The pathogenesis of Chronic Obstructive Pulmonary Disease (COPD) involves activation of the DNA damage response (DDR). However, biologic mechanisms that regulate the DDR and contribute to COPD progression are poorly understood. Because microRNAs are important regulators of the DDR, we hypothesized that microRNA expression changes cause pathologic DDR activation in COPD. Therefore, we evaluated microRNA expression arrays performed on lung samples from 172 subjects and identified miR-24-3p as the microRNA best correlated with radiographic emphysema (rho=-0.353, P=1.3e-04). In a mouse model of cigarette smoke induced emphysema, miR-24-3p inhibition increased emphysema severity. In human airway epithelial cells, miR-24-3p suppressed apoptosis in part via the BH3-only protein BIM, and miR-24-3p suppressed homology-directed DNA repair and the DNA repair protein BRCA1. Finally, we found BIM and BRCA1 are increased in lung samples from subjects with COPD and inversely correlate with miR-24-3p expression. We concluded that downregulation of miR-24-3p increases COPD susceptibility by potentiating the DNA damage response through BIM and BRCA1.

中文翻译：

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miR-24-3p减少会增强DNA损伤反应并增加对COPD的敏感性

慢性阻塞性肺疾病（COPD）的发病机制涉及DNA损伤反应（DDR）的激活。但是，人们对调节DDR并促进COPD进展的生物学机制了解甚少。由于microRNA是DDR的重要调节因子，因此我们假设microRNA的表达变化会导致COPD中的病理性DDR激活。因此，我们评估了对来自172名受试者的肺样品进行的microRNA表达阵列，并将miR-24-3p确定为与放射气肿最相关的microRNA（rho = -0.353，P = 1.3e-04）。在香烟烟雾诱发的肺气肿的小鼠模型中，miR-24-3p抑制作用会增加肺气肿的严重程度。在人类呼吸道上皮细胞中，miR-24-3p部分通过仅BH3蛋白BIM抑制凋亡，miR-24-3p抑制同源性指导的DNA修复和DNA修复蛋白BRCA1。最后，我们发现患有COPD的受试者的肺样本中BIM和BRCA1升高，并且与miR-24-3p表达呈负相关。我们得出的结论是，miR-24-3p的下调通过增强BIM和BRCA1引起的DNA损伤反应而增加了COPD敏感性。