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Neural Mechanisms Underlying the Coughing Reflex

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Abstract

Breathing is an intrinsic natural behavior and physiological process that maintains life. The rhythmic exchange of gases regulates the delicate balance of chemical constituents within an organism throughout its lifespan. However, chronic airway diseases, including asthma and chronic obstructive pulmonary disease, affect millions of people worldwide. Pathological airway conditions can disrupt respiration, causing asphyxia, cardiac arrest, and potential death. The innervation of the respiratory tract and the action of the immune system confer robust airway surveillance and protection against environmental irritants and pathogens. However, aberrant activation of the immune system or sensitization of the nervous system can contribute to the development of autoimmune airway disorders. Transient receptor potential ion channels and voltage-gated Na+ channels play critical roles in sensing noxious stimuli within the respiratory tract and interacting with the immune system to generate neurogenic inflammation and airway hypersensitivity. Although recent studies have revealed the involvement of nociceptor neurons in airway diseases, the further neural circuitry underlying airway protection remains elusive. Unraveling the mechanism underpinning neural circuit regulation in the airway may provide precise therapeutic strategies and valuable insights into the management of airway diseases.

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References

  1. Morice AH, Millqvist E, Bieksiene K, Birring SS, Dicpinigaitis P, Domingo Ribas C. ERS guidelines on the diagnosis and treatment of chronic cough in adults and children. Eur Respir J 2020, 55: 1901136.

    CAS  PubMed  Google Scholar 

  2. Song WJ, Chang YS, Faruqi S, Kim JY, Kang MG, Kim S, et al. The global epidemiology of chronic cough in adults: A systematic review and meta-analysis. Eur Respir J 2015, 45: 1479–1481.

    PubMed  Google Scholar 

  3. Liang H, Ye W, Wang Z, Liang J, Yi F, Jiang M, et al. Prevalence of chronic cough in China: A systematic review and meta-analysis. BMC Pulm Med 2022, 22: 62.

    PubMed  PubMed Central  Google Scholar 

  4. Gibson P, Wang G, McGarvey L, Vertigan AE, Altman KW, Birring SS, et al. Treatment of unexplained chronic cough: CHEST guideline and expert panel report. Chest 2016, 149: 27–44.

    PubMed  PubMed Central  Google Scholar 

  5. Chung KF, McGarvey L, Song WJ, Chang AB, Lai K, Canning BJ, et al. Cough hypersensitivity and chronic cough. Nat Rev Dis Primers 2022, 8: 45.

    PubMed  PubMed Central  Google Scholar 

  6. Zemp E, Elsasser S, Schindler C, Künzli N, Perruchoud A, Domenighetti G, et al. Long-term ambient air pollution and respiratory symptoms in adults (SAPALDIA study). Am J Respir Crit Care Med 1999, 159: 1257–1266.

    CAS  PubMed  Google Scholar 

  7. Moscato G, Pala G, Cullinan P, Folletti I, Gerth van Wijk R, Pignatti P, et al. EAACI Position Paper on assessment of cough in the workplace. Allergy 2014, 69: 292–304.

  8. Wiszniewska M, Dellis P, van Kampen V, Suojalehto H, Munoz X, Walusiak-Skorupa J, et al. Characterization of occupational eosinophilic bronchitis in a multicenter cohort of subjects with work-related asthma symptoms. J Allergy Clin Immunol Pract 2021, 9: 937–944.e4.

    PubMed  Google Scholar 

  9. Fang Z, Huang C, Zhang JJ, Xie J, Dai S, Ge E, et al. Traffic-related air pollution induces non-allergic eosinophilic airway inflammation and cough hypersensitivity in Guinea-pigs. Clin Exp Allergy 2019, 49: 366–377.

    CAS  PubMed  Google Scholar 

  10. He M, Ichinose T, Yoshida S, Ito T, He C, Yoshida Y, et al. PM2.5-induced lung inflammation in mice: Differences of inflammatory response in macrophages and type II alveolar cells. J Appl Toxicol 2017, 37: 1203–1218.

  11. Wu S, Ni Y, Li H, Pan L, Yang D, Baccarelli AA, et al. Short-term exposure to high ambient air pollution increases airway inflammation and respiratory symptoms in chronic obstructive pulmonary disease patients in Beijing. China. Environ Int 2016, 94: 76–82.

