State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center, Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study and the Medical School of Nanjing University, Nanjing, China.
State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center, Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study and the Medical School of Nanjing University, Nanjing, China; College of Life Science, Nanjing Normal University, Nanjing, China.
J Allergy Clin Immunol. 2018 Apr;141(4):1259-1268.e11. doi: 10.1016/j.jaci.2017.05.053. Epub 2017 Jul 25.
Allergic inflammation has long been implicated in asthmatic hyperresponsiveness of airway smooth muscle (ASM), but its underlying mechanism remains incompletely understood. Serving as G protein-coupled receptor agonists, several inflammatory mediators can induce membrane depolarization, contract ASM, and augment cholinergic contractile response. We hypothesized that the signal cascade integrating on membrane depolarization by the mediators might involve asthmatic hyperresponsiveness.
We sought to investigate the signaling transduction of inflammatory mediators in ASM contraction and assess its contribution in the genesis of hyperresponsiveness.
We assessed the capacity of inflammatory mediators to induce depolarization currents by electrophysiological analysis. We analyzed the phenotypes of transmembrane protein 16A (TMEM16A) knockout mice, applied pharmacological reagents, and measured the Ca signal during ASM contraction. To study the role of the depolarization signaling in asthmatic hyperresponsiveness, we measured the synergistic contraction by methacholine and inflammatory mediators both ex vivo and in an ovalbumin-induced mouse model.
Inflammatory mediators, such as 5-hydroxytryptamin, histamine, U46619, and leukotriene D, are capable of inducing Ca-activated Cl currents in ASM cells, and these currents are mediated by TMEM16A. A combination of multiple analysis revealed that a G protein-coupled receptor-TMEM16A-voltage-dependent Ca channel signaling axis was required for ASM contraction induced by inflammatory mediators. Block of TMEM16A activity may significantly inhibit the synergistic contraction of acetylcholine and the mediators and hence reduces hypersensitivity.
A G protein-coupled receptor-TMEM16A-voltage-dependent Ca channel axis contributes to inflammatory mediator-induced ASM contraction and synergistically activated TMEM16A by allergic inflammatory mediators with cholinergic stimuli.
过敏炎症长期以来一直被认为与气道平滑肌（ASM）的哮喘高反应性有关，但其潜在机制仍不完全清楚。作为 G 蛋白偶联受体激动剂，几种炎症介质可以诱导膜去极化、收缩 ASM，并增强胆碱能收缩反应。我们假设，这些介质通过膜去极化整合的信号级联可能涉及哮喘高反应性。
我们旨在研究炎症介质在 ASM 收缩中的信号转导，并评估其在高反应性发生中的作用。
我们通过电生理分析评估了炎症介质诱导去极化电流的能力。我们分析了跨膜蛋白 16A（TMEM16A）敲除小鼠的表型，应用药理学试剂，并在 ASM 收缩期间测量钙信号。为了研究去极化信号在哮喘高反应性中的作用，我们测量了甲酰胆碱和炎症介质在体外和卵清蛋白诱导的小鼠模型中的协同收缩。
炎症介质，如 5-羟色胺、组胺、U46619 和白三烯 D，能够诱导 ASM 细胞中的 Ca 激活的 Cl 电流，这些电流是由 TMEM16A 介导的。多项分析表明，G 蛋白偶联受体-TMEM16A-电压依赖性钙通道信号轴是炎症介质诱导 ASM 收缩所必需的。TMEM16A 活性的阻断可能显著抑制乙酰胆碱和介质的协同收缩，从而降低过敏反应性。
G 蛋白偶联受体-TMEM16A-电压依赖性钙通道轴参与了炎症介质诱导的 ASM 收缩，并且过敏炎症介质与胆碱能刺激共同激活 TMEM16A。
