Endocrine Sciences Research Group, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
Steroids. 2012 Sep;77(11):1041-9. doi: 10.1016/j.steroids.2012.05.007. Epub 2012 Jun 20.
Glucocorticoids (GCs) are the most potent anti-inflammatory agents known. A major factor limiting their clinical use is the wide variation in responsiveness to therapy. The high doses of GC required for less responsive patients means a high risk of developing very serious side effects. Variation in sensitivity between individuals can be due to a number of factors. Congenital, generalized GC resistance is very rare, and is due to mutations in the glucocorticoid receptor (GR) gene, the receptor that mediates the cellular effects of GC. A more common problem is acquired GC resistance. This localized, disease-associated GC resistance is a serious therapeutic concern and limits therapeutic response in patients with chronic inflammatory disease. It is now believed that localized resistance can be attributed to changes in the cellular microenvironment, as a consequence of chronic inflammation. Multiple factors have been identified, including alterations in both GR-dependent and -independent signaling downstream of cytokine action, oxidative stress, hypoxia and serum derived factors. The underlying mechanisms are now being elucidated, and are discussed here. Attempts to augment tissue GC sensitivity are predicted to permit safe and effective use of low-dose GC therapy in inflammatory disease.
糖皮质激素（GCs）是已知最有效的抗炎药物。限制其临床应用的一个主要因素是对治疗的反应存在广泛的差异。对于反应较差的患者，需要使用更高剂量的 GC，这意味着发生非常严重副作用的风险很高。个体之间敏感性的差异可能由多种因素引起。先天性、全身性 GC 抵抗非常罕见，是由于糖皮质激素受体（GR）基因的突变，该基因介导 GC 的细胞作用。更常见的问题是获得性 GC 抵抗。这种局部的、与疾病相关的 GC 抵抗是一个严重的治疗问题，限制了慢性炎症性疾病患者的治疗反应。现在人们认为，局部抵抗可以归因于慢性炎症导致的细胞微环境的变化。已经确定了多种因素，包括细胞因子作用下游的 GR 依赖性和非依赖性信号的改变、氧化应激、缺氧和血清来源的因素。目前正在阐明潜在的机制，并在此进行讨论。增加组织 GC 敏感性的尝试预计将允许在炎症性疾病中安全有效地使用低剂量 GC 治疗。
