• Zheng Deng, Wenliang Zhou, Jiayang Sun, Chenhui Li, Bonian Zhong, and Kefang Lai.
• 1 State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
• Am. J. Respir. Crit. Care Med. 2018 Oct 1; 198 (7): 868-879.

RationaleCough hypersensitivity syndrome is often triggered by a viral infection. The viral infection might trigger cough hypersensitivity via increasing the release of IFN-γ from T lymphocytes in the lung.ObjectivesTo investigate effects of IFN-γ on the vagal sensory neurons and the cough reflex.MethodsEffects of IFN-γ 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-γ in primary cultured rat vagal sensory neurons.Measurements And Main ResultsIntratracheal instillation of IFN-γ enhanced the cough response to citric acid in vivo. IFN-γ 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-γ 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 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid pathways. However, IFN-γ did not elicit Ca2+ release from the endoplasmic reticulum via the phospholipase C pathway. Although IFN-γ-induced action potentials were suppressed by Ca2+ influx inhibitors, IFN-γ-induced Ca2+ influx was not altered by an inhibitor of rapid sodium channels.ConclusionsThe membrane potential in vagal sensory neurons may be depolarized by IFN-γ-induced Ca2+ influx. The depolarization of membrane potentials may enhance the cough reflex sensitivity and cause action potentials. IFN-γ may be a new target for treating cough hypersensitivity syndrome and postviral cough.

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