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Integrative Transcriptomic and Metabolomic Profiling Unravels Anti-Apoptotic and Anti-Inflammatory Properties of Qing-Jin-Hua-Tan Decoction in Chronic Obstructive Pulmonary Disease

ABSTRACT: Qing-Jin-Hua-Tan decoction (QJHTD) is a classic traditional Chinese medicine (TCM) prescription that has proven appropriate for the treatment of inflammatory lung diseases including chronic obstructive pulmonary disease (COPD), but its mechanism of action on COPD is still perplexing. We aim to explore the molecular machinery underpinning the curative effects of QJHTD on COPD. We confirmed in vitro anti-apoptotic and anti-inflammatory activities of QJHTD using the BEAS-2B and RAW264.7 cells challenged by cigarette smoke (CS) extract (CSE) and lipopolysaccharide (LPS) after chemical analysis of QJHTD. In vivo therapeutic activities of QJHTD were evaluated in the CS-LPS-exposed BALB/c mice. The phenotype data showed that anti-apoptotic and anti-inflammatory properties featured prominently in COPD treatment with QJHTD. Network pharmacology-based prediction followed by transcriptomic analysis of mouse lung tissue revealed that inhibiting such signaling pathways as IL-1β, IL-6, TNF, IκB-NF-κB, TLR, MAPK, and apoptosis contributed to the anti-COPD mechanism of QJHTD. Metabolome profiling unveiled the dominant role of dampening apoptosis and sphingolipid (SL) metabolism with choline (Ch) metabolism boosted in QJHTD modality for COPD. Integrative transcriptome-metabolome analysis unraveled the bridge between SL metabolism and apoptosis. In silico molecular docking revealed that acacetin as an active compound in QJHTD could bind with high affinities to the target proteins including MEK1, MEK2, ERK1, ERK2, Bcl2, NF-κB, and alCDase. These findings provide comprehensive insights into the molecular profile of QJHTD action against COPD and justify theoretical promise in a novel pharmacotherapy for the multifactorial disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE223102 | GEO | 2024/02/14

REPOSITORIES: GEO

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Project description:Cigarette smoke (CS)-induced airway inflammation is an important pathologic feature of chronic obstructive pulmonary disease (COPD). Recent studies suggest a potential role of JunD in the regulation of inflammation, but its role in CS-induced airway inflammation has not been reported. This study aimed to determine its role in CS-induced airway inflammation through bioinformatics analysis and in vitro and in vivo experiments. Data from the Gene Expression Omnibus (GEO) database (GSE37147) were analyzed using weighted gene co-expression network analysis (WGCNA) and key driver analysis (KDA), and these analyses were validated using the GSE47460 dataset. The effect of CS on JunD expression was examined in lung tissues of COPD patients and CS-exposed mice and in CS extract (CSE)-exposed BEAS-2B cells. The effects of CSE on airway epithelial inflammatory injury after JunD knockdown or overexpression were also investigated. mRNA-seq and chromatin immunoprecipitation (ChIP)-seq were used to explore the mechanism of JunD-mediated CS-induced airway inflammation. Mice were injected with adeno-associated virus serotype 9 (AAV9)-JunD vector or control vector and then exposed to CS for 4 weeks, and lung tissue morphology and airway inflammation were evaluated. KDA of the lung function-related gene modules in GSE37147 revealed a potential role of JunD in COPD, which was validated in GSE47460. JunD was downregulated in lung tissues of COPD patients and CS-exposed mice and in BEAS-2B cells. JunD knockdown aggravated CSE-induced tumor necrosis factor (TNF)-α and interleukin (IL)-1β release by BEAS-2B cells, while JunD overexpression attenuated these effects. mRNA-seq and ChIP-seq identified several JunD-regulated genes, which are involved in the immune response and TNF signaling pathway and are commonly dysregulated in cell models of airway inflammation. In vivo, JunD overexpression attenuated the CS-induced inflammatory cell infiltration and inflammatory cytokine release in mouse lungs. Thus, JunD is involved in CS-induced airway inflammation and JunD-based therapy may be useful in CS-induced airway disorders.

Project description:The lymphatic vasculature regulates lung homeostasis through drainage of fluid and trafficking of immune cells and plays a key role in the response to lung injury in several disease states. We have previously shown that lymphatic dysfunction occurs early in the pathogenesis of chronic obstructive pulmonary disease (COPD) caused by cigarette smoke (CS) and that this is associated with increased thrombin and fibrin clots in lung lymph. However, the direct effects of CS and thrombin on lymphatic endothelial cells (LECs) in COPD are not entirely clear. Studies of the blood vasculature have shown that COPD is associated with increased thrombin, which causes endothelial dysfunction after CS exposure and is characterized by changes in the expression of coagulation factors and leukocyte adhesion proteins. Here, we determined whether similar changes occur in LECs. We used an in vitro cell culture system and treated human lung microvascular lymphatic endothelial cells with cigarette smoke extract (CSE) and/or thrombin. We found that CSE treatment led to decreased fibrinolytic activity in LECs, which was associated with increased expression of plasminogen activator inhibitor 1 (PAI-1). LECs treated with both CSE and thrombin together had a decreased expression of TFPI and an increased expression of vascular adhesion molecules. RNA sequencing of lung LECs isolated from mice exposed to CS also showed upregulation of prothrombotic and inflammatory pathways at both acute and chronic exposure time points. Analysis of publicly available single-cell RNA sequencing of LECs as well as immunohistochemical staining of lung tissue from COPD patients supported these data and showed an increased expression of inflammatory markers in LECs from COPD patients compared to those from controls. These studies suggest that in parallel with blood vessels, the lymphatic endothelium undergoes inflammatory changes associated with CS exposure and increased thrombin in COPD. Further research is needed to unravel the mechanisms by which these changes affect lymphatic function and drive tissue injury in COPD.

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Integrative Transcriptomic and Metabolomic Profiling Unravels Anti-Apoptotic and Anti-Inflammatory Properties of Qing-Jin-Hua-Tan Decoction in Chronic Obstructive Pulmonary Disease

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