Adcock Ian M, Caramori Gaetano, Ito Kazuhiro
Cell & Molecular Biology, Airways Disease Section, National Heart & Lung Institute, Imperial College London, UK.
Curr Drug Targets. 2006 Jun;7(6):649-60. doi: 10.2174/138945006777435344.
Corticosteroids produce a marked improvement in clinical parameters in most asthmatic patients; in contrast, corticosteroids have little effect on lung function measurements in patients with chronic obstructive pulmonary disease. By uncovering the reason for this paradox, it should be possible to implement treatment regimens that restore corticosteroid sensitivity. Corticosteroids exert their effects by binding to a cytoplasmic receptor, which is subjected to post-translational modifications. Receptor phosphorylation may influence hormone binding and nuclear translocation, alter glucocorticoid receptor interactions and protein half-life. Other modifications such as nitration/nitrosylation may also affect glucocorticoid receptor function. Oxidative stress due to cigarette smoke may be a mechanism for the corticosteroid resistance observed in chronic obstructive pulmonary disease, as it enhances proinflammatory transcription and reduces glucocorticoid receptor-associated repressor functions. Therapies targeting these aspects of the glucocorticoid receptor activation pathway may reverse steroid resistance in patients with chronic obstructive pulmonary disease.
皮质类固醇能使大多数哮喘患者的临床参数显著改善；相比之下，皮质类固醇对慢性阻塞性肺疾病患者的肺功能测量几乎没有影响。通过揭示这一矛盾现象的原因，应该有可能实施恢复皮质类固醇敏感性的治疗方案。皮质类固醇通过与细胞质受体结合发挥作用，该受体经历翻译后修饰。受体磷酸化可能影响激素结合和核转位，改变糖皮质激素受体相互作用和蛋白质半衰期。其他修饰如硝化/亚硝化也可能影响糖皮质激素受体功能。香烟烟雾引起的氧化应激可能是慢性阻塞性肺疾病中观察到的皮质类固醇抵抗的一种机制，因为它增强促炎转录并降低糖皮质激素受体相关的抑制功能。针对糖皮质激素受体激活途径这些方面的治疗可能会逆转慢性阻塞性肺疾病患者的类固醇抵抗。
