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

Abstract

Background

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

Abbreviations

COPD, chronic obstructive pulmonary disease; FE, frequent exacerbation; IE, infrequent exacerbation; LC-MS/MS, liquid chromatography-tandem mass spectrometry; DDA, data-dependent acquisition; DIA, data-independent acquisition; AUC, area under the curve; ROC, receiver operating characteristic; ELISA, enzyme-linked immunosorbent assay; GOLD, Global Initiative for Chronic Obstructive Lung Disease; FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; DEPs, differentially expressed proteins; GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; PPI, protein–protein interaction; PCA, principal component analysis; PLS-DA, partial least squares discrimination analysis; ARPC5, actin-related protein 2/3 complex subunit 5; C4B, complement C4-B; CKM, creatine kinase, M-type; FCRL5, Fc receptor like 5; FITM1, fat storage-inducing transmembrane protein 1; IGLC2, immunoglobulin lambda constant 2; UBE3C, ubiquitin protein ligase E3C; ITIH3, inter-alpha-trypsin inhibitor heavy chain 3; LYVE1, lymphatic vessel endothelial hyaluronan receptor 1; PON1, paraoxonase 1; AGXT, alanine-glyoxylate and serine-pyruvate aminotransferase; IgKV3D-11, immunoglobulin kappa variable 3D-11; SEPTIN2, septin-2; APOF, apolipoprotein F; DBH, dopamine beta-hydroxylase; FAM20C, extracellular serine/threonine protein kinase FAM20C; HLA-DQA1, major histocompatibility complex class II, DQ alpha 1; PIGR, polymeric immunoglobulin receptor; BGN, biglycan; LD, lipid droplet; PGC-1α, peroxisome proliferator-activated receptor-gamma coactivator 1 alpha.

Data Sharing Statement

The data used to support the findings of this study are available from the corresponding authors upon request.

Ethical Approval

The study has been approved by the Ethics Committee of Zhongshan Hospital affiliated with Fudan University (No. B2017-022R).

Acknowledgments

The authors sincerely thank Drs. Kai Fang, Shan Zhong and Nan Niu from Shenzhen University and Dr Qingying Zhang from Shantou University for assisting data analysis of this study.

Disclosure

The authors declare that they have no competing interests.

Additional information

Funding

This study was supported by grants from the Shenzhen Basic Research Program of Science and Technology Innovation Commission (JCYJ20190808122413582), Shanghai Natural Science Foundation (22ZR1411100), and the National Research & Development Program (2016YFC1304000 and 2016YFC1304002).