    CAS  PubMed  Google Scholar 

  12. Miller SI, Ernst RK, Bader MW. LPS, TLR4 and infectious disease diversity. Nat Rev Microbiol 2005, 3: 36–46.

    CAS  PubMed  Google Scholar 

  13. Braman SS. Chronic cough due to chronic bronchitis: ACCP evidence-based clinical practice guidelines. Chest 2006, 129: 104S–115S.

    PubMed  Google Scholar 

  14. Kanezaki M, Ebihara S, Gui P, Ebihara T, Kohzuki M. Effect of cigarette smoking on cough reflex induced by TRPV1 and TRPA1 stimulations. Respir Med 2012, 106: 406–412.

    PubMed  Google Scholar 

  15. Lewis CA, Ambrose C, Banner K, Battram C, Butler K, Giddings J, et al. Animal models of cough: Literature review and presentation of a novel cigarette smoke-enhanced cough model in the Guinea-pig. Pulm Pharmacol Ther 2007, 20: 325–333.

    CAS  PubMed  Google Scholar 

  16. Andrè E, Campi B, Materazzi S, Trevisani M, Amadesi S, Massi D, et al. Cigarette smoke-induced neurogenic inflammation is mediated by alpha, beta-unsaturated aldehydes and the TRPA1 receptor in rodents. J Clin Invest 2008, 118: 2574–2582.

    PubMed  PubMed Central  Google Scholar 

  17. Talavera K, Gees M, Karashima Y, Meseguer VM, Vanoirbeek JAJ, Damann N, et al. Nicotine activates the chemosensory cation channel TRPA1. Nat Neurosci 2009, 12: 1293–1299.

    CAS  PubMed  Google Scholar 

  18. Bonvini SJ, Birrell MA, Grace MS, Maher SA, Adcock JJ, Wortley MA, et al. Transient receptor potential cation channel, subfamily V, member 4 and airway sensory afferent activation: Role of adenosine triphosphate. J Allergy Clin Immunol 2016, 138: 249-261.e12.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Booth CM, Matukas LM, Tomlinson GA, Rachlis AR, Rose DB, Dwosh HA, et al. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA 2003, 289: 2801–2809.

    CAS  PubMed  Google Scholar 

  20. Lin L, Yang ZF, Zhan YQ, Luo W, Liu BJ, Pan JY, et al. The duration of cough in patients with H1N1 influenza. Clin Respir J 2017, 11: 733–738.

    CAS  PubMed  Google Scholar 

  21. von König CHW, Halperin S, Riffelmann M, Guiso N. Pertussis of adults and infants. Lancet Infect Dis 2002, 2: 744–750.

    Google Scholar 

  22. Song WJ, Hui CKM, Hull JH, Birring SS, McGarvey L, Mazzone SB, et al. Confronting COVID-19-associated cough and the post-COVID syndrome: Role of viral neurotropism, neuroinflammation, and neuroimmune responses. Lancet Respir Med 2021, 9: 533–544.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Naqvi KF, Mazzone SB, Shiloh MU. Infectious and inflammatory pathways to cough. Annu Rev Physiol 2023, 85: 71–91.

    CAS  PubMed  Google Scholar 

  24. Talbot S, Abdulnour REE, Burkett PR, Lee S, Cronin SJF, Pascal MA, et al. Silencing nociceptor neurons reduces allergic airway inflammation. Neuron 2015, 87: 341–354.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Ryan NM, Vertigan AE, Ferguson J, Wark P, Gibson PG. Clinical and physiological features of postinfectious chronic cough associated with H1N1 infection. Respir Med 2012, 106: 138–144.

    PubMed  Google Scholar 

  26. Teijaro JR, Walsh KB, Cahalan S, Fremgen DM, Roberts E, Scott F, et al. Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection. Cell 2011, 146: 980–991.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Morris G, Bortolasci CC, Puri BK, Marx W, O'Neil A, Athan E, et al. The cytokine storms of COVID-19, H1N1 influenza, CRS and MAS compared. Can one sized treatment fit all? Cytokine 2021, 144: 155593.

  28. Mizgerd JP, Spieker MR, Doerschuk CM. Early response cytokines and innate immunity: Essential roles for TNF receptor 1 and type I IL-1 receptor during Escherichia coli pneumonia in mice. J Immunol 2001, 166: 4042–4048.

