Ma Pei, Li Shuyi, Yang Hui, Yuan Jiqiao, Zhang Ziqian, Li Xuyu, Fang Nan, Lin Mingbao, Hou Qi
Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Front Cell Dev Biol. 2021 Mar 25;9:628957. doi: 10.3389/fcell.2021.628957. eCollection 2021.
Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is a severe clinical syndrome characterized to describe patients with both asthma and COPD clinical characteristics, which has posed a serious threat to patients' quality of life and life safety. However, there are many difficulties and uncertainties in its diagnosis and treatment in clinic; especially, its animal model has not been fully and thoroughly established, and the evaluation of therapeutic drugs is still in its infancy. Here, we used ovalbumin (OVA), lipopolysaccharide (LPS), and smoke costimulation to establish an ACO mouse model and then used RNA-seq technology to detect gene expression in mouse lung tissue. The results showed that ACO mice showed an overlap syndrome of asthma and COPD in lung histological changes and the levels of inflammatory cytokines in bronchoalveolar lavage fluid. The RNA-seq analysis results showed that 6,324 differentially expressed genes (DEGs) were screened between the ACO group and the control group, of which 2,717 (42.7%) were downregulated, and 3,607 (57.3%) were upregulated. Metascape analysis results showed that in the ACO model we established, due to the damage of the respiratory system, the accumulated diseased tissue involves lung, spleen, blood, bone marrow, thymus, etc. It has certain characteristics of pneumonia, pulmonary fibrosis, and chronic obstructive airway disease, lung tumors, rheumatoid arthritis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis showed that DEGs were enriched in inflammation, immune system activation and imbalance, cell proliferation, and adhesion migration, and the upstream signaling pathways of inflammation were mainly affected by HLA-DRA, SYK, CTLA4, VAV1, NRAS, and JAK3. In short, our research established a mouse model that can better simulate the clinicopathological characteristics of ACO and suggested the foundations in elucidating the molecular mechanisms for pulmonary inflammation and fibrosis in ACO. This work may help further research and contribute substantially to prevention and clinical treatment of ACO in the future.
哮喘-慢性阻塞性肺疾病（COPD）重叠综合征（ACO）是一种严重的临床综合征，其特征是描述同时具有哮喘和COPD临床特征的患者，这对患者的生活质量和生命安全构成了严重威胁。然而，其临床诊断和治疗存在诸多困难和不确定性；特别是，其动物模型尚未完全建立，治疗药物的评估仍处于起步阶段。在此，我们使用卵清蛋白（OVA）、脂多糖（LPS）和烟雾共同刺激建立了ACO小鼠模型，然后使用RNA测序技术检测小鼠肺组织中的基因表达。结果显示，ACO小鼠在肺组织学变化和支气管肺泡灌洗液中炎症细胞因子水平方面表现出哮喘和COPD的重叠综合征。RNA测序分析结果显示，在ACO组和对照组之间筛选出6324个差异表达基因（DEG），其中2717个（42.7%）下调，3607个（57.3%）上调。Metascape分析结果显示，在我们建立的ACO模型中，由于呼吸系统受损，累积的病变组织涉及肺、脾、血液、骨髓、胸腺等。它具有肺炎、肺纤维化、慢性阻塞性气道疾病、肺肿瘤、类风湿性关节炎等一定特征。基因本体论和京都基因与基因组百科全书分析表明，DEG在炎症、免疫系统激活和失衡、细胞增殖以及黏附迁移方面富集，炎症的上游信号通路主要受HLA-DRA、SYK、CTLA4、VAV1、NRAS和JAK3影响。总之，我们的研究建立了一个能够更好模拟ACO临床病理特征的小鼠模型，并为阐明ACO肺部炎症和纤维化的分子机制提供了基础。这项工作可能有助于未来进一步的研究，并为ACO的预防和临床治疗做出重大贡献。
