronic respiratory symptoms. The Singapore Chinese Health Study. Am J Epidemiol 163:1118–1128PubMedCrossRefGoogle Scholar
  35. 35.
    Tarlo SM (2006) Cough: occupational and environmental considerations. ACCP evidence-based clinical practice guidelines. Chest 129:186–196CrossRefGoogle Scholar
  36. 36.
    American Thoracic Society (2003) Occupational contribution to the burden of airway disease. Am J Respir Crit Care Med 167:787–797CrossRefGoogle Scholar
  37. 37.
    Cain WS, Cometto-Muniz JE (1995) Irritation and odor as indicators of indoor pollution. Occup Med 10:133–145PubMedGoogle Scholar
  38. 38.
    Trupin L, Earnest G, SanPedro M, Balmes JR, Eisner MD, Yelin E, Katz PP, Blanc PD (2003) The occupational burden of chronic obstructive pulmonary disease. Eur Respir J 22:462-469PubMedCrossRefGoogle Scholar
  39. 39.
    Tanaka H, Saikai T, Sugawara H, Takeya I, Tsunematsu K, Matsuura A, Abe S (2002) Workplace-related chronic cough on a mushroom farm. Chest 122:1080–1085PubMedCrossRefGoogle Scholar
  40. 40.
    Minnette A (1989) Questionnaire of the European Community for Coal and Steel (ECSC) on respiratory symptoms. 1987–updating of the 1962 and 1967 questionnaires for studying chronic bronchitis and emphysema. Eur J Respir Dis 2:165–177Google Scholar
  41. 41.
    Mustajbegovic J, Zuskin E, Schachter EN, Kern J, Vrcic-Keglevic M, Vitale K, Ebling Z (2001) Respiratory findings in livestock farmworkers. J Occup Environ Med 43:576–584PubMedCrossRefGoogle Scholar
  42. 42.
    Groneberg DA, Nowak D, Wussow A, Fischer A (2006) Chronic cough due to occupational factors. J Occup Med Toxicol 1:3PubMedCrossRefGoogle Scholar
  43. 43.
    Gordon SB, Curran AD, Turley A, Wong CH, Rahman SN, Wiley K, Morice AH (1997) Glass bottle workers exposed to low-dose irritant fumes cough but do not wheeze. Am J Respir Criti Care Med 156:206–210Google Scholar
  44. 44.
    Gordon SB, Curran AD, Fishwick D et al. (1998) Respiratory symptoms among glass bottle workers–cough and airways irritancy syndrome? Occup Med 48: 455–459CrossRefGoogle Scholar
  45. 45.
    Blanc P, Liu D, Juarez C, Boushey HA (1991) Cough in hot pepper workers. Chest 99:27–32PubMedCrossRefGoogle Scholar
  46. 46.
    Bautista DM, Movahed P, Hinman A, Axelsson HE, Sterner O, Högestätt ED, Julius D, Jordt SE, Zygmunt PM (2005) Pungent products from garlic activate the sensory ion channel TRPA1. Proc Natl Acad Sci U S A 102:12248–12252PubMedCrossRefGoogle Scholar
  47. 47.
    Obata K, JKatsura H, Mizushima T, Yamanaka H, Kobayashi K, Dai Y, Fukuoka T, Tokunaga A, Tominaga M, Noguchi K (2005) TRPA1 induced in sensory neurons contribute to cold hyperalgesia after inflammation and nerve injury. J Clin Invest 115:2393–2401PubMedCrossRefGoogle Scholar
  48. 48.
    Trevisani M, Siemens J, Materazzi S, Bautista DM, Nassini R, Campi B, Imamachi N, Andrè E, Patacchini R, Cottrell GS, Gatti R, Basbaum AI, Bunnett NW, Julius D, Geppetti P (2007) 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc Natl Acad Sci U S A 104:13519–13524PubMedCrossRefGoogle Scholar
  49. 49.
    McNamara CR, Mandel-Brehm J, Bautista DM, Siemens J, Deranian KL, Zhao M, Hayward NJ, Chong JA, Julius D, Moran MM, Fanger CM (2007) TRPA1 mediates formalin-induced pain. Proc Natl Acad Sci U S A 104:13525–13530PubMedCrossRefGoogle Scholar
  50. 50.
    Story GM, Peier AM, Reeve AJ, Eld SR, Mosbacher J, Hricik TR, Earley TJ, Hergarden AC, Andersson DA, Hwang SW, McIntyre P, Jegla T, Bevan S, Patapoutian A (2003) ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112:819–829PubMedCrossRefGoogle Scholar
  51. 51.
    Story GM, Gereau RW (2006) Numbing the senses: Role of TRPA1 in mechanical and cold sensation. Neuron 50:177–179PubMedCrossRefGoogle Scholar
  52. 52.
    Dai Y, Wang S, Tominaga M, Yamamoto S, Fukuoka T, Higashi T, Kobayashi K, Obata K, Yamanaka H, Noguchi K (2007) Sensitization of TRPA1 by PARS2 contributes to sensation of inflammatory pain. J Clin Invest 117:1979–1989PubMedCrossRefGoogle Scholar
  53. 53.
    Macpherson LJ, Dubin AE, Evans MJ, Marr R, Schultz PG, Cravatt BF, Patapoutian A (2007) Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines. Nature 445:541–545PubMedCrossRefGoogle Scholar
  54. 54.
    Kiselyov K, Soyombo A, Muallem S (2007) TRPpathies. J Physiol 578(Pt 3):641–653PubMedCrossRefGoogle Scholar
  55. 55.
    Groneberg DA, Quarcoo D, Frossard N, Fischer A (2004) Neurogenic mechanisms in bronchial inflammatory diseases. Allergy 59:1139–1152PubMedCrossRefGoogle Scholar
  56. 56.
    Gatti R, Andre E, Amadesi S, Dinh TQ, Fischer A, Bunnett NW, Harrison S, Geppetti P, Trevisani M (2006) Protease-activated receptor-2 exaggerates TRPV1-mediated cough in guinea pigs. J Appl Physiol 101:506–511PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Colleges of Public HealthUniversity of South FloridaTampaUSA

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