prolyl-glycyl-proline and Lung-Diseases

Matrikines are bioactive fragments of the extracellular matrix (ECM) that are fundamental in regulating a diverse array of physiological processes. The tripeptide Proline-Glycine-Proline (PGP) is a collagen-derived matrikine that has classically been described as a neutrophil chemoattractant. In this article, we describe our current understanding of the pathways that generate, degrade and modify PGP to dictate its bioavailability and stability. Additionally, we discuss our expanding appreciation of the capacity of PGP to regulate diverse cell types and biological processes, independent of its activity on neutrophils, including a putative role in wound repair. We argue that PGP functions as a primitive and conserved damage-associated molecular pattern, which is generated during infection or injury and subsequently acts to shape ensuing inflammatory and repair processes. As a fragment of the ECM that accumulates at the epicentre of the action, PGP is perfectly positioned to focus neutrophils to the exact site required and direct a localised repair response. However, it is essential that PGP is efficiently degraded, as if this matrikine is allowed to persist then pathology can ensue. Accordingly, we discuss how this pathway is subverted in chronic lung diseases giving rise to persistent inflammation and pathological tissue remodelling.

Topics: Airway Remodeling; Animals; Collagen; Extracellular Matrix; Humans; Lung; Lung Diseases; Neutrophil Infiltration; Oligopeptides; Peptide Fragments; Proline; Signal Transduction

Persistent neutrophilia is implicated in the pathology of several chronic lung diseases and consequently targeting the signals that drive the recruitment of these cells offers a plausible therapeutic strategy. The tripeptide Pro-Gly-Pro (PGP) is a neutrophil chemoattractant derived from extracellular matrix collagen and implicated in diseases such as COPD and cystic fibrosis. It was anticipated that PGP exerts its chemoatactic activity by mimicking key sequences found within classical neutrophil chemokines, such as CXCL8, and binding their receptors, CXCR1/2. Recently, however, the role of CXCR1/2 as the receptors for PGP has been questioned. In this issue of European Journal of Pharmacology, three studies address this controversy and demonstrate CXCR1/2 to be a common receptor for CXCL8 and PGP. Accordingly, these studies demonstrate the therapeutic potential of targeting this shared receptor to simultaneously alleviate neutrophilic inflammation driven by multiple neutrophil chemoattractants.

Topics: Acetylation; Chronic Disease; Humans; Interleukin-8; Lung Diseases; Molecular Targeted Therapy; Neutrophils; Oligopeptides; Proline; Receptors, CXCR

Neutrophils represent a prominent source of pathology in an array of persistent pulmonary diseases. A recent article published in Science describes a novel anti-inflammatory pathway that degrades the neutrophil chemoattractant Pro-Gly-Pro (PGP) to limit neutrophilic inflammation of the lung. Degradation of PGP was mediated through the action of leukotriene A4 hydrolase (LTA4H), an enzyme classically recognised for its capacity to generate another neutrophil chemoattractant, leukotriene B4 (LTB4). The same enzyme therefore has opposing proinflammatory (LTB4 generation) and anti-inflammatory (PGP degradation) activities that govern neutrophilic inflammation. Intriguingly, cigarette smoke, a key risk factor for the development of chronic obstructive pulmonary disease, impedes PGP degradation but not LTB4 generation by LTA4H. Cigarette smoke therefore essentially converts LTA4H into an exclusively proinflammatory enzyme, whereby both PGP and LTB4 can drive persistent neutrophila observed in chronic obstructive pulmonary disease. In recent years there has been significant pharmaceutical interest in the development of LTA4H inhibitors to alleviate LTB4-mediated pathologies. In light of these new findings, such strategies should be viewed with caution since they may inadvertently prevent PGP degradation and promote chronic neutrophilic inflammation.

Topics: Chemotactic Factors; Epoxide Hydrolases; Humans; Inflammation Mediators; Lung Diseases; Neutrophil Infiltration; Oligopeptides; Proline; Tobacco Smoke Pollution