Although phosphodiesterase-4 (PDE4) inhibitors have been shown to reduce COPD exacerbation rate, their biological mechanism of action is not completely elucidated at the molecular level. We aimed to characterise the whole genome gene expression profile of the inhaled PDE4-inhibitor CHF6001 on top of triple therapy in sputum cells and whole blood of patients with COPD and chronic bronchitis. Whole genome gene expression analysis was carried out by microarray in 54 patients before and after 32 days treatment with CHF6001 800 and 1600 μg and placebo twice daily (BID) in a randomised crossover study. CHF6001 had a strong effect in sputum, with 1471 and 2598 significantly differentially-expressed probe-sets relative to placebo (p-adjusted for False Discovery Rate < 0.05) with 800 and 1600 μg BID, respectively. Functional enrichment analysis showed significant modulation of key inflammatory pathways involved in cytokine activity, pathogen-associated-pattern-recognition activity, oxidative stress and vitamin D with associated inhibition of downstream inflammatory effectors. A large number of pro-inflammatory genes coding for cytokines and matrix-metalloproteinases were significantly differentially expressed for both doses; the majority (> 87%) were downregulated, including macrophage inflammatory protein-1-alpha and 1-beta, interleukin-27-beta, interleukin-12-beta, interleukin-32, tumour necrosis factor-alpha-induced-protein-8, ligand-superfamily-member-15, and matrix-metalloproteinases-7,12 and 14. The effect in blood was not significant. Inhaled PDE4 inhibition by CHF6001 on top of triple therapy in patients with COPD and chronic bronchitis significantly modulated key inflammatory targets and pathways in the lung but not in blood. Mechanistically these findings support a targeted effect in the lung while minimising unwanted systemic class-effects. ClinicalTrial.gov, EudraCT, 2015–005550-35. Registered 15 July 2016.

中文翻译：

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在慢性支气管炎患者三联疗法的基础上，吸入PDE4抑制剂CHF6001的痰液和血液转录组学特征

尽管已显示磷酸二酯酶4（PDE4）抑制剂可降低COPD病情加重，但在分子水平上尚未完全阐明其生物学作用机理。我们旨在表征COPD和慢性支气管炎患者在痰细胞和全血中进行三联疗法后，吸入的PDE4抑制剂CHF6001的全基因组基因表达谱。在随机交叉研究中，对54名患者在用CHF6001 800和1600μg安慰剂治疗32天之前和之后每天进行两次全基因组基因表达分析，每天两次（BID）。CHF6001对痰液有很强的作用，相对于安慰剂（BID分别为800和1600μg的安慰剂，pF校正误发现率<0.05），1471和2598显着差异表达探针组。功能富集分析显示，涉及细胞因子活性，病原体相关模式识别活性，氧化应激和维生素D的关键炎性途径的显着调节，以及对下游炎性因子的抑制作用。两种剂量的大量编码细胞因子和基质金属蛋白酶的促炎基因均显着差异表达。大多数（> 87％）被下调，包括巨噬细胞炎性蛋白-1-alpha和1-beta，白介素27-beta，白介素12-beta，白介素32，肿瘤坏死因子-α诱导蛋白8 ，配体超家族成员15和基质金属蛋白酶7、12和14。在血液中的作用并不明显。在患有COPD和慢性支气管炎的患者进行三联疗法后，CHF6001吸入的PDE4抑制作用可显着调节肺部而非血液中的关键炎症靶点和通路。从机械上讲，这些发现支持对肺部的靶向作用，同时最大程度地减少了不必要的全身性类效应。ClinicalTrial.gov，EudraCT，2015–005550-35。2016年7月15日注册。