Lin Zhiwei, Liu Shuang, Zhang Ke, Feng Tianyu, Luo Yewei, Liu Yu, Sun Baoqing, Zhou Luqian
Respiratory Mechanics Laboratory, State Key Laboratory of Respiratory Disease, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, 510120, China.
Department of Clinical Laboratory, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, Guangzhou Laboratory, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China.
Respir Res. 2025 Mar 26;26(1):115. doi: 10.1186/s12931-025-03185-x.
Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of global mortality, with acute exacerbations of COPD (AECOPD) significantly increasing the disease's morbidity and mortality. Among the pathogens implicated in AECOPD, Pseudomonas aeruginosa (P. aeruginosa) is increasingly recognized as a major co-infecting bacterium. Despite its clinical importance, the molecular mechanisms and therapeutic targets underlying AECOPD with P. aeruginosa infection remain inadequately understood.
We employed a multi-omics approach, integrating proteomic analyses of bronchoalveolar lavage fluid (BALF) and plasma with transcriptomic analysis of peripheral blood. A discovery cohort of 40 AECOPD with P. aeruginosa infection patients and 20 healthy controls was analyzed, followed by validation in an independent cohort of 20 patients and 10 controls. Differentially expressed proteins (DEPs) and genes (DEGs) were identified and subjected to protein-protein interaction (PPI) network analysis, weighted gene co-expression network analysis (WGCNA), and immune infiltration analysis. Molecular docking simulations were conducted to explore potential therapeutic agents.
Our integrative analysis identified key biomarkers, which played critical roles in oxidative stress and neutrophil extracellular trap (NET) formation, both of which were pivotal in the pathogenesis of AECOPD with P. aeruginosa infection. The combined analysis of BALF, plasma, and peripheral blood underscored the interplay between local lung changes and systemic immune responses. Functional enrichment analyses highlighted significant pathways related to bacterial defense, inflammation, and immune activation. Validation in an independent cohort confirmed the diagnostic value of three key proteins (AZU1, MPO, and RETN), with high area under the curve (AUC) values in ROC analyses. Molecular docking indicated strong binding affinities of these proteins with Pioglitazone and Rosiglitazone, suggesting potential therapeutic utility.
This study provides a comprehensive understanding of the molecular mechanisms underlying AECOPD with P. aeruginosa infection, highlighting the pivotal roles of oxidative stress and NET formation in disease progression. The identified biomarkers offer promising diagnostic and therapeutic targets. Our findings pave the way for novel strategies to improve outcomes for AECOPD patients with P. aeruginosa infection. While the study design limits our ability to establish causality, these results provide important insights that warrant further investigation, particularly through longitudinal studies, to confirm the specific contributions of P. aeruginosa in exacerbations.
Not applicable.
慢性阻塞性肺疾病（COPD）是全球死亡的主要原因，慢性阻塞性肺疾病急性加重（AECOPD）显著增加了该疾病的发病率和死亡率。在与AECOPD相关的病原体中，铜绿假单胞菌（P. aeruginosa）越来越被认为是一种主要的合并感染细菌。尽管其具有临床重要性，但AECOPD合并铜绿假单胞菌感染的分子机制和治疗靶点仍未得到充分了解。
我们采用了多组学方法，将支气管肺泡灌洗液（BALF）和血浆的蛋白质组分析与外周血的转录组分析相结合。对40例AECOPD合并铜绿假单胞菌感染患者和20例健康对照的发现队列进行了分析，随后在一个由20例患者和10例对照组成的独立队列中进行了验证。鉴定出差异表达蛋白（DEP）和基因（DEG），并进行蛋白质-蛋白质相互作用（PPI）网络分析、加权基因共表达网络分析（WGCNA）和免疫浸润分析。进行分子对接模拟以探索潜在的治疗药物。
我们的综合分析确定了关键生物标志物，它们在氧化应激和中性粒细胞胞外陷阱（NET）形成中起关键作用，这两者在AECOPD合并铜绿假单胞菌感染的发病机制中都至关重要。BALF、血浆和外周血的联合分析强调了局部肺部变化与全身免疫反应之间的相互作用。功能富集分析突出了与细菌防御、炎症和免疫激活相关的重要途径。在独立队列中的验证证实了三种关键蛋白（AZU1、MPO和RETN）的诊断价值，在ROC分析中具有较高的曲线下面积（AUC）值。分子对接表明这些蛋白与吡格列酮和罗格列酮具有很强的结合亲和力，提示其潜在的治疗效用。
本研究全面了解了AECOPD合并铜绿假单胞菌感染的分子机制，突出了氧化应激和NET形成在疾病进展中的关键作用。所鉴定的生物标志物提供了有前景的诊断和治疗靶点。我们的发现为改善AECOPD合并铜绿假单胞菌感染患者的预后的新策略铺平了道路。虽然研究设计限制了我们建立因果关系的能力，但这些结果提供了重要的见解，值得进一步研究，特别是通过纵向研究，以确认铜绿假单胞菌在病情加重中的具体作用。
不适用。
