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

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.

Anti-asthmatic fraction screening and mechanisms prediction of Schisandrae Sphenantherae Fructus based on a combined approach

“…The asthma model was established referring to the previous description with minor changes ( Ma et al, 2021 ). The experimental mice were sensitized by intraperitoneal injection of 50 μg OVA (Sigma, St. Louis, MO, United States) with 100 μl alum adjuvant (Thermo Fisher Scientific, Foster City, CA, United States) on days 0, 7, and 14 and then challenged with 5% OVA for 30 min from days 21–23.…”

Unraveling the Pathogenesis of Asthma and Chronic Obstructive Pulmonary Disease Overlap: Focusing on Epigenetic Mechanisms

“…Blood TNF-α concentrations of ACO patients were higher than that of asthmatics, but lower than that of pure COPD patients [ 21 , 22 ]. On the other hand, TNF-α was up-regulated in ACO mice versus either COPD or asthma mice [ 23 ]. As an anti-inflammatory cytokine, IL-10 has the capacity to suppress excessive inflammation by increasing M2 polarization and decreasing neutrophil infiltration.…”

“…IL-6 is a pleotropic cytokine produced in response to tissue damage, and might favor Th2 and Th17 polarization by stimulating STAT3 [ 36 ]. IL-6 was up-regulated in both ACO patients and ACO mice versus COPD or asthma [ 22 , 23 ]. IL-17E also induces allergic inflammation in favor of Th2 immune response.…”

“…First, the ACO animal model has not yet been fully and thoroughly established, and the evaluation of therapeutic drugs for ACO, including agents targeting epigenetic marks, is still in its infancy. However, a mouse model that can better simulate the clinical–pathological characteristics of ACO has been established recently and suggest that the whole-genome gene expression changes of ACO reflect biology beyond Th2 inflammation and are mainly driven by HLA-DRA, SYK, CTLA4, VAV1, NRAS, and JAK3 signaling pathways [ 23 ]. Second, patients with ACO are excluded from the majority of asthma and COPD randomized control trials, which contributes to the lack of efficacy and safety data on effective therapies for ACO.…”

Syk-Targeted, a New 3-Arylbenzofuran Derivative EAPP-2 Blocks Airway Inflammation of Asthma–COPD Overlap in vivo and in vitro

“…13,14 Furthermore, previously, by using comparative RNA-Seq transcriptome analysis on pulmonary inflammation in an ACO mouse model, we also found that Syk was a potential mainly affected signaling pathways of inflammation in ACO mouse. 15 Phosphorylated Syk activated via its SH2 domains binds to the dual phosphorylated immunoreceptor tyrosine-based activation motif (ITAM), 16 and its phosphorylated tyrosine residues can be used as anchor points for ligands binding, then to trigger its downstream signal cascades, including NF-κB and NLRP3, 17,18 which ultimately trigger an inflammatory response. Therefore, targeting on Syk seems to be an effective solution for ACO airway inflammation treatment.…”