Proteomics-Based Study of Potential Emphysema Biomarkers Reveals Systemic Redox System and Extracellular Matrix Component Dysregulation

TL;DR

This study identifies potential biomarkers for emphysema by analyzing blood plasma proteins and highlights systemic changes in redox and extracellular matrix processes.

Contribution

The study proposes NADP-ME as a novel biomarker candidate for emphysema and reveals systemic extracellular matrix dysregulation.

Findings

NADP-dependent malic enzyme (NADP-ME) was the only differentially expressed protein in emphysema vs. COPD without emphysema.

BMP1, ADAMTSL-2, -4, and IGFBP4-6 were upregulated in emphysema compared to healthy never-smokers.

Fibulin-1, -3 and immunoglobulin components were downregulated in emphysema compared to healthy never-smokers.

Abstract

Objective: Emphysema is an important chronic obstructive pulmonary disease (COPD) phenotype characterized by the destruction of air spaces distal to the terminal bronchiole. Aiming to detect potential emphysema biomarkers and to assess the systemic effects of emphysema in blood plasma, we conducted a small cross-sectional shotgun proteomics study. Methods: This study included N = 40 participants divided into four subgroups (N = 10 per group): patients with emphysema and COPD (CE), patients with COPD but without emphysema (CN), healthy smokers (HS) and healthy never-smokers (HN). The participants were sampled non-probabilistically to be similar in terms of age, sex and comorbidities. Participants’ blood plasma was analyzed using liquid chromatography–mass spectrometry. Bioinformatic analysis included detection of differentially expressed proteins (DEPs) and overrepresentation analysis (ORA). Results: Across all groups, a total of 994 proteins were identified, with NADP-dependent malic enzyme (NADP-ME; encoded by ME1) being the only DEP in the CE vs. CN contrast. Proteins such as BMP1, ADAMTSL-2, -4 and IGFBP4, -5, 6 were identified to be upregulated in CE vs. HN. Fibulin-1, -3 and several immunoglobulin components were identified to be downregulated in the CE vs. HN contrast. ORA revealed several enriched processes, including serine-type endopeptidase activity, insulin-like growth factor I and II binding, and signaling receptor binding. Conclusion: We propose NADP-ME, an important enzyme of intermediary metabolism and redox homeostasis, as a potential biomarker candidate of emphysema. Notably, NADP-ME is also implicated in anoikis resistance. Additionally, changes in the expression levels of BMP1, ADAMTSL-2 and -4, and fibulin suggest potential major systemic effects of extracellular matrix perturbation. As all data was derived from LC-MS analysis, these findings need to be further evaluated with complementary methods.

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