Joshi T, Johnson M, Newton R, Giembycz M
Airways Inflammation Research Group, Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
Br J Pharmacol. 2015 Mar;172(5):1360-78. doi: 10.1111/bph.13014. Epub 2015 Jan 8.
International asthma guidelines recommend that inhaled glucocorticoids be used as a monotherapy in all patients with mild to moderate disease because of their ability to suppress airways inflammation. Current evidence suggests that the therapeutic benefit of glucocorticoids is due to the transactivation and transrepression of anti-inflammatory and pro-inflammatory genes respectively. However, the extent to which clinically relevant glucocorticoids are equivalent in their ability to modulate gene expression is unclear.
A pharmacodynamics investigation of glucocorticoid receptor (GR)-mediated gene transactivation in BEAS-2B human airway epithelial cells was performed using a glucocorticoid response element luciferase reporter coupled with an analysis of glucocorticoid-inducible genes encoding proteins with anti-inflammatory and adverse-effect potential.
Using transactivation as a functionally relevant output, a given glucocorticoid displayed a unique, gene expression 'fingerprint' where intrinsic efficacy and GR density were essential determinants. We showed that depending on the gene selected for analysis, a given glucocorticoid can behave as an antagonist, partial agonist, full agonist or even 'super agonist'. In the likely event that different, tissue-dependent gene expression profiles are reproduced in vivo, then the anti-inflammatory and adverse-effect potential of many glucocorticoids currently available as asthma therapeutics may not be equivalent.
The generation of gene expression 'fingerprints' in target and off-target human tissues could assist the rational design of GR agonists with improved therapeutic ratios. This approach could identify compounds that are useful in the management of severe asthma and other inflammatory disorders where systemic exposure is desirable.
国际哮喘指南建议，对于所有轻至中度哮喘患者，吸入性糖皮质激素应作为单一疗法使用，因为其具有抑制气道炎症的能力。目前的证据表明，糖皮质激素的治疗益处分别归因于抗炎基因和促炎基因的反式激活和反式抑制。然而，临床上相关的糖皮质激素在调节基因表达能力方面的等效程度尚不清楚。
使用糖皮质激素反应元件荧光素酶报告基因，并结合对编码具有抗炎和潜在不良反应蛋白质的糖皮质激素诱导基因的分析，在BEAS-2B人呼吸道上皮细胞中进行了糖皮质激素受体（GR）介导的基因反式激活的药效学研究。
以反式激活作为功能相关的指标，特定的糖皮质激素表现出独特的基因表达“指纹”，其中内在效力和GR密度是关键决定因素。我们发现，根据所选分析的基因不同，特定的糖皮质激素可表现为拮抗剂、部分激动剂、完全激动剂甚至“超级激动剂”。如果在体内再现不同的、组织依赖性的基因表达谱，那么目前作为哮喘治疗药物的许多糖皮质激素的抗炎和潜在不良反应可能并不等效。
在靶组织和非靶组织中生成基因表达“指纹”有助于合理设计具有更高治疗指数的GR激动剂。这种方法可以识别出对严重哮喘和其他需要全身暴露的炎症性疾病治疗有用的化合物。
