Cough and gastroesophageal reflux: Insights from animal models

Chronic cough in gastroesophageal reflux disease (GERD) has been attributed to irritation of the esophagus and/or upper airways by reflux of gastric content. Animal models have provided insight into both of these putative mechanisms. In patients with chronic cough and GERD, stimuli associated with reflex in the esophagus sensitize the cough reflex. This sensitization can be reproduced in the guinea pig and is most likely mediated by the esophageal afferent nerve fibers carried by the vagus nerves. Studies in animals have identified several subtypes of vagal esophageal C-fibers that may subserve this function. The putative nociceptive vagal C-fibers in the guinea pig esophagus are stimulated by acid and express the TRPV1 and TRPA1 receptors that confer responsiveness to disparate noxious stimuli. Acute and/or chronic irritation of the upper airways by reflux may contribute to cough by stimulation and/or sensitization of the airway afferent nerves. Studies in animals have identified airway nerves that likely initiate cough due to aspirated reflux; have characterized their pharmacology; and have provided insight into changes of their sensitivity. Studies in animal models have also described the neurophysiology of reflexes that protect the airways from reflux. In conclusion, animal models provide mechanistic insight into the modulation of cough from the esophagus and the pharmacology of neural pathways mediating cough in GERD.