Adcock Ian M, Ito Kazuhiro, Barnes Peter J
National Heart and Lung Institute, Imperial College London, UK.
COPD. 2005 Dec;2(4):445-55. doi: 10.1080/15412550500346683.
Inflammatory lung diseases are characterised by increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors, such as NF-kappaB. Gene expression is regulated by modifications such as acetylation of core histones through the concerted action of coactivators such as CBP (cAMP-response element binding protein (CREB)-binding protein) which have intrinsic histone acetyltransferase (HAT) activity and are able to recruit other HAT enzymes. Conversely gene repression is mediated via histone deacetylases (HDAC) and other corepressors. In biopsies from asthmatic subjects there is an increase in HAT activity and some reduction in HDAC activity. Both of these changes are partially reversed by corticosteroid therapy. Corticosteroids switch off inflammatory genes in asthma through a combination of a direct inhibition of HAT activity and by the recruitment of HDAC2 to the activated NF-kappaB-stimulated inflammatory gene complex. In chronic obstructive pulmonary disease (COPD), a corticosteroid insensitive disease, there is a reduction in HDAC activity and HDAC2 expression, which may account for the amplified inflammation and resistance to the actions of corticosteroids. The reduction in HDAC2 may be secondary to oxidative and nitrative stress as a result of cigarette smoking and severe inflammation. This may also occur to differing degrees in severe asthma, smoking asthmatic patients and cystic fibrosis. Similar mechanisms may also account for the steroid resistance seen within latent adenovirus infections. The reduction in HDAC activity induced by oxidative stress can be restored by theophylline, acting through specific kinases, which may be able to reverse steroid resistance in COPD and other inflammatory lung diseases. The modulation of HAT/HDAC activity may lead to the development of novel anti-inflammatory approaches to inflammatory lung diseases that are currently difficult to treat.
炎症性肺病的特征是多种炎症基因表达增加，这些基因受促炎转录因子如核因子κB（NF-κB）调控。基因表达通过诸如核心组蛋白乙酰化等修饰来调节，这是通过具有内在组蛋白乙酰转移酶（HAT）活性且能够募集其他HAT酶的共激活因子如CBP（环磷酸腺苷反应元件结合蛋白（CREB）结合蛋白）的协同作用实现的。相反，基因抑制是通过组蛋白脱乙酰酶（HDAC）和其他共抑制因子介导的。在哮喘患者的活检组织中，HAT活性增加，HDAC活性有所降低。这两种变化在皮质类固醇治疗后都有部分逆转。皮质类固醇通过直接抑制HAT活性以及将HDAC2募集到活化的NF-κB刺激的炎症基因复合物中，从而关闭哮喘中的炎症基因。在慢性阻塞性肺疾病（COPD）这种对皮质类固醇不敏感的疾病中，HDAC活性和HDAC2表达降低，这可能解释了炎症放大以及对皮质类固醇作用产生抗性的原因。HDAC2的减少可能继发于吸烟和严重炎症导致的氧化应激和硝化应激。在严重哮喘、吸烟的哮喘患者和囊性纤维化中也可能不同程度地出现这种情况。类似的机制也可能解释潜伏性腺病毒感染中出现的类固醇抗性。氧化应激诱导的HDAC活性降低可通过茶碱作用于特定激酶来恢复，这可能能够逆转COPD和其他炎症性肺病中的类固醇抗性。对HAT/HDAC活性的调节可能会导致开发出针对目前难以治疗的炎症性肺病的新型抗炎方法。
