Identifying the vagal bronchopulmonary afferents responsible for eliciting the cough response to inhaled sulfur dioxide in mice

Abstract

Among the three major types of vagal sensory nerves innervating the lung and airways, C‐fibers and rapidly adapting receptors (RARs or irritant receptors) are known to possess the properties and functions of “cough receptors”, but their relative roles in regulating cough reflex responses to inhaled irritants are not yet clearly defined. To address this question, we have recently carried out a series of studies in a mouse cough model, in which the intra‐pleural pressure was continuously recorded by a surgically implanted telemetry sensor. Sulfur dioxide (SO2), a common irritant gas, was chosen for the study because its widespread use as a chemical agent in various industrial operations has led to severe lung injuries in workers in numerous incidences resulting from accidental release of high concentrations of SO2 in industrial facilities. Inhalation of SO2 (300 and 600 ppm) consistently and reproducibly elicited coughs in a concentration‐dependent manner in awake mice moving freely in a recording chamber. The cough frequency increased rapidly after the onset of the SO2 inhalation challenge, which continued for the remaining duration of 8‐min exposure. In the current study, single‐fiber electrophysiological recording of vagal afferent activity in anesthetized mice showed that the high concentration of SO2 (600 ppm) evoked a sustained stimulatory effect on C‐fibers for the entire duration (8 min) of the inhalation challenge. However, in sharp contrast, inhalation of SO2 at the same concentration and duration generated a distinct and consistent inhibitory effect on both phasic RARs and slowly adapting receptors. Their respiratory cycle‐related phasic discharge declined progressively and/or ceased completely within 1‐3 min after the onset of the SO2 inhalation challenge, which gradually recovered after >15 min following the termination of the SO2 inhalation. In a small percentage of RARs that displayed no phasic activity during eupneic breathing and often exhibited sensitivity to certain inhaled irritants, the same SO2 inhalation challenge did not evoke any significant stimulatory effect. Taken together, these observations suggest that stimulation of bronchopulmonary C‐fibers is primarily responsible for triggering airway irritation and coughing in response to the SO2 inhalation challenge.