    CAS  PubMed  Google Scholar 

  29. Bradley JR. TNF-mediated inflammatory disease. J Pathol 2008, 214: 149–160.

    CAS  PubMed  Google Scholar 

  30. Liu Q, Zhou YH, Yang ZQ. The cytokine storm of severe influenza and development of immunomodulatory therapy. Cell Mol Immunol 2016, 13: 3–10.

    CAS  PubMed  Google Scholar 

  31. Yu X, Zhang X, Zhao B, Wang J, Zhu Z, Teng Z, et al. Intensive cytokine induction in pandemic H1N1 influenza virus infection accompanied by robust production of IL-10 and IL-6. PLoS One 2011, 6: e28680.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Hagau N, Slavcovici A, Gonganau DN, Oltean S, Dirzu DS, Brezoszki ES, et al. Clinical aspects and cytokine response in severe H1N1 influenza A virus infection. Crit Care 2010, 14: R203.

    PubMed  PubMed Central  Google Scholar 

  33. Dienz O, Eaton SM, Bond JP, Neveu W, Moquin D, Noubade R, et al. The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells. J Exp Med 2009, 206: 69–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Tamasauskiene L, Sitkauskiene B. Immune system in the pathogenesis of chronic cough. Immunol Lett 2020, 218: 40–43.

    CAS  PubMed  Google Scholar 

  35. Eccles R. Understanding the symptoms of the common cold and influenza. Lancet Infect Dis 2005, 5: 718–725.

    PubMed  PubMed Central  Google Scholar 

  36. Bonham AC, Sekizawa SI, Chen CY, Joad JP. Plasticity of brainstem mechanisms of cough. Respir Physiol Neurobiol 2006, 152: 312–319.

    PubMed  Google Scholar 

  37. Bin NR, Prescott SL, Horio N, Wang Y, Chiu IM, Liberles SD. An airway-to-brain sensory pathway mediates influenza-induced sickness. Nature 2023, 615: 660–667.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Widdicombe JG. Neurophysiology of the cough reflex. Eur Respir J 1995, 8: 1193–1202.

    CAS  PubMed  Google Scholar 

  39. Perner C, Flayer CH, Zhu X, Aderhold PA, Dewan ZNA, Voisin T, et al. Substance P release by sensory neurons triggers dendritic cell migration and initiates the type-2 immune response to allergens. Immunity 2020, 53: 1063-1077.e7.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Driessen AK, McGovern AE, Behrens R, Moe AAK, Farrell MJ, Mazzone SB. A role for neurokinin 1 receptor expressing neurons in the paratrigeminal nucleus in bradykinin-evoked cough in Guinea-pigs. J Physiol 2020, 598: 2257–2275.

    CAS  PubMed  Google Scholar 

  41. Grace MS, Baxter M, Dubuis E, Birrell MA, Belvisi MG. Transient receptor potential (TRP) channels in the airway: Role in airway disease. Br J Pharmacol 2014, 171: 2593–2607.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Rouadi PW, Idriss SA, Bousquet J, Laidlaw TM, Azar CR, Al-Ahmad MS, et al. WAO-ARIA consensus on chronic cough - Part 1: Role of TRP channels in neurogenic inflammation of cough neuronal pathways. World Allergy Organ J 2021, 14: 100617.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Laude EA, Higgins KS, Morice AH. A comparative study of the effects of citric acid, capsaicin and resiniferatoxin on the cough challenge in Guinea-pig and man. Pulm Pharmacol 1993, 6: 171–175.

    CAS  PubMed  Google Scholar 

  44. Ruhl CR, Pasko BL, Khan HS, Kindt LM, Stamm CE, Franco LH, et al. Mycobacterium tuberculosis sulfolipid-1 activates nociceptive neurons and induces cough. Cell 2020, 181: 293-305.e11.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Yu L, Tsuji K, Ujihara I, Liu Q, Pavelkova N, Tsujimura T, et al. Antitussive effects of NaV 17 blockade in Guinea pigs. Eur J Pharmacol 2021, 907: 174192.

    CAS  PubMed  Google Scholar 

  46. Nascimento LA, Fonseca LF, Rosseto EG, Santos CB. Development of a safety protocol for management thirst in the immediate postoperative period. Rev Esc Enferm USP 2014, 48: 834–843.

    PubMed  Google Scholar 

  47. Debeuf N, Haspeslagh E, van Helden M, Hammad H, Lambrecht BN. Mouse models of asthma. Curr Protoc Mouse Biol 2016, 6: 169–184.

