Estrogen receptors differentially regulate intracellular calcium handling in human nonasthmatic and asthmatic airway smooth muscle cells
Estrogen receptors differentially regulate intracellular calcium handling in human nonasthmatic and asthmatic airway smooth muscle cells
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DOI：
10.1152/ajplung.00206.2019
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发表时间：
2020-01-01
影响因子：
4.9
通讯作者：
Sathish, Venkatachalem
中科院分区：
文献类型：
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作者：
Bhallamudi, Sangeeta;Connell, Jennifer;Sathish, Venkatachalem
哮喘被定义为气道的慢性炎症，其特征在于气道重塑。高反应性和气道平滑肌（ASM）细胞的急性支气管收缩。临床研究结果表明，成年女性哮喘的发病率和严重程度较高，这表明性类固醇在调节气道张力方面发挥了具体作用。雌激素是一种主要的女性性类固醇，通过雌激素受体（ER）ER α和ER β介导其作用，ER α和ER β在人类ASM中表达，并且它们的表达在肺部炎症和哮喘中上调。先前的研究表明，雌激素通过ER的快速非基因组信号传导降低细胞内钙（[Ca 2 +]（i）），从而促进ASM的松弛。然而，在炎症或哮喘期间，人ASM中[Ca 2 +]（i）调节的长期ER激活仍然未知。在Fura-2负载的非哮喘和哮喘人ASM细胞中，我们发现与溶剂相比，长时间（24 h）暴露于ER α激动剂（PPT）增加了[Ca 2 +]（i）对组胺的反应，而ER β激活（WAY）导致[Ca 2 +]降低。使用各种支气管收缩剂进行的ER过表达和敲减研究进一步证实了这一点。有趣的是，在TNF-α或IL-13存在下，ER β激活在降低[Ca 2 +]（i）反应方面比17 β-雌二醇更有效，而在任一细胞因子存在下，PPT没有观察到可观察到的变化。ER β的[Ca 2 +]（i）-降低作用部分通过L-型钙通道抑制和肌浆网增加的Ca 2+螯合来介导。总体而言，这些数据突出了炎症期间ASM中ER α和ER β的差异信号传导。特异性ER β激活可降低发炎ASM细胞中的[Ca 2 +]（i），并可能在调节ASM收缩性方面发挥关键作用，从而放松气道。
Asthma is defined as chronic inflammation of the airways and is characterized by airway remodeling. hyperresponsiveness, and acute bronchoconstriction of airway smooth muscle (ASM) cells. Clinical findings suggest a higher incidence and severity of asthma in adult women, indicating a concrete role of sex steroids in modulating the airway tone. Estrogen, a major female sex steroid mediates its role through estrogen receptors (ER) ER alpha and ER beta, which are shown to be expressed in human ASM, and their expression is upregulated in lung inflammation and asthma. Previous studies suggested rapid, non-genomic signaling of estrogen via ERs reduces intracellular calcium ([Ca2+](i)), thereby promoting relaxation of ASM. However, long-term ER activation on [Ca2+](i) regulation in human ASM during inflammation or in asthma is still not known. In Fura-2-loaded nonasthmatic and asthmatic human ASM cells, we found that prolonged (24 h) exposure to ER alpha agonist (PPT) increased [Ca2+](i) response to histamine, whereas ER beta activation (WAY) led to decreased [Ca2+] compared with vehicle. This was further confirmed by ER overexpression and knockdown studies using various bronchoconstrictor agents. Interestingly, ER beta activation was more effective than 17 beta-estradiol in reducing [Ca2+](i) responses in the presence of TNF-alpha or IL-13, while no observable changes were noticed with PPT in the presence of either cytokine. The [Ca2+](i)-reducing effects of ER beta were mediated partially via L-type calcium channel inhibition and increased Ca2+ sequestration by sarcoplasmic reticulum. Overall, these data highlight the differential signaling of ER alpha and ER beta in ASM during inflammation. Specific ER beta activation reduces [Ca2+](i) in the inflamed ASM cells and is likely to play a crucial role in regulating ASM contractility, thereby relaxing airways.