The matrikine PGP as a potential biomarker in COPD

Abstract

The lack of a well-characterized biomarker for the diagnosis of chronic obstructive pulmonary disease (COPD) has increased interest toward finding one, because this would provide potential insight into disease pathogenesis and progression. Since persistent neutrophilia is an important hallmark in COPD Pro-Gly-Pro (PGP), an extracellular matrix-derived neutrophil chemoattractant, has been suggested to be a potential biomarker in COPD. The purpose of this review is to critically examine both biological and clinical data related to the role of PGP in COPD, with particular focus on its role as a clinical biomarker and potential therapeutic target in disease. The data provided in this review will offer insight into the potential use of PGP as end point for future clinical studies in COPD lung disease. Following PGP levels during disease might serve as a guide for the progression of lung disorders.

Keywords: COPD; biomarker; lung disease; proline-glycine-proline; prolyl endopeptidase.

Fig. 1.

Illustration of the Pro-Gly-Pro (PGP) pathology in neutrophilic inflammation. 1: Cigarette smoke inhalation causes tissue resident cells such as macrophages and epithelial cells to release several mediators, including prolyl endopeptidase (PE), IL-8, leukotriene A₄ hydrolase (LTA₄H), and matrix metalloproteinase (MMP)8/9. 2 and 3: The neutrophilic chemokine IL-8 attracts neutrophils from the capillary via binding with CXCR1/2. 4 and 5: Neutrophils subsequently release MMPs and PE, which cleave collagen from the extracellular matrix to release the tripeptide and neutrophil chemoattractant PGP. LTA₄H can cleave and inactivate PGP. However, components of cigarette smoke, such as acrolein, inhibit LTA₄H and can acetylate the PGP to form the more potent acetylated form of PGP (N-α-PGP). Moreover, N-α-PGP cannot be cleaved by LTA₄H. PGP-generating enzymes can now be released by neutrophils after recruitment and activation by PGP: a self-sustaining neutrophilic inflammation. ROS, reactive oxygen species; P+GP, proline + glycine-proline.