Sensory nerves and airway irritability

Abstract

The lung, like many other organs, is innervated by a variety of sensory nerves and by nerves of the parasympathetic and sympathetic nervous systems that regulate the function of cells within the respiratory tract. Activation of sensory nerves by both mechanical and chemical stimuli elicits a number of defensive reflexes, including cough, altered breathing pattern, and altered autonomic drive, which are important for normal lung homeostasis. However, diseases that afflict the lung are associated with altered reflexes, resulting in a variety of symptoms, including increased cough, dyspnea, airways obstruction, and bronchial hyperresponsiveness. This review summarizes the current knowledge concerning the physiological role of different sensory nerve subtypes that innervate the lung, the factors which lead to their activation, and pharmacological approaches that have been used to interrogate the function of these nerves. This information may potentially facilitate the identification of novel drug targets for the treatment of respiratory disorders such as cough, asthma, and chronic obstructive pulmonary disease.

Fig. 1

The characteristic features of airway and lung vagal afferent nerve subtypes are shown in these single-fiber recordings in the rat. C-fibers are generally unresponsive to mechanical stimulation, including the mechanical consequences of lung inflation and deflation, but are vigorously activated by capsaicin. The rapidly adapting stretch receptors (RARs) and the slowly adapting stretch receptors (SARs) are largely insensitive to capsaicin. Both lung stretch receptor subtypes are responsive to lung inflation, with RAR activity more prominent in species with higher respiratory rates. RARs and SARs are differentiated in part by their responses to sustained lung inflation. These vagal afferent nerve subtypes differentially regulate airway autonomic outflow, respiratory pattern, respiratory sensations, and cough. Subtypes of each afferent class have been described and are found in all species thus far studied. (Reproduced with permission from Ho et al. 2001)

Fig. 2

Responsiveness to histamine and capsaicin differentiates RARs from C-fibers. (Reproduced from Canning and Chou and summarizes results published elsewhere)

Fig. 3

Respiratory reflex effects evoked by histamine, adenosine, and capsaicin reveal the differential distribution of airway vagal afferent nerve subtypes and their distinct effects on respiratory pattern. Histamine selectively activates intrapulmonary RARs and initiates tachypnea. Adenosine selectively activates pulmonary C-fibers and also initiates tachypnea. Capsaicin activates both bronchial and pulmonary type C-fibers, initiating a profound slowing of respiration upon laryngeal challenge, tachypnea when capsaicin is inhaled (not shown), and both tachypnea and respiratory slowing following intravenous administration. (Data adapted from Chou et al. 2008)

Fig. 4

Electrophysiological characteristics of the extrapulmonary vagal afferent nerves regulating cough of guinea pigs. Cough receptors and C-fibers are both activated by punctate mechanical stimulation and by acid, but the cough receptors are insensitive to capsaicin. Capsaicin and other C-fiber-selective stimulants initiate coughing in awake animals and in awake human subjects, but have consistently failed to initiate coughing in anesthetized animals. In anesthetized guinea pigs, topical acid challenge of the tracheal mucusa initiates coughing, while topical capsaicin challenge does not evoke coughing. Rather, capsaicin challenge in anesthetized guinea pigs evokes respiratory slowing and, occasionally, a profound apnea followed by gasping and a gradual recovery of a normal respiratory pattern. (Reproduced with permission from Canning et al. 2004)

Fig. 5

Reflex-evoked, airway parasympathetic nerve-dependent regulation of airway smooth muscle tone in guinea pigs in situ. (a) The C-fiber-selective stimulant bradykinin evokes reflex bronchospasm largely independent of any direct effects on airway smooth muscle. Histamine-evoked reflex bronchospasm occurs secondary to its direct effects on airway smooth muscle, which in turn activates intrapulmonary RARs. Evidence for the selective effects of bradykinin and histamine on C-fibers and RARs, respectively, is apparent from the marked inhibition of bradykinin-evoked reflex bronchospasm by intravenous or intracerebroventricular administration of neurokinin receptor antagonists, which are without effect on histamine-evoked reflexes. Neurokinins are selectively expressed by C-fibers in guinea pigs. (b) When RARs and C-fibers are activated simultaneously, marked synergism is apparent. This synergistic effect of RAR and C-fiber activation on airway parasympathetic tone may result from central convergence in the nucleus of the solitary tract of these afferent nerve subtypes. (c, d) The mean data for reflex bronchospasm and whole-lung-inflation pressures evoked by histamine, bradykinin, or the combination of histamine and bradykinin. (Reproduced with permission from Canning et al. and Mazzone and Canning a, b)

Fig. 6

Bronchial hyperresponsiveness (BHR) in asthma. It is convenient to measure changes in forced expiratory volume in 1 s (FEV₁) to increasing doses of methacholine. In asthma, there is an increase in sensitivity (leftward position of the dose–response curve) often measured in terms of PC20 (dotted line) and reactivity (increase in slope) and in severe cases of the disease an inability to define the maximum degree value for airway narrowing compared with healthy subjects. However, BHR as measured by changes in FEV₁ to increasing doses of methacholine may not be a sensitive indicator of the asthma phenotype (see the text). An increase in BHR can occur during exacerbation of disease as observed naturally during the pollen season, in the case of an allergic asthmatic, or following the deliberate exposure to a relevant antigen (arrow). However, asthmatic subjects are invariably responsive to a wide range of physiological stimuli that are otherwise refractory in healthy subjects. An understanding of the mechanisms by which these stimuli induce bronchoconstriction suggests that sensitization of afferent pathways may underlie this phenomenon