桔梗活性成分通过调节Sirt6/RORγt/IL-17A轴和IL-17A/MAPK通路调节哮喘Epithelial-Mesenchymal转换和气道重塑的机制研究

【ETHNOPHARMACOLOGICAL RELEVANCE】Platycodon grandiflorum (Jacq.) A.DC. is a traditional Chinese medicinal herb recognized for its dual role as both food and medicine, renowned for its effects of diffusing the lung, alleviating sore throat, promoting expectoration, and facilitating pus drainage. In traditional medicinal practice, it is often used in combination with herbs such as Ephedra sinica , Prunus armeniaca and Glycyrrhiza uralensis utilized to mitigate symptoms associated with asthma, bronchitis, and other respiratory diseases. However, the therapeutic effects and molecular mechanisms of its principal bioactive components in treating asthma remain insufficiently characterized.

【AIM OF THE STUDY】To investigate the pharmacological effects and elucidate the molecular mechanisms by which triterpenoid saponins derived from Platycodon grandiflorum (PL-TS) inhibit airway epithelial-mesenchymal transition (EMT) and attenuate airway remodeling in asthma.

【MATERIALS AND METHODS】Initially, the chemical constituents of the triterpenoid saponin fraction extracted from Platycodon grandiflorum (Jacq.) A. DC. (PL-TS) were identified by Ultra Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS). Subsequently, network pharmacology approaches were employed to predict potential therapeutic targets and core signaling pathways of PL-TS in asthma. An OVA-induced asthmatic mouse model was established for in vivo experiments. Airway hyperresponsiveness (AHR) was assessed via whole-body plethysmography (WBP), and histopathological changes in lung tissues were examined via hematoxylin-eosin (HE), Masson's trichrome, and periodic acid-Schiff (PAS) staining. Human bronchial epithelial cells (BEAS-2B) were utilized to establish an IL-17A-induced epithelial-mesenchymal transition (EMT) model in vitro. Finally, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), quantitative real-time polymerase chain reaction (qPCR), and Western blotting (WB) were employed to investigate the modulatory effects of PL-TS on proteins associated with airway remodeling, the IL-17A/MAPK signaling pathway, and the Sirt6/RORγt/IL-17A axis in both asthmatic mice and cellular models.

【RESULTS】UPLC-MS/MS analysis identified 38 triterpenoid saponins from PL-TS, providing a chemical foundation for subsequent mechanistic studies. Network pharmacology analysis revealed that the principal targets of PL-TS were predominantly enriched within the IL-17A signaling pathway. In OVA-induced asthmatic mice, PL-TS significantly attenuated inflammatory cell infiltration, mucus hypersecretion, and collagen deposition in lung tissues, while markedly reducing serum levels of IL-4, IL-5, IL-13, and OVA-IgE in vivo. Furthermore, PL-TS was found to inhibit the activation of the IL-17A/MAPK and Sirt6/RORγt/IL-17A signaling pathways in both mouse lung tissue and stimulated cells, while downregulating EMT-related protein Vimentin, Snail, and N-cadherin, upregulating expression of E-cadherin. suppressing the phosphorylation of p38, ERK, and JNK in the MAPK pathway. In addition, PL-TS downregulated Sirt6 expression and reduced RORγt and IL-17A levels, suggesting a potential involvement of the Sirt6/RORγt/IL-17A regulatory axis, although the precise epigenetic mechanism requires further investigation.

【CONCLUSIONS】This study demonstrated that the PL-TS significantly alleviated airway inflammation, mucus hypersecretion, and airway remodeling in asthma model. The effects were associated with suppression of the IL-17A/MAPK pathway and downregulation of the Sirt6/RORγt/IL-17A axis, suggesting a potential dual mechanism that highlight its therapeutic potential.