Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, New South Wales 2007, Australia.
Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, New South Wales 2308, Australia.
Sci Transl Med. 2021 Nov 24;13(621):eaav7223. doi: 10.1126/scitranslmed.aav7223.
Chronic obstructive pulmonary disease (COPD) is the third leading cause of morbidity and death worldwide. Inhalation of cigarette smoke (CS) is the major cause in developed countries. Current therapies have limited efficacy in controlling disease or halting its progression. Aberrant expression of microRNAs (miRNAs) is associated with lung disease, including COPD. We performed miRNA microarray analyses of the lungs of mice with CS-induced experimental COPD. miR-21 was the second highest up-regulated miRNA, particularly in airway epithelium and lung macrophages. Its expression in human lung tissue correlated with reduced lung function in COPD. Prophylactic and therapeutic treatment with a specific miR-21 inhibitor (Ant-21) inhibited CS-induced lung miR-21 expression in mice; suppressed airway macrophages, neutrophils, and lymphocytes; and improved lung function, as evidenced by decreased lung hysteresis, transpulmonary resistance, and tissue damping in mouse models of COPD. In silico analyses identified a potential miR-21/special AT-rich sequence–binding protein 1 (SATB1)/S100 calcium binding protein A9 (S100A9)/nuclear factor κB (NF-κB) axis, which was further investigated. CS exposure reduced lung SATB1 in a mouse model of COPD, whereas Ant-21 treatment restored SATB1 and reduced S100A9 expression and NF-κB activity. The beneficial effects of Ant-21 in mice were reversed by treatment with SATB1-targeting small interfering RNA. We have identified a pathogenic role for a miR-21/SATB1/S100A9/NF-κB axis in COPD and defined miR-21 as a therapeutic target for this disease.
慢性阻塞性肺疾病（COPD）是全球发病率和死亡率的第三大原因。在发达国家，吸入香烟烟雾（CS）是主要原因。目前的治疗方法在控制疾病或阻止其进展方面效果有限。异常表达的 microRNAs（miRNAs）与肺部疾病有关，包括 COPD。我们对 CS 诱导的实验性 COPD 小鼠的肺部进行了 miRNA 微阵列分析。miR-21 是上调第二高的 miRNA，特别是在气道上皮细胞和肺巨噬细胞中。其在人类肺组织中的表达与 COPD 患者肺功能下降有关。用特异性 miR-21 抑制剂（Ant-21）进行预防和治疗可抑制 CS 诱导的小鼠肺部 miR-21 表达；抑制气道巨噬细胞、中性粒细胞和淋巴细胞；并改善肺功能，如 COPD 小鼠模型中肺滞后、跨肺阻力和组织衰减的降低所证明的那样。计算机分析鉴定出一个潜在的 miR-21/特殊 AT 富含序列结合蛋白 1（SATB1）/S100 钙结合蛋白 A9（S100A9）/核因子 κB（NF-κB）轴，并进一步进行了研究。在 COPD 的小鼠模型中，CS 暴露降低了肺部 SATB1，而 Ant-21 治疗则恢复了 SATB1 并降低了 S100A9 的表达和 NF-κB 活性。用 SATB1 靶向的小干扰 RNA 处理可逆转 Ant-21 在小鼠中的有益作用。我们已经确定了 miR-21/SATB1/S100A9/NF-κB 轴在 COPD 中的致病作用，并将 miR-21 定义为该疾病的治疗靶点。
