Modulation of protective reflex cough by acute immune driven inflammation of lower airways in anesthetized rabbits

Autoři: Laurent Foucaud aff001;  Bruno Demoulin aff001;  Anne-Laure Leblanc aff001;  Iulia Ioan aff001;  Cyril Schweitzer aff001;  Silvia Demoulin-Alexikova aff001
Působiště autorů: Research Unit EA 3450 DevAH—Development, Adaptation and Handicap, Campus Biologie Santé, University of Lorraine, Vandœuvre-Lès-Nancy, France aff001;  Department of Pediatric Functional Testing, Hôpital d’Enfants, CHRU de Nancy, Vandoeuvre-Les-Nancy, France aff002
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article


Chronic irritating cough in patients with allergic disorders may reflect behavioral or reflex response that is inappropriately matched to the stimulus present in the respiratory tract. Such dysregulated response is likely caused by sensory nerve damage driven by allergic mediators leading to cough hypersensitivity. Some indirect findings suggest that even acid-sensitive, capsaicin-insensitive A-δ fibers called “cough receptors” that are likely responsible for protective reflex cough may be modulated through immune driven inflammation. The aim of this study was to find out whether protective reflex cough is altered during acute allergic airway inflammation in rabbits sensitized to ovalbumin. In order to evaluate the effect of such inflammation exclusively on protective reflex cough, C-fiber mediated cough was silenced using general anesthesia. Cough provocation using citric acid inhalation and mechanical stimulation of trachea was realized in 16 ovalbumin (OVA) sensitized, anesthetized and tracheotomised rabbits 24h after OVA (OVA group, n = 9) or saline challenge (control group, n = 7). Number of coughs provoked by citric acid inhalation did not differ between OVA and control group (12,2 ±6,1 vs. 17,9 ± 6,9; p = 0.5). Allergic airway inflammation induced significant modulation of cough threshold (CT) to mechanical stimulus. Mechanically induced cough reflex in OVA group was either up-regulated (subgroup named “responders” CT: 50 msec (50–50); n = 5 p = 0.003) or down-regulated (subgroup named “non responders”, CT: 1200 msec (1200–1200); n = 4 p = 0.001) when compared to control group (CT: 150 msec (75–525)). These results advocate that allergen may induce longer lasting changes of reflex cough pathway, leading to its up- or down-regulation. These findings may be of interest as they suggest that effective therapies for chronic cough in allergic patients should target sensitized component of both, reflex and behavioral cough.

Klíčová slova:

Aerosols – Allergens – Citric acid – Coughing – Inflammation – Rabbits – Reflexes – Trachea


1. Undem BJ, Taylor-Clark T (2014) Mechanisms underlying the neuronal-based symptoms of allergy. J Allergy Clin Immunol 133: 1521–1534. doi: 10.1016/j.jaci.2013.11.027 24433703

2. Oetjen LK, Kim BS (2018) Interactions of the immune and sensory nervous systems in atopy. Febs j.

3. Chung KF, McGarvey L, Mazzone SB (2013) Chronic cough as a neuropathic disorder. Lancet Respir Med 1: 414–422. doi: 10.1016/S2213-2600(13)70043-2 24429206

4. Mazzone SB, Undem BJ (2009) Cough sensors. V. Pharmacological modulation of cough sensors. Handb Exp Pharmacol: 99–127.

5. Canning BJ, Chang AB, Bolser DC, Smith JA, Mazzone SB, et al. (2014) Anatomy and neurophysiology of cough: CHEST Guideline and Expert Panel report. Chest 146: 1633–1648. doi: 10.1378/chest.14-1481 25188530

6. Chung KF, Canning B, McGarvey L (2015) Eight International London Cough Symposium 2014: Cough hypersensitivity syndrome as the basis for chronic cough. Pulm Pharmacol Ther 35: 76–80. doi: 10.1016/j.pupt.2015.08.009 26341666

7. Narula M, McGovern AE, Yang SK, Farrell MJ, Mazzone SB (2014) Afferent neural pathways mediating cough in animals and humans. J Thorac Dis 6: S712–719. doi: 10.3978/j.issn.2072-1439.2014.03.15 25383205

8. Shannon R, Baekey DM, Morris KF, Li Z, Lindsey BG (2000) Functional connectivity among ventrolateral medullary respiratory neurones and responses during fictive cough in the cat. J Physiol 525 Pt 1: 207–224.

