Abstract
Background: DayuanYin (DYY) is a traditional Chinese medicine (TCM) formula for the treatment of lung diseases.However, the substance and mechanism of its improvement on acute lung injury (ALI) still need to be studied.
Methods: DYY's effective components and potential targets were identified using Traditional Chinese Medicine Systems Pharmacology(TCMSP), and a network of herb-component-targets was created with Cytoscape3.7.2. The target genes for ALI were sourced from GeneCards, DisGeNET, and DrugBank databases. The drug-disease target protein-protein interaction (PPI) network was constructed and core targets were visually identified with Cytoscape. Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genomes (KEGG) enrichment analysis were conducted using Metscape database.The effective components of DYY were further identified by UHPLC-MS/MS. Subsequently, the therapeutic effect of DYY on ALI and its possible mechanism were studied in LPS-induced ALI rats. Finally, the interaction between nuclear factor erythrocyte 2-associated factor 2(Nrf2), Heme Oxygenase-1 (HO-1), Toll-like receptor 4(TLR4) and active components was evaluated by molecular docking.
Results: A total of 95 active compounds, 234 potential therapeutic targets and 2529 ALI related target genes were obtained. DYY and ALI share a target number of 111. KEGG analysis showed that the PI3K-AKT and MAPK signaling pathways and their mediated oxidative stress pathways are closely related to ALI, which may be the potential mechanism of DYY anti-ALI. Network pharmacology and UHPLC-MS/MS analysis showed that the active ingredients included quercetin, OroxylinA, Magnolol, Wogonin, Glabrone, Honokiol and LicochalconeA. Animal experiments have shown that DYY can reduce the lung wet-to-dry (W/D) ratio, the levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in bronchoalveolar lavage fluid (BALF), and the contents of malondialdehyde (MDA), nitric oxide (NO) and reactive oxygen species (ROS) in lung tissue of LPS-treated rats. It is worth noting that DYY promotes the expression of Uncoupling protein 2 (UCP2) mRNA in vivo, increases the expression of Nrf2 and HO-1, and then inhibits the pro-inflammatory mediators mediated by TLR4. Molecular docking analysis showed that the main components of DYY had strong binding ability with HO-1.
Conclusions: This study shows that DYY can alleviate inflammation, oxidative stress and pathological changes of ALI by targeting Nrf2/HO-1 mediated TLR4 signaling pathway, which has important implications for developing effective ALI treatments.