Roth M, Black J L
Pneumology, Pulmonary Cell Research, University Hospital Basel, Petersgraben 4, CH-4031 Basel Switzerland.
Curr Drug Targets. 2006 May;7(5):589-95. doi: 10.2174/138945006776818638.
The essential features of persistent severe asthma include structural changes in the airway wall (remodelling). It is not known whether these are the sequelae of chronic inflammation or indeed its initiators. Several transcription factors have been implicated in the inflammatory process in asthma, including the glucocorticoid receptor (GR), NFkappaB, Activator Protein-1 (AP-1), Nuclear Factor of Activated T-cells (NF-AT), cyclic AMP Response Element Binding Protein and more recently, the CCAAT/Enhancer Binding Protein (C/EBP), Peroxisome Proliferator-activated Receptor (PPAR) and the bZIP transcription factor, Nrf2. Could a pathological de-regulation of one of these transcription factors explain the broad spectrum of asthma pathology and can their modulation lead to better symptom control? Although some of the transcription factors seem to be valid targets (NFkappaB, Nrf2 or STAT6) or tools (PPARgamma, -alpha and C/EBP-alpha) for new therapeutic approaches, since many transcription factors play a central role in tissue and organ homeostasis, a longterm general suppression or overexpression, would cause severe side effects in other organs. Cell type specific application of decoy or antisense oligonucleotides for NFkappaB, Nrf2 or STAT6, or specific agonists for PPARgamma and -alpha may help to control the inflammatory response in lung epithelial cells and infiltrated immune cells, but additional, unwanted, effects on other resident cells of the lung cannot be excluded and a beneficial effect over known anti-asthma drugs has first to be proven. In order to progress with such novel therapeutic strategies, the only option seems to be to link transcription factor inhibitors/activators to a cell type specific delivery system.
持续性重度哮喘的基本特征包括气道壁结构改变（重塑）。目前尚不清楚这些改变是慢性炎症的后遗症还是其引发因素。几种转录因子与哮喘的炎症过程有关，包括糖皮质激素受体（GR）、核因子κB（NFκB）、活化蛋白-1（AP-1）、活化T细胞核因子（NF-AT）、环磷酸腺苷反应元件结合蛋白，以及最近发现的CCAAT/增强子结合蛋白（C/EBP）、过氧化物酶体增殖物激活受体（PPAR）和碱性亮氨酸拉链转录因子Nrf2。这些转录因子之一的病理性失调能否解释哮喘病理的广泛范围，对它们的调节能否带来更好的症状控制？尽管某些转录因子似乎是新治疗方法的有效靶点（NFκB、Nrf2或信号转导和转录激活因子6（STAT6））或工具（PPARγ、-α和C/EBP-α），但由于许多转录因子在组织和器官稳态中起核心作用，长期的普遍抑制或过表达会在其他器官中引起严重的副作用。针对NFκB、Nrf2或STAT6的细胞类型特异性应用诱饵或反义寡核苷酸，或针对PPARγ和-α的特异性激动剂，可能有助于控制肺上皮细胞和浸润免疫细胞中的炎症反应，但不能排除对肺中其他驻留细胞产生额外的不良影响，且必须首先证明其比已知的抗哮喘药物具有更好的疗效。为了推进此类新型治疗策略，唯一的选择似乎是将转录因子抑制剂/激活剂与细胞类型特异性递送系统相结合。
