Functional implications of the multiple afferent pathways regulating cough

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Abstract

At least 2 airway vagal afferent nerve subtypes can directly initiate coughing upon activation. The capsaicin-insensitive, acid-sensitive mechanoreceptors innervating the larynx, trachea and large bronchi regulate coughing in both conscious and anesthetized animals. Activation of capsaicin-sensitive C-fibers innervating these airways will also produce coughing, but C-fiber dependent cough is prevented entirely by anesthesia. The different stimuli activating these afferent nerve subtypes and their differential sensitivity to anesthesia implies the existence of 2 parallel pathways for cough, and by extension, 2 types of cough, one essential and homeostatic, the second nonessential and pathophysiologic. The basic properties of the afferent nerves regulating cough, their interactions both centrally and peripherally and their responsiveness to tussive stimuli are briefly reviewed. Also reviewed is evidence against the notion of 2 completely separate types of cough regulated by parallel afferent pathways, asserting instead that multiple afferent nerve subtypes contribute to all types of cough.

Introduction

Coughing protects and clears the airways of inhaled irritants, particulates, accumulated secretions and aspirated gastric contents. An inability to cough or an impaired cough reflex greatly increases susceptibility to pneumonia. Cough can thus be considered an essential homeostatic reflex, preserving airway patency and thus lung capacity for gas exchange. Cough can also be problematic. Chronic cough, afflicting as much as 10% of the general population, and nonproductive post-infectious cough are thought to be pathophysiologic and subserving no protective functions [1], [2], [3].

Vagal afferent nerves regulate the cough reflex. Multiple vagal afferent nerve subtypes have been identified and their roles in regulating cough have been reviewed in detail elsewhere [3]. The existence of multiple pathways for cough and the presentation of cough as either homeostatic or pathophysiologic leads to speculation about the utility of these multiple pathways and their role in regulating different types of cough. The physiological and morphological attributes of the vagal afferent nerves regulating cough are briefly reviewed. Also reviewed is the evidence against the notion that different vagal afferent nerve subtypes uniquely and separately regulate homeostatic and pathophysiologic coughing.

Section snippets

Capsaicin-sensitive and insensitive afferent pathways regulating cough

Work carried out in multiple species including humans has identified at least 2 vagal afferent pathways that initiate coughing upon activation: C-fibers and cough receptors [3]. Bronchopulmonary C-fibers are activated selectively by stimuli such as capsaicin, bradykinin, protons and activators of the cation channel TRPA1. These stimuli reliably evoke coughing in humans and in awake guinea pigs [3], [4], [5], [6], [7], [8], [9], [10]. C-fibers terminate in the airway mucosa, submucosa, lung

Is there good cough and bad cough?

The identification of anatomically and functionally distinct vagal afferent pathways known to regulate cough might suggest the existence of 2 types of cough [3], [29]. In this scheme, the acid-sensitive mechanoreceptors innervating the extrapulmonary airways subserve an all-important homeostatic function, producing a “good” cough that protects the airways and lungs from aspirated particulates and gastric contents. Evidence in favor of this function includes the termination sites of these

Afferent interactions regulating cough

Coughing regardless of the tussive stimulus, disease state or the specific vagal afferent nerves activated ultimately utilizes the same efferent signaling pathways and cough pattern generators to produce the forceful expiratory reflexes so readily defined as cough. Implicit in this shared efferent limb is that cough reflex pathways ultimately converge through a single medullary pathway controlling respiratory muscle activity [50]. Afferent pathways regulating cough may also converge more

Conclusions

Two vagal afferent nerve subtypes initiate coughing upon activation, the bronchopulmonary C-fibers and the cough receptors. These afferent pathways produce at least 2 types of cough, one a robust cough that persists even under general anesthesia and produces few, powerful cough efforts in response to chemical and mechanical stimuli in the large airways, the second a cough that is prevented by general anesthesia, can be paroxysmal in patterning and most resembles the dry, nonproductive cough

References (55)

  • D.C. Bolser

    Cough suppressant and pharmacologic protussive therapy: ACCP evidence-based clinical practice guidelines

    Chest

    (2006)
  • D.C. Bolser et al.

    Neurogenesis of cough, other airway defensive behaviors and breathing: a holarchical system?

    Respir Physiol Neurobiol

    (2006)
  • M. Tatar et al.

    Mechanisms of the cough associated with rhinosinusitis

    Pulm Pharmacol Ther

    (2009)
  • J. Plevkova et al.

    Modulation of experimentally-induced cough by stimulation of nasal mucosa in cats and guinea pigs

    Respir Physiol Neurobiol

    (2004)
  • A.H. Morice et al.

    British Thoracic Society Cough Guideline Group. Recommendations for the management of cough in adults

    Thorax

    (2006)
  • B.J. Canning et al.

    Cough sensors. I. Physiological and pharmacological properties of the afferent nerves regulating cough

    Handb Exp Pharmacol

    (2009)
  • M.M. Ricco et al.

    Interganglionic segregation of distinct vagal afferent fibre phenotypes in guinea-pig airways

    J Physiol

    (1996)
  • B.J. Undem et al.

    Subtypes of vagal afferent C-fibres in guinea-pig lungs

    J Physiol

    (2004)
  • C. Nassenstein et al.

    Expression and function of the ion channel TRPA1 in vagal afferent nerves innervating mouse lungs

    J Physiol

    (2008)
  • M.A. Birrell et al.

    TRPA1 agonists evoke coughing in guinea pig and human volunteers

    Am J Respir Crit Care Med

    (2009)
  • E. Andrè et al.

    Transient receptor potential ankyrin receptor 1 is a novel target for pro-tussive agents

    Br J Pharmacol

    (2009)
  • S.B. Mazzone et al.

    Selective expression of a sodium pump isozyme by cough receptors and evidence for its essential role in regulating cough

    J Neurosci

    (2009)
  • A. Laitinen

    Ultrastructural organisation of intraepithelial nerves in the human airway tract

    Thorax

    (1985)
  • P. Chanez et al.

    Bronchial mucosal immunoreactivity of sensory neuropeptides in severe airway diseases

    Am J Respir Crit Care Med

    (1998)
  • J.P. Lamb et al.

    Three-dimensional mapping of sensory innervation with substance p in porcine bronchial mucosa: comparison with human airways

    Am J Respir Crit Care Med

    (2002)
  • B.J. Canning et al.

    Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea-pigs

    J Physiol

    (2004)
  • M. Kollarik et al.

    Mechanisms of acid-induced activation of airway afferent nerve fibres in guinea-pig

    J Physiol

    (2002)
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    The research summarized in this article was funded in part by a grant from the National Institutes of Health (HL083192).

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