Edwards Michael R, Bartlett Nathan W, Clarke Deborah, Birrell Mark, Belvisi Maria, Johnston Sebastian L
Department of Respiratory Medicine & Wright-Fleming Institute of Infection and Immunity, St Mary's Campus, National Heart Lung Institute Imperial College London, London UK.
Pharmacol Ther. 2009 Jan;121(1):1-13. doi: 10.1016/j.pharmthera.2008.09.003. Epub 2008 Oct 6.
Asthma and chronic obstructive pulmonary disease are inflammatory lung disorders responsible for significant morbidity and mortality worldwide. While the importance of allergic responses in asthma is well known, respiratory viral and bacterial infections and pollutants especially cigarette smoke are important factors in the pathogenesis of both diseases. Corticosteroid treatment remains the first preference of treatment in either disease, however these therapies are not always completely effective, and are associated with side effects and steroid resistance. Due to such limitations, development of new treatments represents a major goal for both the pharmaceutical industry and academic researchers. There are now excellent reasons to promote NF-kappaB signalling intermediates and Rel family proteins as potential therapeutic targets for both asthma and chronic obstructive pulmonary disease. This notion is supported by the fact that much of the underlying inflammation of both diseases independent of stimuli, is mediated at least in part, by NF-kappaB mediated signalling events in several cell types. Also, a range of inhibitors of NF-kappaB signalling intermediates are now available, including DNA oligonucleotides and DNA-peptide molecules that act as NF-kappaB decoy sequences, small molecule inhibitors such as IKK-beta inhibitors, and proteasome inhibitors affecting NF-kappaB signalling, that have either shown promise in animal models or have begun clinical trials in other disorders. This review will focus on the role of NF-kappaB in both diseases, will discuss its suitability as a target, and will highlight recent key studies that support the potential of NF-kappaB as a therapeutic target in these two important inflammatory lung diseases.
哮喘和慢性阻塞性肺疾病是肺部炎症性疾病，在全球范围内导致了显著的发病率和死亡率。虽然过敏反应在哮喘中的重要性已广为人知，但呼吸道病毒和细菌感染以及污染物（尤其是香烟烟雾）是这两种疾病发病机制中的重要因素。皮质类固醇治疗仍然是这两种疾病治疗的首选方法，然而这些疗法并不总是完全有效，并且会伴有副作用和类固醇抵抗。由于这些局限性，开发新的治疗方法是制药行业和学术研究人员的主要目标。现在有充分的理由将NF-κB信号转导中间体和Rel家族蛋白作为哮喘和慢性阻塞性肺疾病的潜在治疗靶点。这一观点得到以下事实的支持：这两种疾病中许多独立于刺激因素的潜在炎症至少部分是由几种细胞类型中NF-κB介导的信号事件介导的。此外，现在有一系列NF-κB信号转导中间体抑制剂，包括作为NF-κB诱饵序列的DNA寡核苷酸和DNA-肽分子、小分子抑制剂（如IKK-β抑制剂）以及影响NF-κB信号转导的蛋白酶体抑制剂，这些抑制剂在动物模型中已显示出前景或已在其他疾病中开始临床试验。本综述将重点关注NF-κB在这两种疾病中的作用，讨论其作为靶点的适用性，并突出最近支持NF-κB作为这两种重要肺部炎症性疾病治疗靶点潜力的关键研究。
