Airways Inflammation Research Group, Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
J Pharmacol Exp Ther. 2013 Sep;346(3):473-85. doi: 10.1124/jpet.113.206284. Epub 2013 Jul 2.
Chronic obstructive pulmonary disease (COPD) is a neutrophilic inflammatory disorder that is weakly responsive to glucocorticoids. Identification of ways to enhance the anti-inflammatory activity of glucocorticoids is, therefore, a major research objective. Adenosine receptor agonists that target the A2B-receptor subtype are efficacious in several cell-based assays and preclinical models of inflammation. Accordingly, the present study was designed to determine if a selective A2B-receptor agonist, 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulphanyl]acetamide (Bay 60-6583), and a glucocorticoid, dexamethasone, in combination display putative anti-inflammatory activity that is superior to either drug alone. In BEAS-2B human airway epithelial cells stably transfected with cAMP-response element (CRE) and glucocorticoid response element (GRE) reporter constructs, Bay 60-6583 promoted CRE-dependent transcription and enhanced GRE-dependent transcription by an adenosine A2B-receptor-mediated mechanism that was associated with cAMP formation and abolished by an inhibitor of cAMP-dependent protein kinase. Analysis of the concentration-response relationship that described the enhancement of GRE-dependent transcription showed that Bay 60-6583 increased the magnitude of response without affecting the potency of dexamethasone. Bay 60-6583 and dexamethasone also induced a panel of genes that, collectively, could have benefit in COPD. These were categorized into genes that were induced in a positive cooperative manner (RGS2, p57(kip2)), an additive manner (TTP, BRL-1), or by Bay 60-6583 (CD200, CRISPLD2, SOCS3) or dexamethasone (GILZ) only. Thus, the gene induction "fingerprints" produced by Bay 60-6583 and dexamethasone, alone and in combination, were distinct. Collectively, through their actions on gene expression, an adenosine A2B-receptor agonist and a glucocorticoid administered together may have utility in the treatment of inflammatory disorders that respond suboptimally to glucocorticoids as a monotherapy.
慢性阻塞性肺疾病（COPD）是一种中性粒细胞炎症性疾病，对糖皮质激素的反应较弱。因此，寻找增强糖皮质激素抗炎活性的方法是一个主要的研究目标。靶向 A2B-受体亚型的腺苷受体激动剂在几种基于细胞的测定和炎症的临床前模型中是有效的。因此，本研究旨在确定一种选择性 A2B-受体激动剂，2-[6-氨基-3,5-二氰基-4-[4-（环丙基甲氧基）苯基]吡啶-2-基硫基]乙酰胺（Bay 60-6583），以及一种糖皮质激素，地塞米松，联合使用是否具有优于单独使用任何一种药物的潜在抗炎活性。在稳定转染 cAMP 反应元件（CRE）和糖皮质激素反应元件（GRE）报告构建体的 BEAS-2B 人气道上皮细胞中，Bay 60-6583 通过一种与 cAMP 形成相关的、由腺苷 A2B-受体介导的机制促进 CRE 依赖性转录，并增强 GRE 依赖性转录，该机制被 cAMP 依赖性蛋白激酶抑制剂所阻断。对描述增强 GRE 依赖性转录的浓度-反应关系的分析表明，Bay 60-6583 增加了反应的幅度，而不影响地塞米松的效力。Bay 60-6583 和地塞米松还诱导了一组基因，这些基因在 COPD 中可能具有益处。这些基因被归类为以正协同方式（RGS2、p57（kip2））、加性方式（TTP、BRL-1）或仅由 Bay 60-6583（CD200、CRISPLD2、SOCS3）或地塞米松（GILZ）诱导的基因。因此，Bay 60-6583 和地塞米松单独和联合使用产生的基因诱导“指纹”是不同的。总的来说，通过对基因表达的作用，一种腺苷 A2B-受体激动剂和一种糖皮质激素联合使用可能在治疗对糖皮质激素作为单一疗法反应不佳的炎症性疾病方面具有应用价值。