    PubMed  Google Scholar 

  48. Hiramatsu Y, Suzuki K, Nishida T, Onoda N, Satoh T, Akira S, et al. The mechanism of pertussis cough revealed by the mouse-coughing model. mBio 2022, 13: e0319721.

  49. Li F, Jiang H, Shen X, Yang W, Guo C, Wang Z, et al. Sneezing reflex is mediated by a peptidergic pathway from nose to brainstem. Cell 2021, 184: 3762-3773.e10.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Panneton WM, Gan Q, Juric R. Brainstem projections from recipient zones of the anterior ethmoidal nerve in the medullary dorsal horn. Neuroscience 2006, 141: 889–906.

    CAS  PubMed  Google Scholar 

  51. Chen Z, Lin MT, Zhan C, Zhong NS, Mu D, Lai KF, et al. A descending pathway emanating from the periaqueductal gray mediates the development of cough-like hypersensitivity. iScience 2021, 25: 103641.

    PubMed  PubMed Central  Google Scholar 

  52. Mazzone SB, Cole LJ, Ando A, Egan GF, Farrell MJ. Investigation of the neural control of cough and cough suppression in humans using functional brain imaging. J Neurosci 2011, 31: 2948–2958.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Song WJ, Chang YS. Cough hypersensitivity as a neuro-immune interaction. Clin Transl Allergy 2015, 5: 24.

    PubMed  PubMed Central  Google Scholar 

  54. Papi A, Brightling C, Pedersen SE, Reddel HK. Asthma. Lancet 2018, 391: 783–800.

    PubMed  Google Scholar 

  55. Pinho-Ribeiro FA, Verri WA Jr, Chiu IM. Nociceptor sensory neuron-immune interactions in pain and inflammation. Trends Immunol 2017, 38: 5–19.

    CAS  PubMed  Google Scholar 

  56. Gans MD, Gavrilova T. Understanding the immunology of asthma: Pathophysiology, biomarkers, and treatments for asthma endotypes. Paediatr Respir Rev 2020, 36: 118–127.

    PubMed  Google Scholar 

  57. Kumamoto Y, Linehan M, Weinstein JS, Laidlaw BJ, Craft JE, Iwasaki A. CD301b+ dermal dendritic cells drive T helper 2 cell-mediated immunity. Immunity 2013, 39: 733–743.

    CAS  PubMed  Google Scholar 

  58. Hosoi J, Murphy GF, Egan CL, Lerner EA, Grabbe S, Asahina A, et al. Regulation of Langerhans cell function by nerves containing calcitonin gene-related peptide. Nature 1993, 363: 159–163.

    CAS  PubMed  Google Scholar 

  59. Tussiwand R, Everts B, Grajales-Reyes GE, Kretzer NM, Iwata A, Bagaitkar J, et al. Klf4 expression in conventional dendritic cells is required for T helper 2 cell responses. Immunity 2015, 42: 916–928.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Takatsu K, Nakajima H. IL-5 and eosinophilia. Curr Opin Immunol 2008, 20: 288–294.

    CAS  PubMed  Google Scholar 

  61. Kulkarni NS, Hollins F, Sutcliffe A, Saunders R, Shah S, Siddiqui S, et al. Eosinophil protein in airway macrophages: A novel biomarker of eosinophilic inflammation in patients with asthma. J Allergy Clin Immunol 2010, 126: 61-69.e3.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Crosson T, Wang JC, Doyle B, Merrison H, Balood M, Parrin A, et al. FcεR1-expressing nociceptors trigger allergic airway inflammation. J Allergy Clin Immunol 2021, 147: 2330–2342.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Bins JE, Metting EI, Muilwijk-Kroes JB, Kocks JH, In 't Veen JM. The use of a direct bronchial challenge test in primary care to diagnose asthma. NPJ Prim Care Respir Med 2020, 30: 45.

  64. Doe C, Bafadhel M, Siddiqui S, Desai D, Mistry V, Rugman P, et al. Expression of the T helper 17-associated cytokines IL-17A and IL-17F in asthma and COPD. Chest 2010, 138: 1140–1147.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Takeda N, Takemura M, Kanemitsu Y, Hijikata H, Fukumitsu K, Asano T, et al. Effect of anti-reflux treatment on gastroesophageal reflux-associated chronic cough: Implications of neurogenic and neutrophilic inflammation. J Asthma 2020, 57: 1202–1210.

