目的:The traditional Chinese medicine Citri Grandis Exocarpium (CGE),"Hua-ju-hong" in Chinese,is the dried immature fruit of Citrus grandis ‘Tomentosa’ and has been used as antitussive and expectorant for thousands of years.In our previous studies,CGE and its main bioactive components naringin not only showed significant antitussive and expectorant effects but also could suppress both acute and chronic inflammation in the airways and lungs parenchyma.A variety of respiratory diseases is associated with the symptoms of coughing and expectoration,which are closely related to the many stimuli generated during the respiratory system inflammation.Therefore,CGE has great potential in the treatment of respiratory diseases.However,traditional pharmacology usually regards the cellular and tissue/organ-level systems as a black box,thus leading to a lack of mechanistic understanding of drug actions (pharmacodynamics) and the failure in clinical trials of most new drugs.In the present study,we adopted a network pharmacology approach to explore the interactions between CGE components,targets and its various pharmacological effects on respiratory diseases and tried to clarify its multi-component and multi-target mechanism.方法:By chemogenomics database construction and HTDocking process,the active components of CGE and their corresponding targets were retrieved and the interactions were further experimentally validated using iTRAQ-based proteomics.The network relationships among active components,targets,pathways and therapeutic modules were further built to uncover the pharmacological actions of CGE.结果:A respiratory disease-specific chemogenomics database was constructed and was applied to explore the multi-component and multi-target mechanism of CGE which was proven to have therapeutic effects on respiratory diseases previously at the system level.By HTDocking process,67 potential targets of CGE were identified and some key interactions were further experimentally validated.Then,using iTRAQ-based proteomics analysis,the significantly regulated proteins in lung tissues of the model and CGE-treated mice were identified,which could be mainly attributed to tight junction,focal adhesion or regulation of actin cytoskeleton.Based on this,the network relationships among active components,targets,pathways and therapeutic modules were further built to uncover the pharmacological actions of CGE.Finally,a network consisted of several therapeutic modules was incorporated to dissect the therapeutic effects of CGE in different pathological features-relevant biological processes which suggested that CGE might exert multiple therapeutic actions on the treatments of respiratory diseases probably through modulating cell junction and inflammatory response pathways at the system level.结论:The multiple therapeutic actions of CGE on respiratory diseases were mainly associated with the regulation of cell junctions through focal adhesion and tight junction pathways,and inflammatory response through TNF,MAPK and PI3K-Akt signaling pathways at the system level.These results were corresponding to our previous pharmacodynamics results.This study provides basis for the clinical application and further study of CGE,and a reference for elucidating the complex mechanism of other herbal medicines.