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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >SS_2-Adrenoceptor agonist-induced RGS2 expression is a genomic mechanism of bronchoprotection that is enhanced by glucocorticoids
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SS_2-Adrenoceptor agonist-induced RGS2 expression is a genomic mechanism of bronchoprotection that is enhanced by glucocorticoids

机译：SS_2-肾上腺素受体激动剂诱导的RGS2表达是糖皮质激素增强的支气管保护的基因组机制

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摘要

In asthma and chronic obstructive pulmonary disease, activation of G_q-protein-coupled receptors causes bronchoconstriction. In each case, the management of moderate-to-severe disease uses inhaled corticosteroid (glucocorticoid)/long-acting β_2-adrenoceptor agonist (LABA) combination therapies, which are more efficacious than either monotherapy alone. In primary human airway smooth muscle cells, glucocorticoid/LABA combinations synergistically induce the expression of regulator of G-protein signaling 2 (RGS2), a GTPase-activating protein that attenuates G_q signaling. Functionally, RGS2 reduced intracellular free calcium flux elicited by histamine, meth-acholine, leukotrienes, and other spasmogens. Furthermore, protection against spasmogen-increased intracellular free calcium, following treatment for 6 h with LABA plus corticosteroid, was dependent on RGS2. Finally, Rgs2-deficient mice revealed enhanced bronchoconstriction to spasmogens and an absence of LABA-induced bronchoprotection. These data identify RGS2 gene expression as a genomic mechanism of bronchoprotection that is induced by glucocorticoids plus LABAs in human airway smooth muscle and provide a rational explanation for the clinical efficacy of inhaled corticosteroid (glucocorticoid)/LABA combinations in obstructive airways diseases.
机译：在哮喘和慢性阻塞性肺疾病中，G_q蛋白偶联受体的激活引起支气管收缩。在每种情况下，中度至重度疾病的治疗均采用吸入皮质类固醇（糖皮质激素）/长效β_2-肾上腺素受体激动剂（LABA）联合疗法，比单独使用任何单一疗法更有效。在原代人气道平滑肌细胞中，糖皮质激素/ LABA组合可协同诱导G蛋白信号传导2（RGS2）的调节子的表达，RGS2是一种GTPase激活蛋白，可减弱G_q信号传导。从功能上讲，RGS2减少了组胺，甲基-胆碱，白三烯和其他痉挛引起的细胞内游离钙通量。此外，在用LABA加皮质类固醇治疗6小时后，抵抗痉挛源增加的细胞内游离钙的保护依赖于RGS2。最后，Rgs2缺陷型小鼠显示支气管痉挛对痉挛源增强，并且缺乏LABA诱导的支气管保护作用。这些数据将RGS2基因表达鉴定为糖皮质激素加LABA在人气道平滑肌中诱导的支气管保护的基因组机制，并为吸入性糖皮质激素（糖皮质激素）/ LABA组合在阻塞性气道疾病中的临床疗效提供了合理的解释。

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    Neil S. Holden; Matthew J. Bell; Christopher F. Rider; Elizabeth M. King; David D. Gaunt; Richard Leigh; Malcolm Johnson; David P. Siderovski; Scott P. Heximer; Mark A. Giembycz; Robert Newton;

  • 作者单位

    Airways Inflammation Researeh Group, Faculty of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1;

    Respiratory Inflammation and Autoimmunity Department, Medlmmune, Cambridge CB21 6GH, United Kingdom;

    Airways Inflammation Researeh Group, Faculty of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1;

    Airways Inflammation Researeh Group, Faculty of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1;

    Airways Inflammation Researeh Group, Faculty of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1;

    Airways Inflammation Researeh Group, Faculty of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1;

    GlaxoSmithKline Research and Development, Uxbridge, Middlesex UB6 OHE, United Kingdom;

    Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7365;

    Department of Physiology, University of Toronto, Toronto, ON, Canada M5S 1A8;

    Airways Inflammation Researeh Group, Faculty of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1;

    Airways Inflammation Researeh Group, Faculty of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    adrenoreceptor; beta-2-adrenergic receptor; protein kinase A; glucocorticoid receptor; NR3C1;

    机译：肾上腺素受体β-2-肾上腺素受体;蛋白激酶A;糖皮质激素受体NR3C1;

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