    PubMed  Google Scholar 

  66. Dicker AJ, Crichton ML, Pumphrey EG, Cassidy AJ, Suarez-Cuartin G, Sibila O, et al. Neutrophil extracellular traps are associated with disease severity and microbiota diversity in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol 2018, 141: 117–127.

    PubMed  PubMed Central  Google Scholar 

  67. Canning BJ, Mazzone SB, Meeker SN, Mori N, Reynolds SM, Undem BJ. Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized Guinea-pigs. J Physiol 2004, 557: 543–558.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Shibata M, Tang C. Implications of transient receptor potential cation channels in migraine pathophysiology. Neurosci Bull 2021, 37: 103–116.

    CAS  PubMed  Google Scholar 

  69. Grace MS, Dubuis E, Birrell MA, Belvisi MG. Pre-clinical studies in cough research: Role of Transient Receptor Potential (TRP) channels. Pulm Pharmacol Ther 2013, 26: 498–507.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Mabalirajan U, Rehman R, Ahmad T, Kumar S, Singh S, Leishangthem GD, et al. Linoleic acid metabolite drives severe asthma by causing airway epithelial injury. Sci Rep 2013, 3: 1349.

    PubMed  PubMed Central  Google Scholar 

  71. Caceres AI, Brackmann M, Elia MD, Bessac BF, del Camino D, D’Amours M, et al. A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma. Proc Natl Acad Sci U S A 2009, 106: 9099–9104.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Su X, Camerer E, Hamilton JR, Coughlin SR, Matthay MA. Protease-activated receptor-2 activation induces acute lung inflammation by neuropeptide-dependent mechanisms. J Immunol 2005, 175: 2598–2605.

    CAS  PubMed  Google Scholar 

  73. Kabata H, Artis D. Neuro-immune crosstalk and allergic inflammation. J Clin Invest 2019, 129: 1475–1482.

    PubMed  PubMed Central  Google Scholar 

  74. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000, 405: 458–462.

    CAS  PubMed  Google Scholar 

  75. Pintér E, Helyes Z, Szolcsányi J. Inhibitory effect of somatostatin on inflammation and nociception. Pharmacol Ther 2006, 112: 440–456.

    PubMed  Google Scholar 

  76. Choi JY, Khansaheb M, Joo NS, Krouse ME, Robbins RC, Weill D, et al. Substance P stimulates human airway submucosal gland secretion mainly via a CFTR-dependent process. J Clin Invest 2009, 119: 1189–1200.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Yu W, Moninger TO, Rector MV, Stoltz DA, Welsh MJ. Pulmonary neuroendocrine cells sense succinate to stimulate myoepithelial cell contraction. Dev Cell 2022, 57: 2221-2236.e5.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Rennard S, Decramer M, Calverley PA, Pride NB, Soriano JB, Vermeire PA, et al. Impact of COPD in north America and Europe in 2000: Subjects’ perspective of confronting COPD international survey. Eur Respir J 2002, 20: 799–805.

    CAS  PubMed  Google Scholar 

  79. Hassan SA, Bonetti LV, Kasawara KT, Stanbrook MB, Rozenberg D, Reid WD. Loss of neural automaticity contributes to slower walking in COPD patients. Cells 2022, 11: 1606.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Pauwels RA, Rabe KF. Burden and clinical features of chronic obstructive pulmonary disease (COPD). Lancet 2004, 364: 613–620.

    PubMed  Google Scholar 

  81. Chiu IM, Heesters BA, Ghasemlou N, Von Hehn CA, Zhao F, Tran J, et al. Bacteria activate sensory neurons that modulate pain and inflammation. Nature 2013, 501: 52–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Barrios-Payán J, Revuelta A, Mata-Espinosa D, Marquina-Castillo B, Villanueva EB, Gutiérrez MEH, et al. The contribution of the sympathetic nervous system to the immunopathology of experimental pulmonary tuberculosis. J Neuroimmunol 2016, 298: 98–105.

    PubMed  Google Scholar 

  83. Mazzone SB, Undem BJ. Vagal afferent innervation of the airways in health and disease. Physiol Rev 2016, 96: 975–1024.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Han W, de Araujo IE. Dissection and surgical approaches to the mouse jugular-nodose Ganglia. STAR Protoc 2021, 2: 100474.

