(R)-Albuterol elicits antiinflammatory effects in human airway epithelial cells via iNOS
(R)-Albuterol elicits antiinflammatory effects in human airway epithelial cells via iNOS
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DOI：
10.1165/rcmb.2005-0338oc
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发表时间：
2006-01-01
影响因子：
6.4
通讯作者：
Adler, KB
中科院分区：
文献类型：
--
作者：
Chorley, BN;Li, YH;Adler, KB
儿茶酚胺可以抑制包括气道上皮在内的不同细胞类型中炎症介质的产生，但参与调节这些抗炎作用的下游信号传导机制在很大程度上尚不清楚。我们推测，用沙丁胺醇对气道上皮细胞进行急性β（2）肾上腺素能刺激，可以通过涉及诱导型一氧化氮合酶（iNOS）的途径抑制炎症介质的产生和释放，特别是粒细胞巨噬细胞集落刺激因子（GM-CSF）。将原代培养物中的正常人支气管上皮 (NHBE) 细胞暴露于细胞因子混合物（IFN-γ 和 IL-1 β 各 10 ng/ml）以诱导 iNOS 表达。将沙丁胺醇的 (R)-和 (S)-对映体以及外消旋混合物与这些细胞因子一起添加，并评估对 GM-CSF 表达和产生的影响。使用蛋白激酶 (PK) 的特异性抑制剂和激活剂、β(2)-肾上腺素能受体拮抗剂和针对 iNOS 的小干扰 RNA 来描绘所涉及的信号传导途径。沙丁胺醇活性 (R)-对映体以浓度依赖性方式显着上调 iNOS 信息。 (R)-沙丁胺醇还可以减弱细胞因子引起的 GM-CSF 稳态 mRNA 表达和蛋白质释放的增加。沙丁胺醇的 (S)-对映异构体对这些参数没有影响。 PKC，特别是 delta 同工型，是 iNOS 信息增加所必需的，但 PKA 和 PKG 不参与该途径。总的来说，这项研究确定了一种新的途径，β(2)-肾上腺素能激动剂可以通过该途径在气道上皮和周围环境中表现出抗炎作用。
Catecholamines can suppress production of inflammatory mediators in different cell types, including airway epithelium, but downstream signaling mechanisms involved in regulation of these anti-inflammatory effects are largely unknown. We theorized that acute beta(2)-adrenergic stimulation of airway epithelial cells with albuterol could suppress the production and release of inflammatory mediators, specifically granulocyte macrophage-colony stimulating factor (GM-CSF) via a pathway involving inducible nitric oxide synthase (iNOS). Normal human bronchial epithelial (NHBE) cells in primary culture were exposed to a cytokine mixture (10 ng/ml each IFN-gamma and IL-1 beta) to induce iNOS expression. (R)- and (S)-enantiomers of albuterol, as well as racemic mixtures, were added with these cytokines, and effects on GM-CSF expression and production were assessed. Specific inhibitors and activators of protein kinases (PKs), beta(2)-adrenergic receptor antagonists, and small interfering RNAs against iNOS were used to delineate signaling pathways involved. iNOS message was significantly upregulated in a concentration-dependent manner by the active (R)-enantiomer of albuterol. (R)-albuterol also attenuated cytokine-incluced increases in GM-CSF steady-state mRNA expression and protein release. The (S)-enantomer of albuterol had no effect on these parameters. PKC, specifically, the delta isoform, was required for iNOS message increase, but PKA and PKG were not involved in the pathway. Overall, this study identifies a novel pathway by which beta(2)-adrenergic agonists may exhibit antiinflammatory effects in airway epithelium and surrounding milieu.