Zheng Deng1,2, Wenliang Zhou3, Jiayang Sun1, Chenhui Li1, Bonian Zhong1, Kefang Lai1. 1. 1 State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. 2. 2 School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China; and. 3. 3 School of Life Science, Sun Yat-sen University, Guangzhou, China.
Abstract
RATIONALE: Cough 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. OBJECTIVES: To investigate effects of IFN-γ on the vagal sensory neurons and the cough reflex. METHODS: Effects 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 RESULTS: Intratracheal 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. CONCLUSIONS: The 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.
RATIONALE: Cough 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. OBJECTIVES: To investigate effects of IFN-γ on the vagal sensory neurons and the cough reflex. METHODS: Effects 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 RESULTS: Intratracheal 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. CONCLUSIONS: The 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.
Authors: Woo-Jung Song; Christopher K M Hui; James H Hull; Surinder S Birring; Lorcan McGarvey; Stuart B Mazzone; Kian Fan Chung Journal: Lancet Respir Med Date: 2021-04-12 Impact factor: 102.642
Authors: Clare O Shapiro; Becky J Proskocil; Laura J Oppegard; Emily D Blum; Nicole L Kappel; Christopher H Chang; Allison D Fryer; David B Jacoby; Richard W Costello; Matthew G Drake Journal: Am J Respir Crit Care Med Date: 2021-02-01 Impact factor: 21.405