    PubMed  PubMed Central  Google Scholar 

  85. Nassenstein C, Taylor-Clark TE, Myers AC, Ru F, Nandigama R, Bettner W, et al. Phenotypic distinctions between neural crest and placodal derived vagal C-fibres in mouse lungs. J Physiol 2010, 588: 4769–4783.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Al-Biltagi M, Bediwy AS, Saeed NK. Cough as a neurological sign: What a clinician should know. World J Crit Care Med 2022, 11: 115–128.

    PubMed  PubMed Central  Google Scholar 

  87. Dicpinigaitis PV, Enilari O, Cleven KL. Prevalence of Arnold nerve reflex in subjects with and without chronic cough: Relevance to Cough Hypersensitivity Syndrome. Pulm Pharmacol Ther 2019, 54: 22–24.

    CAS  PubMed  Google Scholar 

  88. Hegland KW, Bolser DC, Davenport PW. Volitional control of reflex cough. J Appl Physiol 1985, 2012(113): 39–46.

    Google Scholar 

  89. Leech J, Mazzone SB, Farrell MJ. Brain activity associated with placebo suppression of the urge-to-cough in humans. Am J Respir Crit Care Med 2013, 188: 1069–1075.

    PubMed  Google Scholar 

  90. Badri H, Gibbard C, Denton D, Satia I, Al-Sheklly B, Dockry RJ, et al. A double-blind randomised placebo-controlled trial investigating the effects of lesogaberan on the objective cough frequency and capsaicin-evoked coughs in patients with refractory chronic cough. ERJ Open Res 2022, 8: 00546–02021.

    PubMed  PubMed Central  Google Scholar 

  91. Koivisto AP, Belvisi MG, Gaudet R, Szallasi A. Advances in TRP channel drug discovery: From target validation to clinical studies. Nat Rev Drug Discov 2022, 21: 41–59.

    CAS  PubMed  Google Scholar 

  92. Bessac BF, Jordt SE. Breathtaking TRP channels: TRPA1 and TRPV1 in airway chemosensation and reflex control. Physiology (Bethesda) 2008, 23: 360–370.

    CAS  PubMed  Google Scholar 

  93. Jiang GT, Shao L, Kong S, Zeng ML, Cheng JJ, Chen TX, et al. Complement C3 aggravates post-epileptic neuronal injury Via activation of TRPV1. Neurosci Bull 2021, 37: 1427–1440.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Groneberg DA, Niimi A, Dinh QT, Cosio B, Hew M, Fischer A, et al. Increased expression of transient receptor potential vanilloid-1 in airway nerves of chronic cough. Am J Respir Crit Care Med 2004, 170: 1276–1280.

    PubMed  Google Scholar 

  95. Zhang G, Lin RL, Wiggers M, Snow DM, Lee LY. Altered expression of TRPV1 and sensitivity to capsaicin in pulmonary myelinated afferents following chronic airway inflammation in the rat. J Physiol 2008, 586: 5771–5786.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Moriyama T, Higashi T, Togashi K, Iida T, Segi E, Sugimoto Y, et al. Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins. Mol Pain 2005, 1: 3.

    PubMed  PubMed Central  Google Scholar 

  97. Belvisi MG, Birrell MA, Wortley MA, Maher SA, Satia I, Badri H, et al. XEN-D0501, a novel transient receptor potential vanilloid 1 antagonist, does not reduce cough in patients with refractory cough. Am J Respir Crit Care Med 2017, 196: 1255–1263.

    CAS  PubMed  Google Scholar 

  98. Mukhopadhyay I, Kulkarni A, Khairatkar-Joshi N. Blocking TRPA1 in respiratory disorders: Does it hold a promise? Pharmaceuticals (Basel) 2016, 9: 70.

    PubMed  Google Scholar 

  99. Hu Y, Shan WQ, Wu B, Liu T. New insight into the origins of itch and pain: How are itch and pain signals coded and discriminated by primary sensory neurons? Neurosci Bull 2021, 37: 575–578.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. West PW, Canning BJ, Merlo-Pich E, Woodcock AA, Smith JA. Morphologic characterization of nerves in whole-mount airway biopsies. Am J Respir Crit Care Med 2015, 192: 30–39.

