上皮细胞的表达及其分泌的STC1通过钙通道调节对哮喘气道高反应性的作用
2021/01/28
摘要
背景：哮喘的特征是气道高反应性（AHR）、炎症和气道重塑。AHR是由可能在上皮源性的松弛因子（EpDRF）控制下的气道平滑肌（ASM）收缩增强所致。但是，关于EpDRF的了解相对较少。
目的：我们旨在阐明上皮源性锡钙素-1(STC1)在AHR和ASM收缩中的作用。
方法：采用ELISA法测定哮喘患者和健康志愿者血清及卵蛋白(OVA)激发的小鼠支气管肺泡灌洗液(BALF)中STC1的水平，以探讨STC1在支气管肺泡灌洗液(BALF)和支气管肺泡灌洗液(BALF)中的作用。观察外源性STC1对小鼠AHR和炎症反应的影响。研究了白细胞介素-13(IL-13)对人支气管上皮细胞系(16HBE)STC1 mRNA和蛋白水平的调节作用。
结果：与健康志愿者相比，哮喘组患者(n=93)的血清STC1降低(1071±30.4pg/ml比1414±751pg/ml，p<0.0001，n=23)，且与哮喘控制(p=0.0270)、肺功能(p=0.0130)和血清IL-13水平(p=0.0009)相关。10例哮喘患者吸入糖皮质激素/长效β2激动剂治疗1年后，STC1表达增强，与哮喘控制改善相关(p=0.022)。STC1主要表达于支气管上皮，鼻内给药重组人STC1(RhSTC1)可减轻小鼠的AHR和炎症反应。IL-13通过抑制间质相互作用分子1(STIM1)抑制16HBE释放STC1，而rhSTC1通过抑制STIM1抑制钙离子内流(SOCE)，并通过抑制钙依赖的肌球蛋白轻链(MLC)磷酸化进一步抑制ASM细胞的收缩。
结论：我们的数据表明哮喘气道中STC1缺乏会促进STIM1过度活跃，增强ASM收缩和AHR。STC1可以是候选EpDRF。
Epithelial expression and role of secreted STC1 on asthma airway hyperresponsiveness through calcium channel modulation
Jiayan Xu, Yaqi Meng, Man Jia, Jie Jiang, Yi Yang, Yingwei Ou, Yunhui Wu, Xiaoyi Yan, Mao Huang, Ian M Adcock, Xin Yao
Abstract
Background: Asthma is characterized by airway hyperresponsiveness (AHR), inflammation and airway remodeling. AHR results from enhanced airway smooth muscle (ASM) contraction potentially under the control of an epithelium-derived relaxing factor (EpDRF). However, relatively rare is known about EpDRF.
Objective：We aimed to elucidate the role of epithelium-derived stanniocalcin-1 (STC1) on AHR and ASM contraction.
Methods:STC1 levels in the serum of asthmatic patients and healthy volunteers and in bronchoalveolar lavage fluid (BALF) from ovalbumin (OVA)-challenged mice were measured by ELISA. The effects of exogenous STC1 on AHR and on inflammation were examined in mice. IL-13 modulation of STC1 mRNA and protein levels was studied in human bronchial epithelial cell lines (16HBE). The function of STC1 on Ca2+ influx and ASM contraction was examined ex vivo.
Results: Serum STC1 was decreased in asthma (n=93) compared with healthy volunteers (1071±30.4 vs 1414±75.1pg/ml, p<0.0001, n=23) and correlated with asthma control (p=0.0270), lung function (FEV1, p=0.0130) and serum IL-13 levels (p=0.0009). Treatment of ten asthmatic subjects with inhaled corticosteroids/long- acting beta2-agonists (ICS/LABA) for one year enhanced STC1 expression which correlated with improved asthma control (p=0.022). STC1 was mainly expressed in bronchial epithelium and intranasal administration of recombinant human STC1 (rhSTC1) reduced AHR and inflammation in mice. IL-13 suppressed STC1 release from 16HBE, whereas rhSTC1 blocked store-operated Ca2+ entry (SOCE) by suppressing stromal interaction molecule 1 (STIM1) and further inhibited ASM cell contractility by suppressing Ca2+ -dependent myosin light chain (MLC) phosphorylation.
Conclusions: Our data indicate that STC1 deficiency in asthmatic airways promotes STIM1 hyperactivity, enhanced ASM contraction and AHR. STC1 may be a candidate EpDRF.
