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J Cyst Fibros. 2019 Jun 5. pii: S1569-1993(19)30769-6. doi: 10.1016/j.jcf.2019.05.017. [Epub ahead of print]

Abnormal pro-gly-pro pathway and airway neutrophilia in pediatric cystic fibrosis.

Author information

1
Cystic Fibrosis and Chronic Lung Infection, National Heart & Lung Institute, Imperial College London, United Kingdom; Paediatric Respiratory Medicine, Royal Brompton & Harefield NHS Foundation Trust, London, United Kingdom.
2
Inflammation Repair and Development, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, United Kingdom.
3
Division of Pulmonary, Allergy and Critical Care Medicine, Program in Protease and Matrix Biology, Gregory Fleming James Cystic Fibrosis Centre and Lung Health Center, University of Alabama at Birmingham, Birmingham, AL 35294., United States of America; Birmingham V.A. Medical Centre, Birmingham, AL 35294, United States of America.
4
Paediatric Respiratory Medicine, Children's Hospital, Lucerne, Switzerland.
5
Paediatric Respiratory Medicine, Royal Brompton & Harefield NHS Foundation Trust, London, United Kingdom.
6
Paediatric Respiratory Medicine, Royal Brompton & Harefield NHS Foundation Trust, London, United Kingdom; Inflammation Repair and Development, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, United Kingdom.
7
Alder Hey Children's NHS Foundation Trust, Liverpool L14 5AB, United Kingdom.
8
Cystic Fibrosis and Chronic Lung Infection, National Heart & Lung Institute, Imperial College London, United Kingdom.
9
Division of Pulmonary, Allergy and Critical Care Medicine, Program in Protease and Matrix Biology, Gregory Fleming James Cystic Fibrosis Centre and Lung Health Center, University of Alabama at Birmingham, Birmingham, AL 35294., United States of America.
10
Inflammation Repair and Development, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, United Kingdom. Electronic address: robert.snelgrove@imperial.ac.uk.

Abstract

BACKGROUND:

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 A4 hydrolase (LTA4H) to limit inflammation and remodelling. This study hypothesized that early and persistent airway neutrophilia in Cystic Fibrosis (CF) may relate to abnormalities in the PGP pathway and sought to understand underlying mechanisms.

METHODS:

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 LTA4H were assessed.

RESULTS:

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 LTA4H commonly being greatly elevated concomitantly with inflammation to promote PGP degradation, this was not the case in CF children, potentially owing to degradation by neutrophil elastase.

CONCLUSIONS:

A striking imbalance between PGP-generating and -degrading enzymes enables PGP accumulation in CF children from early life and potentially supports airway neutrophilia.

KEYWORDS:

Cystic fibrosis; Matrikine; Neutrophil; Protease

PMID:
31176670
DOI:
10.1016/j.jcf.2019.05.017
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