9. Baekey DM, Morris KF, Gestreau C, Li Z, Lindsey BG, et al. (2001) Medullary respiratory neurones and control of laryngeal motoneurones during fictive eupnoea and cough in the cat. J Physiol 534: 565–581. doi: 10.1111/j.1469-7793.2001.t01-1-00565.x 11454973

10. Sun H, Kollarik M, Undem BJ (2017) Blocking voltage-gated sodium channels as a strategy to suppress pathological cough. Pulm Pharmacol Ther 47: 38–41. doi: 10.1016/j.pupt.2017.05.010 28522215

11. Mazzone SB, Undem BJ (2016) Vagal Afferent Innervation of the Airways in Health and Disease. Physiol Rev 96: 975–1024. doi: 10.1152/physrev.00039.2015 27279650

12. Ando A, Farrell MJ, Mazzone SB (2014) Cough-related neural processing in the brain: a roadmap for cough dysfunction? Neurosci Biobehav Rev 47: 457–468. doi: 10.1016/j.neubiorev.2014.09.018 25301754

13. Canning BJ (2006) Anatomy and neurophysiology of the cough reflex: ACCP evidence-based clinical practice guidelines. Chest 129: 33s–47s. doi: 10.1378/chest.129.1_suppl.33S 16428690

14. Canning BJ, Mazzone SB, Meeker SN, Mori N, Reynolds SM, et al. (2004) Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea-pigs. J Physiol 557: 543–558. doi: 10.1113/jphysiol.2003.057885 15004208

15. Canning BJ (2010) Afferent nerves regulating the cough reflex: mechanisms and mediators of cough in disease. Otolaryngol Clin North Am 43: 15–25, vii. doi: 10.1016/j.otc.2009.11.012 20172253

16. Keller JA, McGovern AE, Mazzone SB (2017) Translating Cough Mechanisms Into Better Cough Suppressants. Chest 152: 833–841. doi: 10.1016/j.chest.2017.05.016 28552543

17. Potenzieri C, Meeker S, Undem BJ (2012) Activation of mouse bronchopulmonary C-fibres by serotonin and allergen-ovalbumin challenge. J Physiol 590: 5449–5459. doi: 10.1113/jphysiol.2012.237115 22907059

18. Canning BJ, Mori N (2011) Encoding of the cough reflex in anesthetized guinea pigs. Am J Physiol Regul Integr Comp Physiol 300: R369–377. doi: 10.1152/ajpregu.00044.2010 20926760

19. Canning BJ, Mori N (2010) An essential component to brainstem cough gating identified in anesthetized guinea pigs. Faseb j 24: 3916–3926. doi: 10.1096/fj.09-151068 20581226

20. Myers AC, Kajekar R, Undem BJ (2002) Allergic inflammation-induced neuropeptide production in rapidly adapting afferent nerves in guinea pig airways. Am J Physiol Lung Cell Mol Physiol 282: L775–781. doi: 10.1152/ajplung.00353.2001 11880304

21. Chuaychoo B, Hunter DD, Myers AC, Kollarik M, Undem BJ (2005) Allergen-induced substance P synthesis in large-diameter sensory neurons innervating the lungs. J Allergy Clin Immunol 116: 325–331. doi: 10.1016/j.jaci.2005.04.005 16083787

22. Spina D, Matera GM, Riccio MM, Page CP (1998) A comparison of sensory nerve function in human, guinea-pig, rabbit and marmoset airways. Life Sci 63: 1629–1642. doi: 10.1016/s0024-3205(98)00432-9 9806216

23. Keir S, Page C (2008) The rabbit as a model to study asthma and other lung diseases. Pulm Pharmacol Ther 21: 721–730. doi: 10.1016/j.pupt.2008.01.005 18430597

24. Clay E, Patacchini R, Trevisani M, Preti D, Brana MP, et al. (2016) Ozone-Induced Hypertussive Responses in Rabbits and Guinea Pigs. J Pharmacol Exp Ther 357: 73–83. doi: 10.1124/jpet.115.230227 26837703

25. Petak F, Hantos Z, Adamicza A, Gality H, Habre W (2006) Development of bronchoconstriction after administration of muscle relaxants in rabbits with normal or hyperreactive airways. Anesth Analg 103: 103–109, table of contents. doi: 10.1213/01.ane.0000221439.87488.08 16790635

26. Chambers MA, Williams A, Gavier-Widen D, Whelan A, Hall G, et al. (2000) Identification of a Mycobacterium bovis BCG auxotrophic mutant that protects guinea pigs against M. bovis and hematogenous spread of Mycobacterium tuberculosis without sensitization to tuberculin. Infect Immun 68: 7094–7099. doi: 10.1128/iai.68.12.7094-7099.2000 11083835

