title: 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.
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
authors.forename: Samia
authors.initials: S
authors.lastname: Akthar
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
authors.forename: Dhiren F
authors.initials: DF
authors.lastname: Patel
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Beale
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
authors.forename: Teresa
authors.initials: T
authors.lastname: Peiró
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham and Lung Health Center, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 3529, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham and Lung Health Center, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 3529, USA.|Gregory Fleming James Cystic Fibrosis Center and Program in Protease and Matrix Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.|Birmingham V.A. Medical Center, Birmingham, Alabama 35294, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Gaggar
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham and Lung Health Center, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 3529, USA.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Jackson
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham and Lung Health Center, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 3529, USA.|Birmingham V.A. Medical Center, Birmingham, Alabama 35294, USA.
authors.forename: J Edwin
authors.initials: JE
authors.lastname: Blalock
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
authors.forename: Clare M
authors.initials: CM
authors.lastname: Lloyd
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Snelgrove
mesh_terms: D000818:Animals; D004851:Epoxide Hydrolases / Q000235:genetics* / Q000276:immunology; D005109:Extracellular Matrix / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D006192:Haemophilus Infections / Q000276:immunology*; D019741:Haemophilus influenzae type b; D007249:Inflammation; D019272:Leukocyte Elastase / Q000378:metabolism; D007975:Leukotriene B4 / Q000276:immunology; D008168:Lung / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology*; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D009842:Oligopeptides / Q000276:immunology*; D018410:Pneumonia, Bacterial / Q000276:immunology; D011018:Pneumonia, Pneumococcal / Q000276:immunology*; D011392:Proline / Q000031:analogs & derivatives* / Q000276:immunology; D018102:Receptors, Leukotriene B4 / Q000235:genetics / Q000276:immunology; D013296:Streptococcus pneumoniae
chemical_list: C503704:Ltb4r1 protein, mouse; D009842:Oligopeptides; D018102:Receptors, Leukotriene B4; C113164:prolyl-glycyl-proline; D007975:Leukotriene B4; D011392:Proline; D004851:Epoxide Hydrolases; D019272:Leukocyte Elastase; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D053508:Matrix Metalloproteinase 12; C000602031:matrix metallopeptidase 12, mouse; C043134:leukotriene A4 hydrolase