Tracheobronchial-esophageal reflex initiates esophageal hypersensitivity and aggravates cough hyperreactivity in guinea pigs with esophageal acid infusion

Esophageal-tracheobronchial reflex is considered the main mechanism underlying cough due to gastroesophageal reflux, and is associated with esophageal hypersensitivity. We hypothesized that tracheobronchial-esophageal reflex may also exist, and may be related to esophageal hypersensitivity. To test this hypothesis, conscious and ether-anesthetized guinea pigs were subjected to repetitive capsaicin inhalation to establish models of cough (conscious) and cough-free (anesthetized) airway injury, respectively, followed by esophageal acid infusion. Recurrent capsaicin inhalation induced similar cough hyperreactivity to inhaled capsaicin after esophageal acid infusion in guinea pigs with cough and guinea pigs with cough-free airway injury during recurrent capsaicin inhalation. Cough hyperreactivity, along with overexpression of transient receptor potential vanilloid 1 (TRPV1) receptors in esophageal mucosa and in nerve fibers of tracheal mucosa of guinea pigs were blocked by pretreatment with esophageal infusion of capsazepine, but not atropine. Thus, recurrent airway nociceptive stimuli induce esophageal hyperreactivity via a tracheobronchial-esophageal reflex mediated by vagal C afferents expressing TRPV1, and enhance cough due to reflux.