    PubMed  PubMed Central  Google Scholar 

  101. Birrell MA, Belvisi MG, Grace M, Sadofsky L, Faruqi S, Hele DJ, et al. TRPA1 agonists evoke coughing in Guinea pig and human volunteers. Am J Respir Crit Care Med 2009, 180: 1042–1047.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Bautista DM, Pellegrino M, Tsunozaki M. TRPA1: A gatekeeper for inflammation. Annu Rev Physiol 2013, 75: 181–200.

    CAS  PubMed  Google Scholar 

  103. de Oliveira C, Garami A, Lehto SG, Pakai E, Tekus V, Pohoczky K, et al. Transient receptor potential channel ankyrin-1 is not a cold sensor for autonomic thermoregulation in rodents. J Neurosci 2014, 34: 4445–4452.

    PubMed  PubMed Central  Google Scholar 

  104. Cantero-Recasens G, Gonzalez JR, Fandos C, Duran-Tauleria E, Smit LAM, Kauffmann F, et al. Loss of function of transient receptor potential vanilloid 1 (TRPV1) genetic variant is associated with lower risk of active childhood asthma. J Biol Chem 2010, 285: 27532–27535.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Zhu G, Investigators I, Gulsvik A, Bakke P, Ghatta S, Anderson W, et al. Association of TRPV4 gene polymorphisms with chronic obstructive pulmonary disease. Hum Mol Genet 2009, 18: 2053–2062.

    CAS  PubMed  Google Scholar 

  106. Liedtke W, Simon SA. A possible role for TRPV4 receptors in asthma. Am J Physiol Lung Cell Mol Physiol 2004, 287: L269–L271.

    CAS  PubMed  Google Scholar 

  107. Fendrick AM, Monto AS, Nightengale B, Sarnes M. The economic burden of non-influenza-related viral respiratory tract infection in the United States. Arch Intern Med 2003, 163: 487–494.

    PubMed  Google Scholar 

  108. Nassenstein C, Kwong K, Taylor-Clark T, Kollarik M, MacGlashan DM, Braun A, et al. Expression and function of the ion channel TRPA1 in vagal afferent nerves innervating mouse lungs. J Physiol 2008, 586: 1595–1604.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, et al. A TRP channel that senses cold stimuli and menthol. Cell 2002, 108: 705–715.

    CAS  PubMed  Google Scholar 

  110. Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J, Hricik TR, et al. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 2003, 112: 819–829.

    CAS  PubMed  Google Scholar 

  111. Fisher JT. TRPM8 and dyspnea: From the frigid and fascinating past to the cool future? Curr Opin Pharmacol 2011, 11: 218–223.

    CAS  PubMed  Google Scholar 

  112. Millqvist E, Ternesten-Hasseus E, Bende M. Inhalation of menthol reduces capsaicin cough sensitivity and influences inspiratory flows in chronic cough. Respir Med 2013, 107: 433–438.

    PubMed  Google Scholar 

  113. Kenia P, Houghton T, Beardsmore C. Does inhaling menthol affect nasal patency or cough? Pediatr Pulmonol 2008, 43: 532–537.

    PubMed  Google Scholar 

  114. Plevkova J, Kollarik M, Poliacek I, Brozmanova M, Surdenikova L, Tatar M, et al. The role of trigeminal nasal TRPM8-expressing afferent neurons in the antitussive effects of menthol. J Appl Physiol 1985, 2013(115): 268–274.

    Google Scholar 

  115. Buday T, Brozmanova M, Biringerova Z, Gavliakova S, Poliacek I, Calkovsky V, et al. Modulation of cough response by sensory inputs from the nose - role of trigeminal TRPA1 versus TRPM8 channels. Cough 2012, 8: 11.

    PubMed  PubMed Central  Google Scholar 

  116. Stinson RJ, Morice AH, Sadofsky LR. Modulation of transient receptor potential (TRP) channels by plant derived substances used in over-the-counter cough and cold remedies. Respir Res 2023, 24: 45.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Sabnis AS, Reilly CA, Veranth JM, Yost GS. Increased transcription of cytokine genes in human lung epithelial cells through activation of a TRPM8 variant by cold temperatures. Am J Physiol Lung Cell Mol Physiol 2008, 295: L194–L200.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Clapham DE, Runnels LW, Strübing C. The TRP ion channel family. Nat Rev Neurosci 2001, 2: 387–396.

