Double-stranded RNA induces molecular and inflammatory signatures that are directly relevant to COPD.
Double-stranded RNA induces molecular and inflammatory signatures that are directly relevant to COPD.
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聚肌苷酸：聚胞苷酸（poly I：C）是双链（ds）RNA的合成类似物，这是一种与病毒感染相关的分子模式，用于加重肺损伤模型中的炎症。尽管它的频繁使用，有没有详细的研究引起的反应，由一个单一的局部给药的聚I：C小鼠的肺。我们的数据提供了第一个证明，在气道中的分子反应诱导的聚I：C相关的慢性阻塞性肺疾病（COPD）患者的肺中观察到的。这些表达数据还揭示了对poly I：C的反应的三个不同阶段，与气道中不断变化的炎性细胞浸润一致。Poly I：C诱导气道中嗜中性粒细胞和自然杀伤细胞数量增加，这分别被CXCR 2和CCR 5拮抗剂阻断。使用基因集变异分析的代表性的临床数据集，基因集定义的多聚I：C诱导的差异表达的基因富集在COPD的分子谱，但不是特发性肺纤维化患者。总的来说，这些数据代表了验证临床前动物模型临床相关性的新方法，并证明了CXCR 2/CCR 5双重拮抗剂可能是COPD患者的有效治疗方法。
Polyinosinic:polycytidylic acid (poly I:C) is a synthetic analogue of double-stranded (ds)RNA, a molecular pattern associated with viral infections, that is used to exacerbate inflammation in lung injury models. Despite its frequent use, there are no detailed studies of the responses elicited by a single topical administration of poly I:C to the lungs of mice. Our data provides the first demonstration that the molecular responses in the airways induced by poly I:C correlate to those observed in the lungs of chronic obstructive pulmonary disease (COPD) patients. These expression data also revealed three distinct phases of response to poly I:C, consistent with the changing inflammatory cell infiltrate in the airways. Poly I:C induced increased numbers of neutrophils and natural killer cells in the airways, which were blocked by CXCR2 and CCR5 antagonists, respectively. Using gene set variation analysis on representative clinical data sets, gene sets defined by poly I:C–induced differentially expressed genes were enriched in the molecular profiles of COPD but not idiopathic pulmonary fibrosis patients. Collectively, these data represent a new approach for validating the clinical relevance of preclinical animal models and demonstrate that a dual CXCR2/CCR5 antagonist may be an effective treatment for COPD patients.