Platycodon Decoction alleviates chronic obstructive pulmonary disease associated inflammation with potential dual-layer regulation of PI3K/AKT/NLRP3 signaling and ADGRE5-mediated intercellular interactions.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese medicine formula Platycodon Decoction (PD) is known to be effective to alleviate respiratory system-related symptoms, its effect and integrated mechanism for treating COPD requires elucidation.

AIM OF THE STUDY: This study aims to systematically address the pharmocology of PD in treating COPD through analyzing how PD inhibiting the intracellular inflammatory pathway and intercellular interactions.

MATERIALS AND

METHODS

PD composition was ascertained via LC-MS/MS. PD-induced organ damage was assessed through an acute toxicity test. Following the intervention of PD, body weight, lung index, sputum volume, pulmonary function, expression of inflammatory factors, pulmonary tissue injury, mucus secretion, and MUC5AC expression of the COPD-modeled mice were measured. PD's impacts on the levels of inflammatory factors, cellular activity, proliferation, cell cycle, reactive oxygen species (ROS), mitochondrial membrane potential, and inter-cellular communication were assessed through Beas-2b human bronchus epithelial cells and THP-1 human macrophage. The PD-associated, COPD relevant inflammatory pathways were analyzed through network pharmacology, molecular docking and molecular dynamics and then verified through Western blots. The involved cells for cell receptor identified by network pharmacology was analyzed by single-cell sequencing and verified by molecular dynamics and Western blot.

RESULTS

The acute toxicity assessment provided preliminary evidence of PD tolerability under the tested conditions. Fifty compounds were identified in PD. Animal experiments demonstrated that PD can decrease the inflammatory levels and alleviate excessive mucus secretion in mice. In vitro cell experiments indicated that PD can efficiently abate inflammation and oxidative stress within the COPD-related airway microenvironment and diminish epithelial-macrophage interactions. Integration of single-cell and network pharmacology analyses identified ADGRE5 as a candidate receptor that may mediate epithelial-macrophage interactions. PD treatment reduced PI3K/AKT/NLRP3 signaling and was accompanied by decreased ADGRE5 expression. Computational analyses suggested a potential interaction between platycodin D and ADGRE5.

CONCLUSIONS

PD alleviates inflammation in COPD, potentially involving dual-layer regulation of PI3K/AKT/NLRP3 signaling and ADGRE5-mediated intercellular interactions.