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

Samia Akthar, Dhiren F. Patel, Rebecca C. Beale, Teresa Peiró, Xin Xu, Amit Gaggar, Patricia L. Jackson, J. Edwin Blalock, Clare M. Lloyd and Robert J. Snelgrove ()
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Samia Akthar: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London
Dhiren F. Patel: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London
Rebecca C. Beale: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London
Teresa Peiró: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London
Xin Xu: Allergy and Critical Care Medicine, University of Alabama at Birmingham and Lung Health Center, University of Alabama at Birmingham
Amit Gaggar: Allergy and Critical Care Medicine, University of Alabama at Birmingham and Lung Health Center, University of Alabama at Birmingham
Patricia L. Jackson: Allergy and Critical Care Medicine, University of Alabama at Birmingham and Lung Health Center, University of Alabama at Birmingham
J. Edwin Blalock: Allergy and Critical Care Medicine, University of Alabama at Birmingham and Lung Health Center, University of Alabama at Birmingham
Clare M. Lloyd: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London
Robert J. Snelgrove: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9423

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