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Lian Hua Qing Wen Capsules, a Potent Epithelial Protector in Acute Lung Injury Model, Block Proapoptotic Communication Between Macrophages, and Alveolar Epithelial Cells

ABSTRACT: Besides pathogen evading, Acute Lung Injury (ALI), featuring the systematic inflammation and severe epithelial damages, is widely believed to be the central non-infectious factor controlling the progression of infectious diseases. ALI is partly caused by host immune responses. Under the inspiration of unsuccessful treatment in COVID-19, recent insights into pathogen–host interactions are leading to identification and development of a wide range of host-directed therapies with different mechanisms of action. The interaction unit consisting of macrophages and the alveolar epithelial cells has recently revealed as the therapeutic basis targeting ALI. Lian Hua Qing Wen capsule is the most effective and commonly-used clinical formula in treating respiratory infection for thousands of years in China. However, little is known about its relevance with ALI, especially its protective role against ALI-induced alveolar tissue damages. Aiming to evaluate its contribution in antibiotics-integrating therapies, this study pharmacologically verified whether LHQW could alleviate lipopolysaccharide (LPS)-induced ALI and explore its potential mechanisms in maintaining the physiology of macrophage-epithelial unit. In ALI mouse model, the pathological parameters, including the anal temperature, inflammation condition, lung edema, histopathological structures, have all been systematically analyzed. Results consistently supported the effectiveness of the combined strategy for LHQW and low-dose antibiotics. Furthermore, we established the macrophages-alveolar epithelial cells co-culture model and firstly proved that LHQW inhibited LPS-induced ER stress and TRAIL secretion in macrophages, thereby efficiently protected epithelial cells against TRAIL-induced apoptosis. Mechanistically, results showed that LHQW significantly deactivated NF-?B and reversed the SOCS3 expression in inflammatory macrophages. Furthermore, we proved that the therapeutic effects of LHQW were highly dependent on JNK-AP1 regulation. In conclusion, our data proved that LHQW is an epithelial protector in ALI, implying its promising potential in antibiotic alternative therapy.

SUBMITTER: Li Q

PROVIDER: S-EPMC7538620 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe traditional Chinese Medicine (TCM) herbal formula Lian Hua Qing Wen (LHQW) improves the results of COVID-19 treatment. Three very recent studies analyzed with network pharmacology some working mechanisms of LHQW. However, we used more techniques and also included Angiotensin converting enzyme 2 (ACE2) (a SARS-CoV receptor, possibly the viral entry point in alveolar lung cells) and the immune system, as cytokine storm is essential in the late phase.PurposeExtensive detailed Network Pharmacology analysis of the LHQW- treatment mechanism in COVID-19.MethodsTCM-herb-meridian and protein interaction network (PIN) of LHQW, based on LHQW herbs meridian information and the protein-protein interaction (PPI) information of the LHQW-component targets. Hub and topological property analyses to obtain crucial targets and construct the crucial LHQW-PIN. Functional modules determination using MCODE, GO and KEGG pathway analysis of biological processes and pathway enrichment. Intersection calculations between the LHQW-proteins and ACE2 co-expression-proteins.ResultsLHQW herbs have relationships to Stomach-, Heart-, Liver- and Spleen-systems, but most (10 of the 13 herbs) to the Lung system, indicating specific effects in lung diseases. The crucial LHQW PIN has the scale-free property, contains 2,480 targets, 160,266 PPIs and thirty functional modules. Six modules are enriched in leukocyte-mediated immunity, the interferon-gamma-mediated signaling pathway, immune response regulating signaling pathway, interleukin 23 mediated signaling pathway and Fc gamma receptor-mediated phagocytosis (GO analysis). These 6 are also enriched in cancer, immune system-, and viral infection diseases (KEGG). LHQW shared 189 proteins with ACE2 co-expression proteins.ConclusionsDetailed network analysis shows, that LHQW herbal TCM treatment modulates the inflammatory process, exerts antiviral effects and repairs lung injury. Moreover, it also relieves the "cytokine storm" and improves ACE2-expression-disorder-caused symptoms. These innovative findings give a rational pharmacological basis and support for treating COVID-19 and possibly other diseases with LHQW.

