Targeting inducible epigenetic reprogramming pathways in chronic airway remodeling.
Targeting inducible epigenetic reprogramming pathways in chronic airway remodeling.
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DOI：
10.7573/dic.2019-8-3
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发表时间：
2019-01-01
期刊：
影响因子：
--
通讯作者：
Boldogh, Istvan
中科院分区：
文献类型：
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作者：
Brasier, Allan R;Boldogh, Istvan
过敏性哮喘是一种慢性炎症性气道疾病，其临床过程被空气过敏原暴露或呼吸道病毒感染引起的急性加重所打断。空气过敏原和呼吸道病毒刺激Toll样受体（TLR）信号传导，产生氧化损伤和炎症。反复加重产生复杂的粘膜适应、细胞状态改变和结构重塑。这些结构性变化会导致严重的发病率，降低肺活量，并损害生活质量。我们将回顾最近的系统水平研究，这些研究为先天信号通路的重复激活如何产生表观遗传“训练”以诱导适应性上皮反应提供了基本的新见解。TLR信号传导下游产生的氧化应激诱导炎症基因调控区中鸟嘌呤碱基的瞬时氧化。表观遗传标记8-oxoG与多效性DNA修复酶8-oxoguanine DNA糖基化酶（OGG 1）结合，OGG 1诱导邻近DNA的构象变化以募集NF κ B·含溴结构域蛋白4（BRD 4）复合物。NF κ B·BRD 4复合物不仅在炎症中起核心作用，而且还触发间质转化和细胞外基质重塑。已经开发了OGG 1 -8-oxoG结合和BRD 4-乙酰化组蛋白相互作用的小分子抑制剂。我们目前的研究表明这些在临床前模型中减少气道炎症的功效。靶向诱导型表观遗传重编程途径显示了逆转多种慢性气道疾病气道重塑的治疗前景。
Allergic asthma is a chronic inflammatory airway disease whose clinical course is punctuated by acute exacerbations from aeroallergen exposure or respiratory virus infections. Aeroallergens and respiratory viruses stimulate toll-like receptor (TLR) signaling, producing oxidative injury and inflammation. Repetitive exacerbations produce complex mucosal adaptations, cell-state changes, and structural remodeling. These structural changes produce substantial morbidity, decrease lung capacity, and impair quality of life. We will review recent systems-level studies that provide fundamental new insights into how repetitive activation of innate signaling pathways produce epigenetic 'training' to induce adaptive epithelial responses. Oxidative stress produced downstream of TLR signaling induces transient oxidation of guanine bases in the regulatory regions of inflammatory genes. The epigenetic mark 8-oxoG is bound by a pleiotropic DNA repair enzyme, 8-oxoguanine DNA glycosylase (OGG1), which induces conformational changes in adjacent DNA to recruit the NFkappaB·bromodomain-containing protein 4 (BRD4) complex. The NFkappaB·BRD4 complex not only plays a central role in inflammation, but also triggers mesenchymal transition and extracellular matrix remodeling. Small molecule inhibitors of OGG1-8-oxoG binding and BRD4-acetylated histone interaction have been developed. We present studies demonstrating efficacy of these in reducing airway inflammation in preclinical models. Targeting inducible epigenetic reprogramming pathway shows promise for therapeutics in reversing airway remodeling in a variety of chronic airway diseases.