    CAS  PubMed  Google Scholar 

  119. Catterall WA, Goldin AL, Waxman SG. International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev 2005, 57: 397–409.

    CAS  PubMed  Google Scholar 

  120. Muroi Y, Undem BJ. Targeting voltage gated sodium channels NaV1.7, NaV1.8, and NaV1.9 for treatment of pathological cough. Lung 2014, 192: 15–20.

    CAS  PubMed  Google Scholar 

  121. Dib-Hajj SD, Yang Y, Black JA, Waxman SG. The Na(V)1.7 sodium channel: From molecule to man. Nat Rev Neurosci 2013, 14: 49–62.

    CAS  PubMed  Google Scholar 

  122. Muroi Y, Ru F, Chou YL, Carr MJ, Undem BJ, Canning BJ. Selective inhibition of vagal afferent nerve pathways regulating cough using Nav 1.7 shRNA silencing in Guinea pig nodose Ganglia. Am J Physiol Regul Integr Comp Physiol 2013, 304: R1017–R1023.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Muroi Y, Ru F, Kollarik M, Canning BJ, Hughes SA, Walsh S, et al. Selective silencing of Na(V)1.7 decreases excitability and conduction in vagal sensory neurons. J Physiol 2011, 589: 5663–5676.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Jarvis MF, Honore P, Shieh CC, Chapman M, Joshi S, Zhang XF, et al. A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc Natl Acad Sci U S A 2007, 104: 8520–8525.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Amaya F, Wang H, Costigan M, Allchorne AJ, Hatcher JP, Egerton J, et al. The voltage-gated sodium channel Na(v)1.9 is an effector of peripheral inflammatory pain hypersensitivity. J Neurosci 2006, 26: 12852–12860.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Sun H, Kollarik M, Undem BJ. Blocking voltage-gated sodium channels as a strategy to suppress pathological cough. Pulm Pharmacol Ther 2017, 47: 38–41.

    CAS  PubMed  Google Scholar 

  127. Zhou X, Ma T, Yang L, Peng S, Li L, Wang Z, et al. Spider venom-derived peptide induces hyperalgesia in Nav1.7 knockout mice by activating Nav1.9 channels. Nat Commun 2020, 11: 2293.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Kasteel EE, Westerink RH. Comparison of the acute inhibitory effects of Tetrodotoxin (TTX) in rat and human neuronal networks for risk assessment purposes. Toxicol Lett 2017, 270: 12–16.

    CAS  PubMed  Google Scholar 

  129. Smith JA, Woodcock A. Chronic cough. N Engl J Med 2016, 375: 1544–1551.

    PubMed  Google Scholar 

  130. Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald JM, et al. Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J. 2008, 31: 143–178. https://doi.org/10.1183/09031936.00138707.

    Article  CAS  PubMed  Google Scholar 

  131. Roth M, Johnson PRA, Rüdiger JJ, King GG, Ge Q, Burgess JK, et al. Interaction between glucocorticoids and beta2 agonists on bronchial airway smooth muscle cells through synchronised cellular signalling. Lancet 2002, 360: 1293–1299.

    CAS  PubMed  Google Scholar 

  132. Brusselle GG, Koppelman GH. Biologic therapies for severe asthma. N Engl J Med 2022, 386: 157–171.

    CAS  PubMed  Google Scholar 

  133. Fass R, Boeckxstaens GE, El-Serag H, Rosen R, Sifrim D, Vaezi MF. Gastro-oesophageal reflux disease. Nat Rev Dis Primers 2021, 7: 55.

    PubMed  Google Scholar 

  134. Linn KA, Long MT, Pagel PS. Robo-tripping: Dextromethorphan abuse and its anesthetic implications. Anesth Pain Med 2014, 4: e20990.

    PubMed  PubMed Central  Google Scholar 

  135. United States Food and Drug Administration. FDA Drug Safety Communication: FDA requires labeling changes for prescription opioid cough and cold medicines to limit their use to adults 18 years and older. 2018.

  136. Fortenberry M, Crowder J, So TY. The use of codeine and tramadol in the pediatric population-what is the verdict now? J Pediatr Health Care 2019, 33: 117–123.

    PubMed  Google Scholar 

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Lu, H., Cao, P. Neural Mechanisms Underlying the Coughing Reflex. Neurosci. Bull. 39, 1823–1839 (2023). https://doi.org/10.1007/s12264-023-01104-y

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