Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Pharmacol Res. 2020 Oct;160:105045. doi: 10.1016/j.phrs.2020.105045. Epub 2020 Jun 23.
MicroRNAs (miRNAs) are short single-stranded RNAs that have pivotal roles in disease pathophysiology through transcriptional and translational modulation of important genes. It has been implicated in the development of many diseases, such as stroke, cardiovascular conditions, cancers and inflammatory airway diseases. There is recent evidence that miRNAs play important roles in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD), and could help to distinguish between T2-low (non-eosinophilic, steroid-insensitive) versus T2-high (eosinophilic, steroid-sensitive) disease endotypes. As these are the two most prevalent chronic respiratory diseases globally, with rising disease burden, miRNA research might lead to the development of new diagnostic and therapeutic targets. Research involving miRNAs in airway disease is challenging because: (i) asthma and COPD are heterogeneous inflammatory airway diseases; there are overlapping but distinct inter- and intra-disease differences in the immunological pathophysiology, (ii) there exists more than 2000 known miRNAs and a single miRNA can regulate multiple targets, (iii) differential effects of miRNAs could be present in different cellular subtypes and tissues, and (iv) dysregulated miRNA expression might be a direct consequence of an indirect effect of airway disease onset or progression. As miRNAs are actively secreted in fluids and remain relatively stable, they have the potential for biomarker development and therapeutic targets. In this review, we summarize the preclinical data on potential miRNA biomarkers that mediate different pathophysiological mechanisms in airway disease. We discuss the framework for biomarker development using miRNA and highlight the need for careful patient characterization and endotyping in the screening and validation cohorts, profiling both airway and blood samples to determine the biological fluids of choice in different disease states or severity, and adopting an untargeted approach. Collaboration between the various stakeholders - pharmaceutical companies, laboratory professionals and clinician-scientists is crucial to reduce the difficulties and cost required to bring miRNA research into the translational stage for airway diseases.
MicroRNAs (miRNAs) 是短的单链 RNA，通过转录和翻译调节重要基因在疾病病理生理学中起关键作用。它与许多疾病的发展有关，如中风、心血管疾病、癌症和炎症性气道疾病。最近有证据表明，miRNAs 在哮喘和慢性阻塞性肺疾病 (COPD) 的发病机制中发挥重要作用，并有助于区分 T2 低（非嗜酸性粒细胞，类固醇不敏感）与 T2 高（嗜酸性粒细胞，类固醇敏感）疾病表型。由于这两种疾病是全球最常见的慢性呼吸道疾病，且疾病负担不断增加，miRNA 研究可能会导致新的诊断和治疗靶点的开发。涉及气道疾病的 miRNA 研究具有挑战性，原因如下：（i）哮喘和 COPD 是异质性炎症性气道疾病；免疫病理生理学在不同的疾病之间和之内存在重叠但不同的差异，（ii）已知有超过 2000 种 miRNA，单个 miRNA 可以调节多个靶标，（iii）miRNA 的差异效应可能存在于不同的细胞亚型和组织中，以及（iv）miRNA 表达的失调可能是气道疾病发作或进展的间接影响的直接后果。由于 miRNA 可以在体液中主动分泌且相对稳定，因此它们具有开发生物标志物和治疗靶点的潜力。在这篇综述中，我们总结了潜在 miRNA 生物标志物在气道疾病不同病理生理机制中的临床前数据。我们讨论了使用 miRNA 开发生物标志物的框架，并强调了在筛选和验证队列中需要仔细对患者进行特征描述和表型分类，对气道和血液样本进行分析以确定不同疾病状态或严重程度下的首选生物体液，并采用非靶向方法。制药公司、实验室专业人员和临床科学家之间的合作对于减少将 miRNA 研究转化为气道疾病的转化阶段所需的困难和成本至关重要。
