Critical Care Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
Department of Pharmacology, Reno School of Medicine, University of Nevada, Reno, NV, USA.
Adv Exp Med Biol. 2021;1303:89-105. doi: 10.1007/978-3-030-63046-1_6.
Asthma is a chronic inflammatory obstructive lung disease that is stratified into endotypes. Th2 high asthma is due to an imbalance of Th1/Th2 signaling leading to abnormally high levels of Th2 cytokines, IL-4, IL-5, and IL-13 and in some cases a reduction in type I interferons. Some asthmatics express Th2 low, Th1/Th17 high phenotypes with or without eosinophilia. Most asthmatics with Th2 high phenotype respond to beta-adrenergic agonists, muscarinic antagonists, and inhaled corticosteroids. However, 5-10% of asthmatics are not well controlled by these therapies despite significant advances in lung immunology and the pathogenesis of severe asthma. This problem is being addressed by developing novel classes of anti-inflammatory agents. Numerous studies have established efficacy of targeting pro-inflammatory microRNAs in mouse models of mild/moderate and severe asthma. Current approaches employ microRNA mimics and antagonists designed for use in vivo. Chemically modified oligonucleotides have enhanced stability in blood, increased cell permeability, and optimized target specificity. Delivery to lung tissue limits clinical applications, but it is a tractable problem. Future studies need to define the most effective microRNA targets and effective delivery systems. Successful oligonucleotide drug candidates must have adequate lung cell uptake, high target specificity, and efficacy with tolerable off-target effects.
哮喘是一种慢性炎症性阻塞性肺疾病，可分为表型。Th2 高型哮喘是由于 Th1/Th2 信号失衡导致 Th2 细胞因子（IL-4、IL-5 和 IL-13）水平异常升高，在某些情况下，I 型干扰素减少。一些哮喘患者表现出 Th2 低、Th1/Th17 高表型，伴有或不伴有嗜酸性粒细胞增多。大多数 Th2 高表型的哮喘患者对β-肾上腺素能激动剂、毒蕈碱拮抗剂和吸入性皮质类固醇反应良好。然而，尽管在肺免疫学和严重哮喘的发病机制方面取得了显著进展，仍有 5-10%的哮喘患者对这些治疗方法反应不佳。这个问题正在通过开发新型抗炎药物来解决。许多研究已经在轻度/中度和重度哮喘的小鼠模型中证实了靶向促炎 microRNA 的疗效。目前的方法采用了体内使用的 microRNA 模拟物和拮抗剂。经过化学修饰的寡核苷酸在血液中的稳定性增强，细胞通透性增加，目标特异性优化。向肺部组织的递送至临床应用带来了限制，但这是一个可以解决的问题。未来的研究需要确定最有效的 microRNA 靶点和有效的递送系统。成功的寡核苷酸候选药物必须具有足够的肺细胞摄取、高靶特异性和疗效，同时具有可耐受的脱靶效应。