背景：哮喘的特征是气道高反应性（AHR）、炎症和气道重塑。AHR是由可能在上皮源性的松弛因子（EpDRF）控制下的气道平滑肌（ASM）收缩增强所致。但是，关于EpDRF的了解相对较少。
目的：我们旨在阐明上皮源性锡钙素-1(STC1)在AHR和ASM收缩中的作用。
方法：采用ELISA法测定哮喘患者和健康志愿者血清及卵蛋白(OVA)激发的小鼠支气管肺泡灌洗液(BALF)中STC1的水平，以探讨STC1在支气管肺泡灌洗液(BALF)和支气管肺泡灌洗液(BALF)中的作用。观察外源性STC1对小鼠AHR和炎症反应的影响。研究了白细胞介素-13(IL-13)对人支气管上皮细胞系(16HBE)STC1 mRNA和蛋白水平的调节作用。
结果：与健康志愿者相比，哮喘组患者(n=93)的血清STC1降低(1071±30.4pg/ml比1414±751pg/ml，p<0.0001，n=23)，且与哮喘控制(p=0.0270)、肺功能(p=0.0130)和血清IL-13水平(p=0.0009)相关。10例哮喘患者吸入糖皮质激素/长效β2激动剂治疗1年后，STC1表达增强，与哮喘控制改善相关(p=0.022)。STC1主要表达于支气管上皮，鼻内给药重组人STC1(RhSTC1)可减轻小鼠的AHR和炎症反应。IL-13通过抑制间质相互作用分子1(STIM1)抑制16HBE释放STC1，而rhSTC1通过抑制STIM1抑制钙离子内流(SOCE)，并通过抑制钙依赖的肌球蛋白轻链(MLC)磷酸化进一步抑制ASM细胞的收缩。
结论：我们的数据表明哮喘气道中STC1缺乏会促进STIM1过度活跃，增强ASM收缩和AHR。STC1可以是候选EpDRF。
(中日友好医院呼吸与危重症医学科 王静茹 摘译 林江涛 审校)
(Allergy.2020 Dec 30.doi: 10.1111/all.14727.)
(Allergy.2020 Dec 30.doi: 10.1111/all.14727.)
Epithelial expression and role of secreted STC1 on asthma airway hyperresponsiveness through calcium channel modulation
Jiayan Xu, Yaqi Meng, Man Jia, Jie Jiang, Yi Yang, Yingwei Ou, Yunhui Wu, Xiaoyi Yan, Mao Huang, Ian M Adcock, Xin Yao
Abstract
Background: Asthma is characterized by airway hyperresponsiveness (AHR), inflammation and airway remodeling. AHR results from enhanced airway smooth muscle (ASM) contraction potentially under the control of an epithelium-derived relaxing factor (EpDRF). However, relatively rare is known about EpDRF.
Objective：We aimed to elucidate the role of epithelium-derived stanniocalcin-1 (STC1) on AHR and ASM contraction.
Methods:STC1 levels in the serum of asthmatic patients and healthy volunteers and in bronchoalveolar lavage fluid (BALF) from ovalbumin (OVA)-challenged mice were measured by ELISA. The effects of exogenous STC1 on AHR and on inflammation were examined in mice. IL-13 modulation of STC1 mRNA and protein levels was studied in human bronchial epithelial cell lines (16HBE). The function of STC1 on Ca2+ influx and ASM contraction was examined ex vivo.
Results: Serum STC1 was decreased in asthma (n=93) compared with healthy volunteers (1071±30.4 vs 1414±75.1pg/ml, p<0.0001, n=23) and correlated with asthma control (p=0.0270), lung function (FEV1, p=0.0130) and serum IL-13 levels (p=0.0009). Treatment of ten asthmatic subjects with inhaled corticosteroids/long- acting beta2-agonists (ICS/LABA) for one year enhanced STC1 expression which correlated with improved asthma control (p=0.022). STC1 was mainly expressed in bronchial epithelium and intranasal administration of recombinant human STC1 (rhSTC1) reduced AHR and inflammation in mice. IL-13 suppressed STC1 release from 16HBE, whereas rhSTC1 blocked store-operated Ca2+ entry (SOCE) by suppressing stromal interaction molecule 1 (STIM1) and further inhibited ASM cell contractility by suppressing Ca2+ -dependent myosin light chain (MLC) phosphorylation.
Conclusions: Our data indicate that STC1 deficiency in asthmatic airways promotes STIM1 hyperactivity, enhanced ASM contraction and AHR. STC1 may be a candidate EpDRF.
