代谢标志物组群与慢阻肺急性加重全身激素疗效关系的研究

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) significantly increases the mortality of the patients with COPD. Guidelines have recommended systemic glucocorticoid as regular treatment. Recently, evidences have shown that systemic glucocorticoid cannot not be benefit to all of the patients with AECOPD. Thus the problem that how the clinicians can screen the patients who can benefit from systemic glucocorticoid needs to be solved urgently. A previous study found that plasma metabolome changed significantly after dexamethasone treatment in health participants. Furthermore, inter-person variability was high and remained uninfluenced by treatment, suggesting the potential of metabolomics for predicting the efficacy and side effects of systemic glucocorticoid. Our previous study found that serum metabolites profile in COPD patients differed from that in controls. Therefore, we hypothesized that metabolome changes in patients with AECOPD may be associated with the efficacy of systemic glucocorticoid. In this study, we will utilize ultraperformance liquid chromatography / mass spectrometry (LC-MS) and gas chromatography / mass spectrometry (GC-MS) methods for analysis of the metabolites in AECOPD patients and compare the metabolites profiles between patients with systemic glucocorticoid treatment success and treatment failure. We aim to detect the metabolic biomarkers and metabolic pathways which are related to efficacy of systemic glucocorticoid and contribute to the precise treatment of COPD.

慢性阻塞性肺疾病（慢阻肺）急性加重显著增加患者的病死率。现行指南推荐全身糖皮质激素（激素）作为慢阻肺急性加重的常规药物之一。近年来多个研究显示，全身激素治疗并不能使所有慢阻肺急性加重的患者获益，而如何预测哪些患者能从中获益，是临床中亟待解决的问题。国外研究发现，健康受试者在接受激素治疗后血浆代谢谱发生显著改变，且不同个体之间差异显著、不受治疗的影响，提示代谢组学有助于预测激素的反应和副作用。我们前期研究发现，慢阻肺患者的血清代谢标志物轮廓与对照组存在显著差异。因此，我们提出研究假说：慢阻肺急性加重期代谢标志物轮廓的个体差异可能与全身激素的疗效有关。我们将采用液相色谱-质谱联用、气相色谱-质谱联用的方法，在慢阻肺急性加重期接受全身激素治疗的患者中，分析激素治疗成功组和失败组之间代谢标志物轮廓的差异，寻找与全身激素疗效相关的代谢标志物及代谢调控通路，为慢阻肺急性加重的精准治疗策略提供理论依据。

慢性阻塞性肺疾病（慢阻肺）急性加重显著增加患者的病死率。慢阻肺急性加重的临床表型在治疗反应和远期预后存在明显的异质性，受到国内外广泛关注。慢阻肺急性加重的发病机制复杂，涉及多种细胞类型及通路，机体代谢紊乱可能与慢阻肺急性加重密切相关。代谢产物作为细胞生理活动的最终物质，能更为真实、灵敏地反映细胞的功能状态。有少量研究显示，慢阻肺急性加重患者血液脂质代谢谱发生改变，且不同于稳定期或社区获得性肺炎的患者。本研究收集慢阻肺急性加重住院患者的血清样本，应用高效液相色谱-质谱联用及经典脂质组学检测方法，对比慢阻肺急性加重期与恢复期血清脂质代谢物轮廓的差异，并对比在不同急性加重临床表型中血清脂质代谢物轮廓的差异。重要结果：急性加重不同表型之间的临床特征存在显著性差异；急性加重期与恢复期血清脂质代谢物轮廓存在显著差异；急性加重不同表型之间血清脂质代谢物轮廓存在显著差异。关键数据：急性加重期与恢复期相比，血清甘油三酯谱、磷脂谱、鞘磷脂谱、糖脂谱存在显著性差异；合并与不合并高碳酸血症相比，血清鞘磷脂谱、糖脂谱存在显著性差异；ICU住院与非ICU住院相比，血清甘油三酯谱、磷脂谱、鞘磷脂谱、糖脂谱存在显著性差异。本项目对于从脂质代谢的层面深入阐述慢阻肺急性加重的发病机制、筛选与之相关的生物标志物并发现潜在的、新的治疗靶点提供一定的理论依据。