Armstrong David A, Nymon Amanda B, Ringelberg Carol S, Lesseur Corina, Hazlett Haley F, Howard Louisa, Marsit Carmen J, Ashare Alix
Pulmonary and Critical Care Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH USA.
Geisel School of Medicine at Dartmouth, Hanover, NH USA.
Clin Epigenetics. 2017 May 30;9:56. doi: 10.1186/s13148-017-0355-1. eCollection 2017.
Numerous pulmonary diseases manifest with upper lobe predominance including cystic fibrosis, smoking-related chronic obstructive pulmonary disease, and tuberculosis. Zonal hypoxia, characteristic of these pulmonary maladies, and oxygen stress in general is known to exert profound effects on various important aspects of cell biology. Lung macrophages are major participants in the pulmonary innate immune response and regional differences in macrophage responsiveness to hypoxia may contribute in the development of lung disease. MicroRNAs are ubiquitous regulators of human biology and emerging evidence indicates altered microRNA expression modulates respiratory disease processes. The objective of this study is to gain insight into the epigenetic and cellular mechanisms influencing regional differences in lung disease by investigating effect of hypoxia on regional microRNA expression in the lung. All studies were performed using primary alveolar macrophages ( = 10) or bronchoalveolar lavage fluid ( = 16) isolated from human subjects. MicroRNA was assayed via the NanoString nCounter microRNA assay.
Divergent molecular patterns of microRNA expression were observed in alternate lung lobes, specifically noted was disparate expression of miR-93 and miR-4454 in alveolar macrophages along with altered expression of miR-451a and miR-663a in bronchoalveolar lavage fluid. Gene ontology was used to identify potential downstream targets of divergent microRNAs. Targets include cytokines and matrix metalloproteinases, molecules that could have a significant impact on pulmonary inflammation and fibrosis.
Our findings show variant regional microRNA expression associated with hypoxia in alveolar macrophages and BAL fluid in the lung-upper vs lower lobe. Future studies should address whether these specific microRNAs may act intracellularly, in a paracrine/endocrine manner to direct the innate immune response or may ultimately be involved in pulmonary host-to-pathogen trans-kingdom cross-talk.
许多肺部疾病以上叶为主,包括囊性纤维化、吸烟相关的慢性阻塞性肺疾病和肺结核。这些肺部疾病的特征性区域缺氧以及一般的氧应激对细胞生物学的各个重要方面都有深远影响。肺巨噬细胞是肺部固有免疫反应的主要参与者,巨噬细胞对缺氧反应的区域差异可能有助于肺部疾病的发展。微小RNA是人类生物学中普遍存在的调节因子,新出现的证据表明,微小RNA表达的改变会调节呼吸系统疾病的进程。本研究的目的是通过研究缺氧对肺区域微小RNA表达的影响,深入了解影响肺部疾病区域差异的表观遗传和细胞机制。所有研究均使用从人类受试者分离的原代肺泡巨噬细胞(n = 10)或支气管肺泡灌洗液(n = 16)进行。通过NanoString nCounter微小RNA检测法检测微小RNA。
在交替的肺叶中观察到微小RNA表达的不同分子模式,特别值得注意的是,肺泡巨噬细胞中miR-93和miR-4454的表达不同,同时支气管肺泡灌洗液中miR-451a和miR-663a的表达也发生了改变。基因本体论用于识别不同微小RNA的潜在下游靶点。靶点包括细胞因子和基质金属蛋白酶,这些分子可能对肺部炎症和纤维化有重大影响。
我们的研究结果表明,肺上叶与下叶的肺泡巨噬细胞和支气管肺泡灌洗液中,与缺氧相关的区域微小RNA表达存在差异。未来的研究应探讨这些特定的微小RNA是否可能在细胞内以旁分泌/内分泌方式发挥作用,以指导固有免疫反应,或者最终是否参与肺部宿主与病原体的跨王国相互作用。