27. Basmajian JV, Stecko G (1963) The Role of Muscles in Arch Support of the Foot. J Bone Joint Surg Am 45: 1184–1190. 14077983

28. Varechova S, Poussel M, Schweitzer C, Demoulin B, Chenuel B, et al. (2012) Stimulus response latency of cough and expiration reflex depends on breathing in the rabbit. Pulm Pharmacol Ther 25: 242–247. doi: 10.1016/j.pupt.2012.03.006 22465564

29. Varechova S, Poussel M, Demoulin B, Chenuel B, Schweitzer C, et al. (2010) Within breath ventilatory responses to mechanical tracheal stimulation in anaesthetised rabbits. Pulm Pharmacol Ther 23: 397–402. doi: 10.1016/j.pupt.2010.05.008 20538068

30. Varechova S, Demoulin B, Leblanc AL, Coutier L, Ioan I, et al. (2015) Neonatal hyperoxia up regulates cough reflex in young rabbits. Respir Physiol Neurobiol 208: 51–56. doi: 10.1016/j.resp.2015.01.003 25583662

31. Kamaruzaman NA, Kardia E, Kamaldin NA, Latahir AZ, Yahaya BH (2013) The rabbit as a model for studying lung disease and stem cell therapy. BioMed research international 2013: 691830–691830. doi: 10.1155/2013/691830 23653896

32. Stevenson CS, Birrell MA (2011) Moving towards a new generation of animal models for asthma and COPD with improved clinical relevance. Pharmacol Ther 130: 93–105. doi: 10.1016/j.pharmthera.2010.10.008 21074553

33. Kianmehr M, Ghorani V, Hosein Boskabady M (2016) Animal Model of Asthma, Various Methods and Measured Parameters: A Methodological Review. Iranian Journal of Allergy, Asthma and Immunology 15: 445–465.

34. Zschauer AO, Sielczak MW, Wanner A (1999) Altered contractile sensitivity of isolated bronchial artery to phenylephrine in ovalbumin-sensitized rabbits. J Appl Physiol (1985) 86: 1721–1727.

35. Zosky GR, Larcombe AN, White OJ, Burchell JT, Janosi TZ, et al. (2008) Ovalbumin-sensitized mice are good models for airway hyperresponsiveness but not acute physiological responses to allergen inhalation. Clin Exp Allergy 38: 829–838. doi: 10.1111/j.1365-2222.2007.02884.x 18070158

36. Brozmanova M, Calkovsky V, Plevkova J, Bartos V, Plank L, et al. (2006) Early and late allergic phase related cough response in sensitized guinea pigs with experimental allergic rhinitis. Physiol Res 55: 577–584. 16343041

37. Xue Z, Yu Y, Gao H, Gunst SJ, Tepper RS (2011) Chronic continuous positive airway pressure (CPAP) reduces airway reactivity in vivo in an allergen-induced rabbit model of asthma. J Appl Physiol (1985) 111: 353–357.

38. Haczku A, Atochina EN, Tomer Y, Cao Y, Campbell C, et al. (2002) The late asthmatic response is linked with increased surface tension and reduced surfactant protein B in mice. Am J Physiol Lung Cell Mol Physiol 283: L755–765. doi: 10.1152/ajplung.00062.2002 12225952

39. Voilley N, de Weille J, Mamet J, Lazdunski M (2001) Nonsteroid anti-inflammatory drugs inhibit both the activity and the inflammation-induced expression of acid-sensing ion channels in nociceptors. J Neurosci 21: 8026–8033. doi: 10.1523/JNEUROSCI.21-20-08026.2001 11588175

40. Cadiou H, Studer M, Jones NG, Smith ES, Ballard A, et al. (2007) Modulation of acid-sensing ion channel activity by nitric oxide. J Neurosci 27: 13251–13260. doi: 10.1523/JNEUROSCI.2135-07.2007 18045919

41. Mamet J, Baron A, Lazdunski M, Voilley N (2002) Proinflammatory mediators, stimulators of sensory neuron excitability via the expression of acid-sensing ion channels. J Neurosci 22: 10662–10670. doi: 10.1523/JNEUROSCI.22-24-10662.2002 12486159

42. Lieu TM, Myers AC, Meeker S, Undem BJ (2012) TRPV1 induction in airway vagal low-threshold mechanosensory neurons by allergen challenge and neurotrophic factors. Am J Physiol Lung Cell Mol Physiol 302: L941–948. doi: 10.1152/ajplung.00366.2011 22345578

