Integrated network pharmacology, metabolomics and experimental validation to reveal the pharmacological substances and mechanism of Wendan decoction on chronic obstructive pulmonary disease

Abstract

Wendan Decoction (WDD), a classic formula for the expectoration of phlegm, has been acknowledged for the management of chronic obstructive pulmonary disease (COPD). Nevertheless, the therapeutic components and mechanism of WDD in COPD remain elusive. Hence, an analytical strategy for extensive investigation of the constituents in WDD combining UFLC-ESI-Q/TOF-MS and subsequent network pharmacology was conducted, and the appropriate preparation of bio-samples was involved with mechanistic bioanalysis including multi-technique metabolomics and molecular biological means, that pivotal factors such as PTGS2, arachidonic acid (AA) metabolism, and PI3K-AKT signaling pathway were recommended as potential central elements for the anti-COPD effects. Subsequently, based on the rat model of COPD, a dose-dependent manner for the significant attenuation effect of WDD on pulmonary injury, inflammation, and oxidative stress was observed. Metabolomics analysis revealed the restoration of 65 COPD biomarkers by WDD intervention. A comprehensive analysis highlighted AA metabolism as the predominant metabolic pathway. The significance of vital targets within the AA metabolism pathway, including PTGS2 and PLA2, and their robust binding affinities with key constituents of WDD such as naringenin and baicalin were characterized and verified from the aspects of docking fitting and thermal stability. Notably, the upregulation levels of protein and mRNA of key targets within the AA metabolism pathway caused by COPD was significantly reversed by WDD. Hence, the efficacy of WDD against COPD was uncovered from the aspects of components and mechanism in this research, implying the effective treatment of COPD and the clinical application of WDD.