prolyl-glycyl-proline and Airway-Remodeling

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

Proline-glycine-proline (PGP) is a bioactive fragment of collagen generated by the action of matrix metalloproteinase-9 (MMP-9) and prolylendopeptidase (PE), and capable of eliciting neutrophil chemotaxis and epithelial remodelling. PGP is normally then degraded by leukotriene A. Broncho-alveolar lavage (BAL) fluid was obtained from 38 CF (9 newborns and 29 older children) and 24 non-CF children. BAL cell differentials and levels of PGP, MMP-9, PE and LTA. Whilst PGP was present in all but one of the older CF children tested, it was absent in non-CF controls and the vast majority of CF newborns. BAL levels of MMP-9 and PE were elevated in older children with CF relative to CF newborns and non-CF controls, correlating with airway neutrophilia and supportive of PGP generation. Furthermore, despite extracellular LTA. A striking imbalance between PGP-generating and -degrading enzymes enables PGP accumulation in CF children from early life and potentially supports airway neutrophilia.

Topics: Airway Remodeling; Bronchoalveolar Lavage Fluid; Bronchoscopy; Chemotaxis, Leukocyte; Child; Cystic Fibrosis; Female; Humans; Infant, Newborn; Inflammation; Leukocyte Elastase; Male; Matrix Metalloproteinase 9; Neutrophils; Oligopeptides; Proline; Prolyl Oligopeptidases; Sputum

It is anticipated that bioactive fragments of the extracellular matrix (matrikines) can influence the development and progression of chronic diseases. The enzyme leukotriene A

Topics: Airway Remodeling; Airway Resistance; Animals; Asthma; Bronchi; Cell Count; Disease Models, Animal; Epithelial Cells; Epoxide Hydrolases; Extracellular Matrix; Humans; Hypersensitivity; Inflammation; Inflammation Mediators; Mice, Inbred C57BL; Mucus; Neutrophils; Oligopeptides; Proline; Pyroglyphidae; Respiratory Hypersensitivity; Sputum; T-Lymphocytes, Helper-Inducer