IFN-γ Enhances the Cough Reflex Sensitivity via Calcium Influx in Vagal Sensory Neurons
IFN-γ Enhances the Cough Reflex Sensitivity via Calcium Influx in Vagal Sensory Neurons
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IFN-γ 通过迷走神经感觉神经元中的钙流入增强咳嗽反射敏感性
DOI：
10.1164/rccm.201709-1813oc
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发表时间：
2018-10-01
影响因子：
24.7
通讯作者：
Lai, Kefang
中科院分区：
文献类型：
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作者：
Deng, Zheng;Zhou, Wenliang;Lai, Kefang
理由：咳嗽过敏综合征通常由病毒感染引起。病毒感染可能通过增加肺部T淋巴细胞释放ifn - γ而引发咳嗽过敏。目的：探讨ifn - γ对迷走神经感觉神经元及咳嗽反射的影响。方法：观察干扰素γ对豚鼠咳嗽反射的影响。采用细胞免疫荧光成像、钙显像和膜片钳技术研究ifn - γ对原代培养大鼠迷走神经感觉神经元的影响。实验结果和主要结果：ifn - γ气管内灌注可增强小鼠对柠檬酸的咳嗽反应。ifn - γ在体外显著增加磷酸化信号转导和转录激活因子-1的水平，但不磷酸化瞬时受体电位香草样蛋白1。ifn - γ不仅增强了神经元对辣椒素和电刺激的反应，还通过Janus激酶、蛋白激酶A和-氨基-3-羟基-5-甲基- 1-4-异恶唑丙酸途径直接诱导神经元的Ca2+内流、膜去极化和动作电位。然而，ifn - γ并不能通过磷脂酶C途径诱导ca2从内质网释放。虽然ifn - γ诱导的动作电位被Ca2+内流抑制剂抑制，但ifn - γ诱导的Ca2+内流不被快速钠通道抑制剂改变。结论：ifn - γ诱导的Ca2+内流可能导致迷走神经感觉神经元的膜电位去极化。膜电位的去极化可增强咳嗽反射敏感性，引起动作电位。ifn - γ可能是治疗咳嗽过敏综合征和病毒后咳嗽的新靶点。
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.