Adcock Ian M, Ito Kazuhiro
Cell and Molecular Biology, Airways Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK.
Proc Am Thorac Soc. 2005;2(4):313-9; discussion 340-1. doi: 10.1513/pats.200504-035SR.
Lung function measures in patients with chronic obstructive pulmonary disease remain insensitive to corticosteroid actions, in contrast to the clinical improvements observed in most patients with asthma. By uncovering the reason for this paradox, physicians should be able to implement treatment regimens that restore corticosteroid sensitivity. Corticosteroids exert their effects by binding to a cytoplasmic glucocorticoid receptor, which is subjected to post-translational modification by phosphorylation. Receptor phosphorylation may influence hormone binding and nuclear translocation, as well as alter other glucocorticoid receptor interactions, its protein half-life, and downregulation processes. This suggests that a "phosphorylation code" may exist for glucocorticoid receptor function. Oxidative stress due to cigarette smoke may also be a mechanism for the corticosteroid resistance observed in chronic obstructive pulmonary disease, as it enhances proinflammatory transcription. Reduced glucocorticoid nuclear translocation along with attenuated histone deacetylase activity may be partially responsible for this effect. Therapies targeting these aspects of the glucocorticoid receptor activation pathway may reverse steroid resistance in patients with chronic obstructive pulmonary disease.
与大多数哮喘患者所观察到的临床改善情况不同，慢性阻塞性肺疾病患者的肺功能指标对皮质类固醇的作用仍不敏感。通过揭示这一矛盾现象的原因，医生应该能够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糖皮质激素受体结合发挥作用，该受体可通过磷酸化进行翻译后修饰。受体磷酸化可能影响激素结合和核转位，以及改变其他糖皮质激素受体相互作用、其蛋白质半衰期和下调过程。这表明可能存在一种糖皮质激素受体功能的“磷酸化密码”。香烟烟雾引起的氧化应激也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，因为它会增强促炎转录。糖皮质激素核转位减少以及组蛋白脱乙酰酶活性减弱可能部分导致了这种效应。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。
