Naveed, Shams-un-nisa, Clements, Debbie, Jackson, David J., Philp, Christopher, Billington, Charlotte K., Soomro, Irshad N., Reynolds, Catherine, Harrison, Timothy W., Johnston, Sebastian L., Shaw, Dominick E. and Johnson, Simon R.
(2017)
MMP-1 activation contributes to airway smooth muscle growth and asthma severity.
American Journal of Respiratory and Critical Care Medicine, 195
(8).
pp. 1000-1009.
ISSN 1535-4970
Abstract
Introduction: Matrix metalloproteinase-1 and mast cells are present in the airways of people with asthma. We hypothesised that matrix metalloproteinase-1 could be activated by mast cells and increase asthma severity. Methods: Patients with stable asthma and healthy controls underwent spirometry, methacholine challenge, bronchoscopy and their airway smooth muscle cells were grown in culture. A second asthma group and controls had symptom scores, spirometry and bronchoalveolar lavage before and after rhinovirus-induced asthma exacerbations. Extra-cellular matrix was prepared from decellularised airway smooth muscle cultures. Matrix metalloproteinase-1 protein and activity were assessed. Results: Airway smooth muscle cells generated pro-matrix metalloproteinase-1 which was proteolytically activated by mast cell tryptase. Airway smooth muscle treated with activated mast cell supernatants produced extra-cellular matrix which enhanced subsequent airway smooth muscle growth by 1.5 fold (p<0.05) which was dependent on matrix metalloproteinase-1 activation. In asthma, airway pro-matrix metalloproteinase-1 was 5.4 fold higher than control subjects (p=0.002). Mast cell numbers were associated with airway smooth muscle proliferation and matrix metalloproteinase-1 protein associated with bronchial hyper-responsiveness. During exacerbations, matrix metalloproteinase-1 activity increased and was associated with fall in FEV1 and worsening asthma symptoms. Conclusions: Matrix metalloproteinase-1 is activated by mast cell tryptase resulting in a pro-proliferative extra-cellular matrix. In asthma, mast cells are associated with airway smooth muscle growth, matrix metalloproteinase-1 levels are associated with bronchial hyper-responsiveness and matrix metalloproteinase-1 activation with exacerbation severity. Our findings suggest that airway smooth muscle/mast cell interactions contribute to asthma severity by transiently increasing matrix metalloproteinase activation, airway smooth muscle growth and airway responsiveness.
| Item Type: |
Article
|
| Keywords: |
Asthma, Extracellular matrix, Airway remodeling, Airway smooth muscle, Mast cells |
| Schools/Departments: |
University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences > School of Molecular Medical Sciences
University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine > Division of Respiratory Medicine
University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine |
| Identification Number: |
https://doi.org/10.1164/rccm.201604-0822OC |
| Depositing User: |
Eprints, Support
|
| Date Deposited: |
24 Jan 2017 12:09 |
| Last Modified: |
13 Oct 2017 22:17 |
| URI: |
https://eprints.nottingham.ac.uk/id/eprint/40029 |
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