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IFN‐&ggr; 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‐&ggr; from T lymphocytes in the lung. Objectives: To investigate effects of IFN‐&ggr; on the vagal sensory neurons and the cough reflex. Methods: Effects of IFN‐&ggr; 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‐&ggr; in primary cultured rat vagal sensory neurons. Measurements and Main Results: Intratracheal instillation of IFN‐&ggr; enhanced the cough response to citric acid in vivo. IFN‐&ggr; 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‐&ggr; 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 &agr;‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid pathways. However, IFN‐&ggr; did not elicit Ca2+ release from the endoplasmic reticulum via the phospholipase C pathway. Although IFN‐&ggr;‐induced action potentials were suppressed by Ca2+ influx inhibitors, IFN‐&ggr;‐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‐&ggr;‐induced Ca2+ influx. The depolarization of membrane potentials may enhance the cough reflex sensitivity and cause action potentials. IFN‐&ggr; may be a new target for treating cough hypersensitivity syndrome and postviral cough.