Study On Syndrome Elements And Drug Repositioning For Bronchiectasis-Chronic Obstructive Pulmonary Disease Overlap Syndrome

Objectives: 1.Exploring the distribution of syndrome elements and syndrome types in inpatients with the Bronchiectasis-Chronic Obstructive Pulmonary Disease Overlap Syndrome(BCOS),the heterogeneity of the syndrome elements,and analyzing the differences in clinical features between the syndrome types.2.Developing a tool of drug repositioning for Chinese medicine formulations,screening classical formulas for the treatment of BCOS based on the strategy of "treating different diseases together",and exploring the potential pharmacological mechanisms.Methods: 1.The first part was a single-center cross-sectional study based on hospital electronic medical record data.Electronic medical record data of all adult BCOS patients admitted to the pulmonary and cardiology departments of the Affiliated Hospital of the Shandong University of Chinese Medicine from January 2019 to December 2021 were included,excluding patients who were not admitted for chronic obstructive pulmonary disease(COPD)or bronchiectasis.Demographic data,hospitalization information,smoking history,information from the four Chinese medicine consultations,comorbidities,laboratory tests,and imaging data were extracted.The syndrome elements were inferred based on the "Syndrome Element Identification",and a latent class model was constructed to achieve syndrome element-based classification,and Boruta’s algorithm,hypothesis testing,generalized linear regression model,and correlation analysis were applied to identify the heterogeneity of syndrome elements and differences in clinical characteristics among the syndrome elements.2.The second part is a drug repositioning study of classical famous prescriptions.The130 prescriptions from the “Catalogue of Ancient Classical Masterpieces” and the “Expert Consensus on Commonly Used Classical Masterpieces for Pulmonary Diseases” were used as candidate classical masterpieces,and the targets were derived from known and predicted targets of TCMSP,BATMAN-TCM,HERB,and CTD.The RNA-seq data of airway epithelial cells from COPD patients was used to construct the COPD disease network.The non-cystic fibrosis bronchiectasis-related genes from Phenolyzer,Mala Cards,and Dis Ge Net were integrated to construct a bronchiectasis disease network.A tool was developed in R language to implement the pathway fingerprinting algorithm and the network destructiveness analysis algorithm,which was used as a tool to score drug repositioning of candidate classical formulas and identify classical formulas that satisfy both COPD and bronchiectasis drug repositioning.A robust rank aggregation algorithm was applied to integrate the two scores,and the best classical formula was identified by combining the syndrome elements and the score.Using the association analysis,network topology analysis,network community identification algorithms,and functional enrichment analysis,key drug combinations,key network targets,and key pharmacological mechanisms were analyzed.Results: 1.Cross-sectional study of syndrome elements: the 131 patients with BCOS were included.The syndrome elements with frequencies above 90% were phlegm(99.24%),qi deficiency(97.71%),yang deficiency(91.60%),lung(100%)and heart(92.37%).Three latent classes(syndrome types)were identified from the syndrome elements profiler of BCOS: Gan Fei Bu He(Class 1),Pi Fei Tan Yu(Class 2),and Xin Fei Liang Xu(Class 3).Age,a CCI score and N-terminal brain natriuretic peptide precursor were significantly higher in patients with Gan Fei Bu He and Pi Fei Tan Yu than in those with Xin Fei Liang Xu.The absolute eosinophil count,eosinophil percentage and glomerular filtration rate were significantly lower in patients with Gan Fei Bu He and Pi Fei Tan Yu,while the pulmonary artery systolic blood pressure was significantly higher than in these two syndrome types.2.Drug repositioning study: The R package immcp was developed based on the R language to implement the pathway fingerprinting algorithm and network anti-destructive analysis algorithm,which were used as tools to screen 26 Chinese classic formulas.The network pharmacology analysis showed that IL1 B,IL6,CXCL8,TNF,PTGS2,ALDH3A1,CYP1A1,NQO1,ALB,GPX2 and STAT3 were the core targets of the target interaction network of the Chinese classic formulas.After the integration of the two algorithm scores,the top 5 rank-ranked formulas in the order of scoring were Sangyi Tang,Er Chen Tang,Han Xia Bai Zhu Tian Ma Tang,Ma Huang Tang,and Ma Heng Shi Gan Tang,whose key herbal combinations were Ma Huang – Ku Xing Ren,Han Xia-Bai Zhu-Fu Ling and Chuan Xiong-Bai Zhi-Bai Shao.The core targets of the target interaction network of the key drug combinations were IL1 B,IL6,CXCL8,TNF,PTGS2,ALDH3A1,CYP1A1,NQO1,and ALB.functional enrichment analysis showed that the potential pharmacological mechanisms of the classical famous formulae were related to the upstream production and downstream effects of pro-inflammatory cytokines and inflammatory mediators.Conclusions: 1.The lung,heart,phlegm,qi deficiency and yang deficiency are the basic syndrome elements of BCOS;spleen,liver,kidney,qi stagnation,blood deficiency,blood stasis,cold,yang hyperactivity,dampness,and water retention are the syndrome elements that exist heterogeneously in patients with BCOS.2.The BCOS can be divided into three syndrome types: Gan Fei Bu He,Pi Shen Tan Yu and Xin Fei Liang Xu.3.Differences in the clinical features of the three syndrome types are mainly reflected in differences in the burden of comorbidities.4.The key pathogenic mechanism of BCOS is the deficiency of the Wei-Qi,which manifests itself as a deficiency of the heart and lung in the upper jiao,which in turn affects the spleen and stomach in the middle jiao and the liver and kidney in the lower jiao;and a deficiency of the Qi in the lower jiao,which develops into an abnormality of water and fluid metabolism,stagnation of the blood and Qi in the whole body.5.The Sanpian Decoction,Erchen Decoction,Banxia Baizhu Tianma Decoction,Mahuang Decoction and Maxingshigan Decoction are potentially classical famous formulas for the treatment of BCOS;ephedra-bitter almond,chuanxiong-dahurica-bai shao,henfangporing-bai zhi are the core herbal combinations for the treatment of BCOS.6.The regulation of Senescence-Associated Secretory Phenotype is the key pharmacological mechanism of classical famous formulae for the treatment of BCOS.