MMP-1 activation contributes to airway smooth muscle growth and asthma severity

Naveed, Shams-un-nisa and Clements, Debbie and Jackson, David J. and Philp, Christopher and Billington, Charlotte K. and Soomro, Irshad N. and Reynolds, Catherine and Harrison, Timothy W. and Johnston, Sebastian L. and 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

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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: 10.1164/rccm.201604-0822OC
Depositing User: Eprints, Support
Date Deposited: 24 Jan 2017 12:09
Last Modified: 23 May 2017 00:55
URI: http://eprints.nottingham.ac.uk/id/eprint/40029

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