Comparative RNA-Seq Transcriptome Analysis on Pulmonary Inflammation in a Mouse Model of Asthma-COPD Overlap Syndrome.

Hui Yang,Xuyu Li,Shuyi Li,Jiqiao Yuan,Qi Hou,Nan Fang,Mingbao Lin,Ziqian Zhang,Pei Ma

doi:10.3389/fcell.2021.628957

Abstract

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.

Highlights

Asthma–chronic obstructive pulmonary disease (COPD) overlap (ACO) is a well-accepted concept defining persistent airflow limitation with features of asthma and COPD
In the analysis of the DisGeNET database, the results showed that the ACO model had specific characteristics of pneumonia, pulmonary fibrosis, chronic obstructive airway neoplasms, lung tumors, and rheumatoid arthritis, indicating that the ACO model was a type of abnormal activation of immune system diseases with lung inflammation and tracheal lesions caused by allergic stimuli, which was very consistent with the clinical manifestations of ACO
We focused on the genes that were significantly increased in the ACO group and their related differentially expressed genes (DEGs)

Summary

Introduction

Asthma–chronic obstructive pulmonary disease (COPD) overlap (ACO) is a well-accepted concept defining persistent airflow limitation with features of asthma and COPD. Because of the difference in the clinical course, it is thought the pathogenesis of ACO is different from asthma or COPD. Asthma is usually characterized by airway hyperresponsiveness (AHR), leading to reversible airflow obstruction based on type 2 inflammation with eosinophils. Asthma and COPD have some similarities, such as airflow obstruction, pulmonary inflammation, and AHR. The distinction between asthma and COPD becomes blurred, especially in asthmatic subjects who smoke or in acute exacerbations of patients with COPD (Cai et al, 2010). Compared with simple asthma and COPD, ACO episodes are more frequent, the condition is more serious, the frequency of hospitalization increases, the medical utilization rate and medical expenses increase significantly, the quality of life decreases, and the survival time is significantly shortened. It has become fundamentally important to uncover the underlying mechanisms in ACO

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Conclusion