Journal Article

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

Beale, Rebecca C., Gaggar, Amit, Akthar, Samia, Snelgrove, Robert J., Xu, Xin, Blalock, J. Edwin, Patel, Dhiren F., Peiró, Teresa, Jackson, Patricia L., Lloyd, Clare M.

2015

Overview

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 A 4 hydrolase (LTA 4 H). LTA 4 H classically functions in the generation of pro-inflammatory leukotriene B 4 , thus LTA 4 H 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 LTA 4 H and thus has consequences for the generation of global LTA 4 H inhibitors currently being developed. Proteases degrade extracellular matrix during inflammation, releasing peptides that can recruit neutrophils. Here the authors show that degradation of such bioactive peptide by the enzyme leukotriene A4 hydrolase is critical to limit pulmonary inflammation during bacterial infection in mice.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Pub. Group
• Subject: 13/21 / 13/31 / 631/250/255/1578 / 631/250/256 / 631/80/86 / 64/110 / 64/60 / 82/58 / 96 / Animals / Epoxide Hydrolases - genetics / Epoxide Hydrolases - immunology / Extracellular Matrix - immunology / Extracellular Matrix - metabolism / Flow Cytometry / Haemophilus Infections - immunology / Haemophilus influenzae type b / Humanities and Social Sciences / Inflammation / Leukocyte Elastase - metabolism / Leukotriene B4 - immunology / Lung - immunology / Macrophages, Alveolar - immunology / Matrix Metalloproteinase 12 - metabolism / Matrix Metalloproteinase 9 - metabolism / Mice / Mice, Knockout / multidisciplinary / Neutrophils - immunology / Oligopeptides - immunology / Pneumonia, Bacterial - immunology / Pneumonia, Pneumococcal - immunology / Proline - analogs & derivatives / Proline - immunology / Receptors, Leukotriene B4 - genetics / Receptors, Leukotriene B4 - immunology / Science / Science (multidisciplinary) / Streptococcus pneumoniae