Afferent nerves regulating the cough reflex: mechanisms and mediators of cough in disease

Abstract

Bronchopulmonary C fibers and acid-sensitive, capsaicin-insensitive mechanoreceptors innervating the larynx, trachea, and large bronchi regulate the cough reflex. These vagal afferent nerves may interact centrally with sensory input arising from afferent nerves innervating the intrapulmonary airways or even extrapulmonary afferents such as those innervating the nasal mucosa and esophagus to produce chronic cough or enhanced cough responsiveness. The mechanisms of cough initiation in health and in disease are briefly described.

Figure 1

Representative extracellular recordings from the vagal afferent nerve subtypes innervating the airways and lungs. A) The cough receptors innervate the larynx, trachea and mainstem bronchi. They are insensitive to capsaicin, airway smooth muscle contraction (not shown) and distending or collapsing airway luminal pressures (not shown) but are activated by punctate mechanical stimulation and acid. When activated, these afferent nerves initiate coughing. B) Bronchopulmonary C-fibers terminate throughout the airways and lungs. C-fibers are less sensitive to mechanical stimulation than other airway afferent nerves but are activated by chemical stimuli such as capsaicin, bradykinin, acid and adenosine. When activated, C-fibers initiate coughing, changes in respiratory pattern and autonomic reflexes (e.g. airway smooth muscle contraction, mucus secretion. C-fiber subtypes have been described. C) Slowly adapting receptors are active during the dynamic and static phases of lung inflation. Slowly adapting receptor activation initiates respiratory slowing but does not initiate coughing. D) Rapidly adapting receptors are active during the dynamic phases of lung inflation and deflation and are activated by airway smooth muscle contraction/ bronchospasm and lung collapse/ negative airway luminal pressures. Rapidly adapting receptor activation initiates parasympathetic reflexes such as mucus secretion and airway smooth muscle contraction as well as tachypnea. Figures are reproduced with permission from Canning et al., 2004 (49). Canning BJ, Mazzone SB, Meeker SN et al. Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea-pigs. J Physiol 2004;557:543-58.

Figure 2

A representative trace of coughing recorded from a guinea pig following exposure to an aerosol of bradykinin aerosol is shown. Many animal species cough in response to the same stimuli that initiate coughing in human subjects. This permits more mechanistic studies of the cough reflex and has led to the development of novel therapeutic strategies for the treatment of cough. The figure is reproduced with permission from Canning et al. (49). Canning BJ, Mazzone SB, Meeker SN et al. Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea-pigs. J Physiol 2004;557:543-58.

Figure 3

Cough reflex sensitivity can be enhanced by coincident activation of airway afferent nerve subtypes. Coughing was evoked electrically from the tracheal mucosa of anesthetized guinea pigs. Optimal stimulation frequencies (16 Hz) and pulse duration were maintained during 10 second stimuli delivered at varying stimulation voltages. The percentage of animals coughing at various voltages was determined in animals inhaling saline (black bars) or the C-fiber stimulant bradykinin (1mg/ mL; grey bars). This graph is reproduced with permission from Mazzone et al. (43). Mazzone SB, Mori N, Canning BJ. Synergistic interactions between airway afferent nerve subtypes regulating the cough reflex in guinea-pigs. J Physiol 2005;569:559-73.