(S)-albuterol activates pro-constrictory and pro-inflammatory pathways in human bronchial smooth muscle cells
(S)-albuterol activates pro-constrictory and pro-inflammatory pathways in human bronchial smooth muscle cells
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DOI：
10.1016/j.jaci.2003.12.039
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发表时间：
2004-03-01
影响因子：
14.2
通讯作者：
Kelbe, PW
中科院分区：
文献类型：
--
作者：
Agrawal, DK;Ariyarathna, K;Kelbe, PW
背景：（S）-沙丁胺醇在体内和体外条件下的促收缩和促炎症特性已被广泛报道。然而，潜在的mechanisms是uncleared.Objective：我们研究和比较沙丁胺醇对映体的细胞效应的关键细胞内分子参与收缩和炎症途径在人支气管平滑肌cells（hBSMCs）。乙酰甲胆碱用于刺激细胞。G（s）和G（i）蛋白的表达和活性，细胞内游离钙浓度（[Ca 2 +]（i））、磷脂酰肌醇3 '-OH-激酶（PI 3）激酶活性和转录核因子κ B结果：G蛋白的表达和活性显著增加（S）沙丁胺醇处理8小时后，hBSMC中G（s）蛋白的表达降低。以剂量依赖性方式观察到（S）-沙丁胺醇的这些作用。（S）沙丁胺醇可减弱毛喉素对腺苷酸环化酶的非受体介导的激活。用（S）-沙丁胺醇处理细胞24小时显著增加乙酰甲胆碱刺激的[Ca 2 +]（i）。有趣的是，（R）-沙丁胺醇的作用与（S）-沙丁胺醇相反。在某些情况下，外消旋沙丁胺醇的作用与（S）-沙丁胺醇相似。结论：（S）-沙丁胺醇诱导hBSMCs中G（i α-1）蛋白和[Ca ~（2+）]（i）参与的促收缩通路表达和活性增加，G（s）蛋白参与的支气管扩张通路活性降低。此外，（S）-沙丁胺醇激活涉及PI 3激酶和NF-κ B的促炎通路。由于（S）-沙丁胺醇的代谢比（R）-沙丁胺醇慢至少10倍，并且具有更长的消除半衰期，因此（S）-沙丁胺醇的这些细胞效应可能解释了在治疗气道疾病（如支气管哮喘）中长期给予外消旋沙丁胺醇所观察到的有害作用。
Background: Pro-constrictory and proinflammatory properties of (S)-albuterol have been widely reported both under in vivo and in vitro conditions. However, underlying mechanisms are unclear.Objective: We examined and compared the cellular effects of albuterol enantiomers on key intracellular molecules involved in constrictory and inflammatory pathways in human bronchial smooth muscle cells (hBSMCs).Methods: Primary hBSMCs were grown in culture and treated with various concentrations of albuterol enantiomers for various periods. Methacholine was used to stimulate cells. The expression and activity of G(s) and G(i) proteins, the intracellular free calcium concentration ([Ca2+](i)), the activity of phosphatidylinositol 3'-OH-kinase (PI3) kinase, and the transcriptional nuclear factor kappaB (NF-kappaB) level were examined.Results: There was a significant increase in the expression and activity of G(ialpha-1) protein and a decrease in the expression of G(s) protein in hBSMCs after 8 hours of treatment with (S)albuterol. These effects of (S)-albuterol were observed in a dose-dependent manner. Nonreceptor-mediated activation of adenylate cyclase by forskolin was attenuated with (S)albuterol. Treatment of the cells for 24 hours with (S)-albuterol significantly increased [Ca2+](i) on stimulation with methacholine. Interestingly, the effect of (R)-albuterol was opposite to that of (S)-albuterol. The effect of the racemic albuterol in some cases was similar to that of (S)-albuterol. (S)-Albuterol significantly activated both PI3 kinase and NF-kappaB in hBSMCs.Conclusion: These studies demonstrated an (S)albuterol-induced increase in the expression and activity of pro-constrictory pathways involving G(ialpha-1) protein and [Ca2+](i) and a decrease in the activity of the bronchodilatory pathway involving G(s) proteins in hBSMCs. Additionally, (S)-albuterol activated proinflammatory pathways involving PI3 kinase and NF-kappaB. Because (S)-albuterol metabolizes at least 10-fold slower than (R)-albuterol and has a longer elimination half-life, these cellular effects of (S)-albuterol might explain the detrimental effect seen with chronic administration of racemic albuterol in the treatment of airway diseases, such as bronchial asthma.