克服气道疾病治疗过程中的激素无应答性
2009/09/17
常规治疗方法能成功治疗大多数哮喘患者。但仍然有小部分哮喘患者对糖皮质激素，甚至大剂量糖皮质激素或辅助治疗无应答。此外，大剂量糖皮质激素对慢性阻塞性肺疾病（COPD）患者肺功能下降的治疗作用有限，且对于减少疾病的恶化的疗效甚微。因此，糖皮质激素治疗的无应答性已成为气道疾病治疗的一个难题。糖皮质激素通过胞浆受体（GR）发挥作用，GR被糖皮质激素活化后转位至细胞核内，一旦进入细胞核，糖皮质激素可与DNA结合调节抗炎症基因的表达，也可抑制不同信号通路，如NF-κB（核因子κB）、AP-1（激活蛋白-1）及MAPKs（丝裂原活化蛋白激酶）的活性。后面一步需要辅助抑制因子分子的参与。对糖皮质激素应答失败可能是由于糖皮质激素GR结合不足、GR表达下降、辅助抑制因子的活性不足或炎症信号传导通路活化增加等有关。这些事件可由氧化应激或高水平的炎症细胞因子调节，最终导致临床预后不理想。
对GR活化、失活分子机制的了解能促使研究者开发出新的抗炎药物，逆转上述疾病中的糖皮质激素不敏感性。
（陈欣 审校）
Adcock IM, Chou PC, Durham A, et al.
Biochem Soc Trans. 2009 Aug;37(Pt 4):824-9.
Overcoming steroid unresponsiveness in airways disease
Airways Disease Section, National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK. ian.adcock@imperial.ac.uk
Most of the patients with asthma are found to be successfully treated with conventional therapy. However, there are a small proportion of asthmatic patients who fail to respond to corticosteroids even at high doses or with supplementary therapy. In addition, even high doses of corticosteroids have a minimal effect on the inexorable decline in lung function in COPD (chronic obstructive pulmonary disease) and only a small effect in reducing exacerbations. Corticosteroid-insensitivity therefore presents a profound management problem. Corticosteroids act through a cytosolic receptor [GR (glucocorticoid receptor)], which is activated and translocates to the nucleus. Once in the nucleus, it either binds to DNA and switches on the expression of anti-inflammatory genes or represses the activity of distinct signalling pathways such as NF-kappaB (nuclear factor kappaB), AP-1 (activator protein-1) or MAPKs (mitogen-activated protein kinases). This latter step requires the recruitment of co-repressor molecules. A failure to respond to corticosteroids may therefore result from lack of binding to GR, reduced GR expression, lack of co-repressor activity or enhanced activation of inflammatory pathways. These events can be modulated by oxidative stress or high levels of inflammatory cytokines, which may lead to a reduced clinical outcome. Understanding the molecular mechanisms of GR action, and inaction, may lead to the development of new anti-inflammatory drugs or reverse the relative corticosteroid-insensitivity that is characteristic of these diseases.
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