Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
Mol Pharmacol. 2015 Jan;87(1):64-76. doi: 10.1124/mol.114.093393. Epub 2014 Oct 16.
Glucocorticoids, also known as corticosteroids, induce effector gene transcription as a part of their anti-inflammatory mechanisms of action. Such genomic effects can be significantly enhanced by long-acting β2-adrenoceptor agonists (LABAs) and may contribute to the clinical superiority of inhaled corticosteroid (ICS)/LABA combinations in asthma and chronic obstructive pulmonary disease (COPD) over ICSs alone. Using models of cAMP- and glucocorticoid-induced transcription in human bronchial epithelial BEAS-2B cells, we show that combining inhibitors of phosphodiesterase (PDE) 3 and PDE4 provides greater benefits compared with inhibiting either PDE alone. In respect to cAMP-dependent transcription, inhibitors of PDE3 (siguazodan, cilostazol) and PDE4 (rolipram, GSK256066, roflumilast N-oxide) each sensitized to the LABA, formoterol. This effect was magnified by dual PDE3 and PDE4 inhibition. Siguazodan plus rolipram was also more effective at inducing cAMP-dependent transcription than either inhibitor alone. Conversely, the concentration-response curve describing the enhancement of dexamethasone-induced, glucocorticoid response element-dependent transcription by formoterol was displaced to the left by PDE4, but not PDE3, inhibition. Overall, similar effects were described for bona fide genes, including RGS2, CD200, and CRISPLD2. Importantly, the combination of siguazodan plus rolipram prolonged the duration of gene expression induced by formoterol, dexamethasone, or dexamethasone plus formoterol. This was most apparent for RGS2, a bronchoprotective gene that may also reduce the proinflammatory effects of constrictor mediators. Collectively, these data provide a rationale for the use of PDE3 and PDE4 inhibitors in the treatment of COPD and asthma where they may enhance, sensitize, and prolong the effects of LABA/ICS combination therapies.
糖皮质激素，也称为皮质类固醇，作为其抗炎作用机制的一部分，诱导效应基因转录。这种基因组效应可以通过长效β2-肾上腺素能受体激动剂（LABA）显著增强，并可能有助于吸入皮质类固醇（ICS）/LABA 联合治疗在哮喘和慢性阻塞性肺疾病（COPD）中的临床优势超过 ICS 单独使用。我们使用人支气管上皮 BEAS-2B 细胞中的 cAMP 和糖皮质激素诱导转录模型表明，与单独抑制一种 PDE 相比，联合抑制磷酸二酯酶（PDE）3 和 PDE4 可带来更大的益处。在 cAMP 依赖性转录方面，PDE3 抑制剂（西洛他唑、昔多芬）和 PDE4 抑制剂（罗利普兰、GSK256066、罗氟司特 N-氧化物）都使 LABA（福莫特罗）敏感化。这种作用通过双重 PDE3 和 PDE4 抑制而放大。西洛他唑加罗利普兰在诱导 cAMP 依赖性转录方面也比单独使用任何一种抑制剂更有效。相反，福莫特罗对 dexamethasone 诱导的糖皮质激素反应元件依赖性转录的增强作用的浓度-反应曲线被 PDE4 而不是 PDE3 抑制向左移位。总体而言，对于真正的基因，包括 RGS2、CD200 和 CRISPLD2，描述了类似的作用。重要的是，西洛他唑加罗利普兰联合可延长福莫特罗、地塞米松或地塞米松加福莫特罗诱导的基因表达持续时间。这在支气管保护基因 RGS2 中最为明显，它还可能减轻收缩介质的促炎作用。总的来说，这些数据为在 COPD 和哮喘中使用 PDE3 和 PDE4 抑制剂提供了依据，它们可能增强、敏化和延长 LABA/ICS 联合治疗的作用。
