Plasma Proteomics Study Between the Frequent Exacerbation and Infrequent Exacerbation Phenotypes of Chronic Obstructive Pulmonary Disease

Chengyu Yang,1,2,&ast; Li Yang,3,4,&ast; Lei Yang,5 Shuiming Li,5 Ling Ye,1,6 Jinfeng Ye,5 Chengshui Chen,3,4,7 Yiming Zeng,8 Mengchan Zhu,1 Xiaoping Lin,8 Qing Peng,9 Yun Wang,5,10 Meiling Jin1,6 1Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, Huadong Hospital, Fudan University, Shanghai, 200040, People’s Republic of China; 3Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, People’s Republic of China; 4Key Laboratory of Interventional Pulmonology of Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, People’s Republic of China; 5Longhua Innovation Institute for Biotechnology, Shenzhen University, Shenzhen, Guangdong, 518055, People’s Republic of China; 6Department of Allergy, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 7Department of Pulmonary and Critical Care Medicine, the Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Zhejiang, 324000, People’s Republic of China; 8Department of Pulmonary and Critical Care Medicine, the Second Affiliated Hospital of Fujian Medical University, Respiratory Medicine Center of Fujian Province, Quanzhou, Fujian, 362000, People’s Republic of China; 9Department of Pulmonary and Critical Care Medicine, Minhang Hospital, Fudan University, Shanghai, 201199, People’s Republic of China; 10Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou, Guangdong, 515041, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Meiling Jin, Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China, Email jin.meiling@zs-hospital.sh.cn Yun Wang, Longhua Innovation Institute for Biotechnology, Shenzhen University, Shenzhen, Guangdong, 518055, People’s Republic of China, Email yunw@szu.edu.cnBackground: Frequent exacerbation (FE) and infrequent exacerbation (IE) are two phenotypes of chronic obstructive pulmonary disease (COPD), of which FE is associated with a higher incidence of exacerbation and a serious threat to human health. Because the pathogenesis mechanisms of FE are unclear, this study aims to identify FE-related proteins in the plasma via proteomics for use as predictive, diagnostic, and therapeutic biomarkers of COPD.Methods: A cross-sectional study was conducted in which plasma protein profiles were analyzed in COPD patients at stable stage, and differentially expressed proteins (DEPs) were screened out between the FE and IE patients. FE-related DEPs were identified using data-independent acquisition-based proteomics and bioinformatics analyses. In addition, FE-related candidates were verified by enzyme-linked immunosorbent assay.Results: In this study, 47 DEPs were screened out between the FE and IE groups, including 20 upregulated and 27 downregulated proteins. Key biological functions (eg, neutrophil degranulation, extracellular exosome, protein homodimerization activity) and signaling pathways (eg, arginine and proline metabolism) were enriched in association with the FE phenotype. Receiver operating characteristic (ROC) analysis of the 11 combined DEPs revealed an area under the curve of 0.985 (p < 0.05) for discriminating FE from IE. Moreover, correlation and ROC curve analyses indicated that creatine kinase, M-type (CKM) and fat storage-inducing transmembrane protein 1 (FITM1) might be clinically significant in patients with the FE phenotype. In addition, plasma expression levels of CKM and FITM1 were validated to be significantly decreased in the FE group compared with the IE group (CKM: p < 0.01; FITM1: p < 0.05).Conclusion: In this study, novel insights into COPD pathogenesis were provided by investigating and comparing plasma protein profiles between the FE and IE patients. CKM, FITM1, and a combinative biomarker panel may serve as useful tools for assisting in the precision diagnosis and effective treatment of the FE phenotype of COPD.Keywords: chronic obstructive pulmonary disease, frequent exacerbation, data-independent acquisition, proteomics, bioinformatics analysis