Matrikines are key regulators in modulating the amplitude of lung inflammation in acute pulmonary infection

Abstract

Bioactive matrix fragments (matrikines) have been identified in a myriad of disorders, but their impact on the evolution of airway inflammation has not been demonstrated. We recently described a pathway where the matrikine and neutrophil chemoattractant proline–glycine–proline (PGP) could be degraded by the enzyme leukotriene A4 hydrolase (LTA4H). LTA4H classically functions in the generation of pro-inflammatory leukotriene B4, thus LTA4H exhibits opposing pro- and anti-inflammatory activities. The physiological significance of this secondary anti-inflammatory activity remains unknown. Here we show, using readily resolving pulmonary inflammation models, that loss of this secondary activity leads to more pronounced and sustained inflammation and illness owing to PGP accumulation. PGP elicits an exacerbated neutrophilic inflammation and protease imbalance that further degrades the extracellular matrix, generating fragments that perpetuate inflammation. This highlights a critical role for the secondary anti-inflammatory activity of LTA4H and thus has consequences for the generation of global LTA4H inhibitors currently being developed.

Control of angiogenesis and host response by modulating the cell adhesion properties of an Elastin-Like Recombinamer-based hydrogel

“…Firstly, the presence of both general cell adhesion sequences (RGD) and specific endothelial cell adhesion sequences (REDV) previously described by Hubbell et al [43], which together function as a trigger agent for the adhesion and spreading of the proangiogenic cells. Secondly, the presence of the VGVAPG sequence that is well demonstrated to be chemotactic for monocytes and sensitive to proteolysis by elastolytic enzymes [44]. This sequence promotes a cell guided degradation of the RR-gels by recruitment of monocytes that will help matrix colonization, opening the way to further cells like endothelial cells and fibroblasts as confirmed by the histological images.…”

Bioactive extracellular matrix fragments in lung health and disease

“…Each matrikine increased airway inflammation, and silencing of PGP prevented the later generation of elastin fragments. The interplay of these bioactive fragments in lung disease appears to be both temporally and spatially hierarchical (101). Future studies on matrikines in lung disease should correlate different stages of disease (i.e., clinical stability versus exacerbation) with measurements of matrikines, immune cells, and other cytokines in order to understand how matrikines influence known markers of disease progression.…”

The extracellular matrix in myocardial injury, repair, and remodeling

“…In injured and remodeling tissues, protease-mediated fragmentation of matrix proteins results in generation of matrikines (29)(30)(31)(32). Elastin fragments and collagen-derived peptides are the best-studied matrikines and have been implicated in activation of immune cells and fibroblasts (29,33).…”