Proteinase 3; a potential target in chronic obstructive pulmonary disease and other chronic inflammatory diseases

Abstract

Chronic Obstructive Pulmonary Disease (COPD) is a common, multifactorial lung disease which results in significant impairment of patients' health and a large impact on society and health care burden. It is believed to be the result of prolonged, destructive neutrophilic inflammation which results in progressive damage to lung structures. During this process, large quantities of neutrophil serine proteinases (NSPs) are released which initiate the damage and contribute towards driving a persistent inflammatory state.Neutrophil elastase has long been considered the key NSP involved in the pathophysiology of COPD. However, in recent years, a significant role for Proteinase 3 (PR3) in disease development has emerged, both in COPD and other chronic inflammatory conditions. Therefore, there is a need to investigate the importance of PR3 in disease development and hence its potential as a therapeutic target. Research into PR3 has largely been confined to its role as an autoantigen, but PR3 is involved in triggering inflammatory pathways, disrupting cellular signalling, degrading key structural proteins, and pathogen response.This review summarises what is presently known about PR3, explores its involvement particularly in the development of COPD, and indicates areas requiring further investigation.

Keywords: Chronic obstructive pulmonary disease; Inflammation; Lungs; Proteinase 3/myeloblastin; Serine proteinases.

Fig. 1

Diagrammatically demonstrates the substrate binding pockets S4-S3’ of PR3 with substrate cleavage positions P4-P3’, according to the Schechter and Berger enzyme-ligand binding site numbering convention [19]. The arrows indicate the sites for Val/Ala-containing peptide cleavage and hydrophobic residue binding sites, whilst + indicates positive and – indicates negative residue binding site. Adapted from [13]

Fig. 2

Three-dimensional visualisation of Proteinase 3 by ribbon plot, with the catalytic triad and PR3-specific residues stylised in a stick representation and annotated. Image developed from the Proteinase 3 Protein Data Bank entry (PDB ID: 1FUJ) [15, 21] using YASARA [22]

Fig. 3

Summary of the actions of Proteinase 3 (PR3), as outlined in this review, which likely impact on COPD and other systemic diseases. The processes with a putative central role in the pathophysiology of emphysema are highlighted in bold