Project description:BackgroundQing-Jin-Hua-Tan decoction (QJHTD) is a classic traditional Chinese medicine (TCM) prescription that first appeared in the ancient book Yi-Xue-Tong-Zhi. QJHTD has shown effectiveness for treating chronic obstructive pulmonary disease (COPD), although its mechanisms of action are still perplexing. The molecular mechanisms underlying the curative effects of QJHTD on COPD is worth exploring.MethodsIn vitro antiapoptotic and antiinflammatory activities of QJHTD were evaluated using cell viability, proliferation, apoptosis rate, and expression of IL-1β and TNF-α in BEAS-2B and RAW264.7 cells challenged with cigarette smoke (CS) extract (CSE) and lipopolysaccharide (LPS). In vivo therapeutic activities of QJHTD were evaluated using respiratory parameters (peak inspiratory flow (PIFb) and peak expiratory flow (PEFb) values), histopathology (mean linear intercept, MLI), and proinflammatory cytokine (IL-1β and TNF-α) and cleaved caspase-3 (c-Casp3) levels in the lung tissue of CS-LPS-exposed BALB/c mice. Network pharmacology-based prediction, transcriptomic analysis, and metabolic profiling were employed to investigate the signaling molecules and metabolites pertinent to the anti-COPD action of QJHTD.ResultsIncreased cell viability and proliferation with decreased apoptosis rate and proinflammatory cytokine expression were noted after QJHTD intervention. QJHTD administration elevated PEFb and PIFb values, reduced MLI, and inhibited IL-1β, TNF-α, and c-Casp3 expression in vivo. Integrated network pharmacology-transcriptomics revealed that suppressing inflammatory signals (IL-1β, IL-6, TNF, IκB-NF-κB, TLR, and MAPK) and apoptosis contributed to the anti-COPD property of QJHTD. Metabolomic profiling unveiled prominent roles for the suppression of apoptosis and sphingolipid (SL) metabolism and the promotion of choline (Ch) metabolism in the anti-COPD effect of QJHTD. Integrative transcriptomics-metabolomics unraveled the correlation between SL metabolism and apoptosis. In silico molecular docking revealed that acacetin, as an active compound in QJHTD, could bind with high affinity to MEK1, MEK2, ERK1, ERK2, Bcl2, NF-κB, and alCDase target proteins.ConclusionThe therapeutic effect of QJHTD on COPD is dependent on regulating inflammatory signals and apoptosis-directed SL metabolism. These findings provide deeper insights into the molecular mechanism of action of QJHTD against COPD and justify its theoretical promise in novel pharmacotherapy for this multifactorial disease.

Project description:Influenza (Flu) is a severe health, medical, and economic problem, but no medication that has excellent outcomes and lowers the occurrence of these problems is now available. GanghuoQingwenGranules (GHQWG) is a common Chinese herbal formula for the treatment of influenza (flu). However, its methods of action remain unknown. We used network pharmacology, molecular docking, and molecular dynamics simulation techniques to investigate the pharmacological mechanism of GHQWG in flu. TCMSP and various types of literature were used to obtain active molecules and targets of GHQWG. Flu-related targets were found in the Online Mendelian Inheritance in Man (OMIM) database, the DisFeNET database, the Therapeutic Target Database (TTD), and the DrugBank database. To screen the key targets, a protein-protein interaction (PPI) network was constructed. DAVID was used to analyze GO and KEGG pathway enrichment. Target tissue and organ distribution was assessed. Molecular docking was used to evaluate interactions between possible targets and active molecules. For the ideal core protein-compound complexes obtained using molecular docking, a molecular dynamics simulation was performed. In total, 90 active molecules and 312 GHQWG targets were discovered. The PPI network's topology highlighted six key targets. GHQWG's effects are mediated via genes involved in inflammation, apoptosis, and oxidative stress, as well as the TNF and IL-17 signaling pathways, according to GO and KEGG pathway enrichment analysis. Molecular docking and molecular dynamics simulations demonstrated that the active compounds and tested targets had strong binding capabilities. This analysis accurately predicts the effective components, possible targets, and pathways involved in GHQWG flu treatment. We proposed a novel study strategy for future studies on the molecular processes of GHQWG in flu treatment. Furthermore, the possible active components provide a dependable source for flu drug screening.

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Lian Hua Qing Wen Capsules, a Potent Epithelial Protector in Acute Lung Injury Model, Block Proapoptotic Communication Between Macrophages, and Alveolar Epithelial Cells

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