National Heart and Lung Institute, Imperial College, London, United Kingdom.
J Allergy Clin Immunol. 2013 Mar;131(3):636-45. doi: 10.1016/j.jaci.2012.12.1564. Epub 2013 Jan 26.
Reduced responsiveness to the anti-inflammatory effects of corticosteroids is a major barrier to effective management of asthma in smokers and patients with severe asthma and in the majority of patients with chronic obstructive pulmonary disease (COPD). The molecular mechanisms leading to steroid resistance are now better understood, and this has identified new targets for therapy. In patients with severe asthma, several molecular mechanisms have been identified that might account for reduced steroid responsiveness, including reduced nuclear translocation of glucocorticoid receptor (GR) α after binding corticosteroids. This might be due to modification of the GR by means of phosphorylation as a result of activation of several kinases (p38 mitogen-activated protein kinase α, p38 mitogen-activated protein kinase γ, and c-Jun N-terminal kinase 1), which in turn might be due to reduced activity and expression of phosphatases, such as mitogen-activated protein kinase phosphatase 1 and protein phosphatase A2. Other mechanisms proposed include increased expression of GRβ, which competes with and thus inhibits activated GRα; increased secretion of macrophage migration inhibitory factor; competition with the transcription factor activator protein 1; and reduced expression of histone deacetylase (HDAC) 2. HDAC2 appears to mediate the action of steroids to switch off activated inflammatory genes, but in patients with COPD, patients with severe asthma, and smokers with asthma, HDAC2 activity and expression are reduced by oxidative stress through activation of phosphoinositide 3-kinase δ. Strategies for managing steroid resistance include alternative anti-inflammatory drugs, but a novel approach is to reverse steroid resistance by increasing HDAC2 expression, which can be achieved with theophylline and phosphoinositide 3-kinase δ inhibitors. Long-acting β2-agonists can also increase steroid responsiveness by reversing GRα phosphorylation. Identifying the molecular mechanisms of steroid resistance in asthmatic patients and patients with COPD can thus lead to more effective anti-inflammatory treatments.
糖皮质激素抗炎作用反应降低是有效治疗吸烟者哮喘、严重哮喘和大多数慢性阻塞性肺疾病（COPD）患者哮喘的主要障碍。导致类固醇耐药的分子机制现在已得到更好的理解，这为治疗确定了新的靶点。在严重哮喘患者中，已经确定了几种可能导致类固醇反应性降低的分子机制，包括糖皮质激素受体（GR）α结合皮质类固醇后核转位减少。这可能是由于几种激酶（p38 丝裂原活化蛋白激酶α、p38 丝裂原活化蛋白激酶γ和 c-Jun N 端激酶 1）的激活导致 GR 的磷酸化修饰所致，而这些激酶的激活又可能是由于磷酸酶（如丝裂原活化蛋白激酶磷酸酶 1 和蛋白磷酸酶 A2）活性和表达降低所致。其他提出的机制包括 GRβ表达增加，其与激活的 GRα竞争并因此抑制其功能；巨噬细胞迁移抑制因子分泌增加；与转录因子激活蛋白 1 竞争；和组蛋白去乙酰化酶（HDAC）2 表达减少。HDAC2 似乎介导类固醇作用以关闭激活的炎症基因，但在 COPD 患者、严重哮喘患者和哮喘吸烟者中，HDAC2 活性和表达通过磷酸肌醇 3-激酶 δ的激活而被氧化应激降低。管理类固醇耐药的策略包括替代抗炎药物，但一种新方法是通过增加 HDAC2 表达来逆转类固醇耐药，茶碱和磷酸肌醇 3-激酶 δ 抑制剂可以实现这一点。长效β2-激动剂也可以通过逆转 GRα 磷酸化来增加类固醇反应性。因此，鉴定哮喘患者和 COPD 患者中类固醇耐药的分子机制可以导致更有效的抗炎治疗。
