Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease
Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease
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DOI：
10.1016/j.jaci.2012.12.1564
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发表时间：
2013-03-01
影响因子：
14.2
通讯作者：
Barnes, Peter J.
中科院分区：
文献类型：
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作者：
Barnes, Peter J.
对于吸烟者和患有严重哮喘的患者以及大多数慢性阻塞性肺疾病(COPD)患者，对皮质类固醇抗炎作用的反应性降低是有效治疗哮喘的主要障碍。现在对导致类固醇耐药的分子机制有了更好的了解，这为治疗确定了新的靶点。在严重哮喘患者中，已发现几种可能导致类固醇反应性降低的分子机制，包括结合皮质类固醇后糖皮质激素受体(GR)α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氨基末端激酶1)被激活而通过磷酸化修饰GR，这可能是由于磷酸酶的活性和表达降低所致，如丝裂原活化蛋白激酶磷酸酶1和蛋白磷酸酶A2。建议的其他机制包括GRβ的表达增加，GRβ与激活的GRα竞争，从而抑制激活的GRα；巨噬细胞移动抑制因子的分泌增加；与转录因子激活蛋白1竞争；以及组蛋白脱乙酰酶(HDAC)2的表达减少。HDAC2似乎介导了类固醇关闭激活的炎症基因的作用，但在COPD患者、严重哮喘患者和哮喘吸烟者中，HDAC2的活性和表达因氧化应激而通过激活磷脂酰肌醇3-激酶Delta而降低。治疗类固醇耐药的策略包括替代抗炎药，但一种新的方法是通过增加HDAC2的表达来逆转类固醇耐药，这可以通过茶碱和肌醇磷脂3-激酶增量抑制剂来实现。长效的β(2)激动剂也可以通过逆转GRα磷酸化来增加类固醇的反应性。因此，确定哮喘患者和COPD患者类固醇耐药的分子机制可以导致更有效的抗炎治疗。(《过敏与免疫杂志》2013；131：636-45。)
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) alpha 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 alpha, p38 mitogen-activated protein kinase gamma, 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 GR beta, which competes with and thus inhibits activated GR alpha; 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 delta. 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 delta inhibitors. Long-acting beta(2)-agonists can also increase steroid responsiveness by reversing GR alpha phosphorylation. Identifying the molecular mechanisms of steroid resistance in asthmatic patients and patients with COPD can thus lead to more effective anti-inflammatory treatments. (J Allergy Clin Immunol 2013;131:636-45.)