43. Zhang G, Lin RL, Wiggers M, Snow DM, Lee LY (2008) Altered expression of TRPV1 and sensitivity to capsaicin in pulmonary myelinated afferents following chronic airway inflammation in the rat. J Physiol 586: 5771–5786. doi: 10.1113/jphysiol.2008.161042 18832423

44. Fischer A, McGregor GP, Saria A, Philippin B, Kummer W (1996) Induction of tachykinin gene and peptide expression in guinea pig nodose primary afferent neurons by allergic airway inflammation. J Clin Invest 98: 2284–2291. doi: 10.1172/JCI119039 8941645

45. Mutoh T, Bonham AC, Joad JP (2000) Substance P in the nucleus of the solitary tract augments bronchopulmonary C fiber reflex output. Am J Physiol Regul Integr Comp Physiol 279: R1215–1223. doi: 10.1152/ajpregu.2000.279.4.R1215 11003986

46. Mutolo D, Bongianni F, Fontana GA, Pantaleo T (2007) The role of excitatory amino acids and substance P in the mediation of the cough reflex within the nucleus tractus solitarii of the rabbit. Brain Res Bull 74: 284–293. doi: 10.1016/j.brainresbull.2007.07.001 17720551

47. Joad JP, Kott KS, Bric JM, Peake JL, Plopper CG, et al. (2006) Structural and functional localization of airway effects from episodic exposure of infant monkeys to allergen and/or ozone. Toxicol Appl Pharmacol 214: 237–243. doi: 10.1016/j.taap.2005.12.012 16466656

48. Riccio MM, Myers AC, Undem BJ (1996) Immunomodulation of afferent neurons in guinea-pig isolated airway. J Physiol 491 (Pt 2): 499–509.

49. McAlexander MA, Myers AC, Undem BJ (1999) Adaptation of guinea-pig vagal airway afferent neurones to mechanical stimulation. J Physiol 521 Pt 1: 239–247.

50. Mazzone SB, Reynolds SM, Mori N, Kollarik M, Farmer DG, et al. (2009) Selective Expression of a Sodium Pump Isozyme by Cough Receptors and Evidence for Its Essential Role in Regulating Cough. The Journal of Neuroscience 29: 13662–13671. doi: 10.1523/JNEUROSCI.4354-08.2009 19864578

51. Innes AL, Carrington SD, Thornton DJ, Kirkham S, Rousseau K, et al. (2009) Ex Vivo Sputum Analysis Reveals Impairment of Protease-dependent Mucus Degradation by Plasma Proteins in Acute Asthma. American Journal of Respiratory and Critical Care Medicine 180: 203–210. doi: 10.1164/rccm.200807-1056OC 19423716

52. Persson CG (1986) Role of plasma exudation in asthmatic airways. Lancet 2: 1126–1129. doi: 10.1016/s0140-6736(86)90533-7 2877275

53. Fahy JV, Dickey BF (2010) Airway mucus function and dysfunction. N Engl J Med 363: 2233–2247. doi: 10.1056/NEJMra0910061 21121836

54. Nadel JA (2001) Role of epidermal growth factor receptor activation in regulating mucin synthesis. Respir Res 2: 85–89. doi: 10.1186/rr43 11686870

55. Nadel JA (2013) Mucous hypersecretion and relationship to cough. Pulm Pharmacol Ther 26: 510–513. doi: 10.1016/j.pupt.2013.02.003 23434445

56. Thornton DJ, Sheehan JK (2004) From mucins to mucus: toward a more coherent understanding of this essential barrier. Proc Am Thorac Soc 1: 54–61. doi: 10.1513/pats.2306016 16113413

57. Demoulin-Alexikova S, Foucaud L, Demoulin B, Leblanc A-L, Ioan I, et al. (2017) Up-regulation of chemically-induced but not mechanically-induced cough during early-phase response to allergen inhalation in ovalbumin sensitized rabbits. European Respiratory Journal 50: PA1149.

58. Tatar M, Hanacek J, Widdicombe J (2008) The expiration reflex from the trachea and bronchi. Eur Respir J 31: 385–390. doi: 10.1183/09031936.00063507 17959638

59. Tanaka M, Maruyama K (2003) Cough reflex induced by microinjection of citric acid into the larynx of guinea pigs: new coughing model. J Pharmacol Sci 93: 465–470. doi: 10.1254/jphs.93.465 14737018

Článek vyšel v časopise


2019 Číslo 12
Nejčtenější tento týden