Matrix metalloproteinase activation by free neutrophil elastase contributes to bronchiectasis progression in early cystic fibrosis.
Neutrophil elastase is the most significant predictor of bronchiectasis in early-life cystic fibrosis; however, the causal link between neutrophil elastase and airway damage is not well understood. Matrix metalloproteinases (MMPs) play a crucial role in extracellular matrix modelling and are activated by neutrophil elastase. The aim of this study was to assess if MMP activation positively correlates with neutrophil elastase activity, disease severity and bronchiectasis in young children with cystic fibrosis.Total MMP-1, MMP-2, MMP-7, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-2 and TIMP-1 levels were measured in bronchoalveolar lavage fluid collected from young children with cystic fibrosis during annual clinical assessment. Active/pro-enzyme ratio of MMP-9 was determined by gelatin zymography. Annual chest computed tomography imaging was scored for bronchiectasis.A higher MMP-9/TIMP-1 ratio was associated with free neutrophil elastase activity. In contrast, MMP-2/TIMP-2 ratio decreased and MMP-1 and MMP-7 were not detected in the majority of samples. Ratio of active/pro-enzyme MMP-9 was also higher in the presence of free neutrophil elastase activity, but not infection. Across the study cohort, both MMP-9/TIMP-1 and active MMP-9 were associated with progression of bronchiectasis.Both MMP-9/TIMP-1 and active MMP-9 increased with free neutrophil elastase and were associated with bronchiectasis, further demonstrating that free neutrophil elastase activity should be considered an important precursor to cystic fibrosis structural disease.
School of Paediatrics and Child Health, University of Western Australia, Perth, Australia Telethon Kids Institute, University of Western Australia, Perth, Australia.
Luke W
LW
Garratt
Telethon Kids Institute, University of Western Australia, Perth, Australia Dept of Respiratory Medicine, Princess Margaret Hospital for Children, Perth, Australia.
Erika N
EN
Sutanto
Telethon Kids Institute, University of Western Australia, Perth, Australia.
Kak-Ming
KM
Ling
School of Paediatrics and Child Health, University of Western Australia, Perth, Australia.
Kevin
K
Looi
School of Paediatrics and Child Health, University of Western Australia, Perth, Australia Centre for Cell Therapy and Regenerative Medicine, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia.
Thomas
T
Iosifidis
Telethon Kids Institute, University of Western Australia, Perth, Australia.
Kelly M
KM
Martinovich
Telethon Kids Institute, University of Western Australia, Perth, Australia.
Nicole C
NC
Shaw
Telethon Kids Institute, University of Western Australia, Perth, Australia Dept of Respiratory Medicine, Princess Margaret Hospital for Children, Perth, Australia.
Elizabeth
E
Kicic-Starcevich
School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, Australia Priority Research Centre for Asthma and Respiratory Disease, Hunter Medical Research Institute, Newcastle, Australia Dept of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
Darryl A
DA
Knight
Dept of Respiratory Medicine, Royal Children's Hospital, Melbourne, Australia Murdoch Childrens Research Institute, Melbourne, Australia Dept of Paediatrics, University of Melbourne, Melbourne, Australia.
Sarath
S
Ranganathan
School of Paediatrics and Child Health, University of Western Australia, Perth, Australia Telethon Kids Institute, University of Western Australia, Perth, Australia Dept of Respiratory Medicine, Princess Margaret Hospital for Children, Perth, Australia Centre for Cell Therapy and Regenerative Medicine, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia.
Stephen M
SM
Stick
School of Paediatrics and Child Health, University of Western Australia, Perth, Australia Telethon Kids Institute, University of Western Australia, Perth, Australia Dept of Respiratory Medicine, Princess Margaret Hospital for Children, Perth, Australia Centre for Cell Therapy and Regenerative Medicine, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia Anthony.Kicic@telethonkids.org.au.
Anthony
A
Kicic
D001987:Bronchiectasis / Q000150:complications / Q000201:enzymology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000150:complications* / Q000201:enzymology; D018450:Disease Progression; D005260:Female; D006801:Humans; D007223:Infant; D019272:Leukocyte Elastase / Q000378:metabolism*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*; D014057:Tomography, X-Ray Computed
C560822:TIMP1 protein, human; C560823:TIMP2 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D019272:Leukocyte Elastase; D020782:Matrix Metalloproteinases