IFN-γ Enhances the Cough Reflex Sensitivity via Calcium Influx in Vagal Sensory Neurons

Rationale: Cough hypersensitivity syndrome is often triggered by a viral infection. The viral infection might trigger cough hypersensitivity via increasing the release of IFN-gamma from T lymphocytes in the lung. Objectives: To investigate effects of IFN-gamma on the vagal sensory neurons and the cough reflex. Methods: Effects of IFN-gamma on the cough reflex were investigated in guinea pigs. Cellular immunofluorescence imaging, calcium imaging, and patch clamp techniques were used to study effects of IFN-gamma in primary cultured rat vagal sensory neurons. Measurements and Main Results: Intratracheal instillation of IFN-gamma enhanced the cough response to citric acid in vivo. IFN-gamma significantly increased levels of phosphorylated signal transducer and activator of transcription-1 but not phosphorylated transient receptor potential vanilloid 1 in vitro. Not only did IFN-gamma enhance the response of neurons to capsaicin and electric stimulation, but also it directly induced Ca2+ influx, membrane depolarization, and action potentials in neurons via the Janus kinase, protein kinase A, and a -amino-3-hydroxy-5-methy1-4-isoxazolepropionic acid pathways. However, IFN-gamma did not elicit Ca 2 release from the endoplasmic reticulum via the phospholipase C pathway. Although IFN-gamma induced action potentials were suppressed by Ca2+ influx inhibitors, IFN-gamma-induced Ca2+ influx was not altered by an inhibitor of rapid sodium channels. Conclusions: The membrane potential in vagal sensory neurons may be depolarized by IFN-gamma-induced Ca2+ influx. The depolarization of membrane potentials may enhance the cough reflex sensitivity and cause action potentials. IFN-gamma may be a new target for treating cough hypersensitivity syndrome and postviral cough.