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

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Title: MMP-1 activation contributes to airway smooth muscle growth and asthma severity
Authors: Naveed, SU
Clements, D
Jackson, DJ
Philp, C
Billington, CK
Soomro, I
Reynolds, C
Harrison, TW
Johnston, SL
Shaw, DE
Johnson, SR
Item Type: Journal Article
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.
Issue Date: 14-Dec-2016
Date of Acceptance: 7-Dec-2016
URI: http://hdl.handle.net/10044/1/44587
DOI: https://dx.doi.org/10.1164/rccm.201604-0822OC
ISSN: 1535-4970
Publisher: American Thoracic Society
Start Page: 1000
End Page: 1009
Journal / Book Title: American Journal of Respiratory and Critical Care Medicine
Volume: 195
Issue: 8
Copyright Statement: © 2016 American Thoracic Society
Sponsor/Funder: Commission of the European Communities
Asthma UK
Asthma UK
Medical Research Council (MRC)
National Institute for Health Research
Funder's Grant Number: 233015
CH11SJ
CH11SJ
G1000758
NF-SI-0514-10092
Keywords: Science & Technology
Life Sciences & Biomedicine
Critical Care Medicine
Respiratory System
General & Internal Medicine
asthma
extracellular matrix
airway remodeling
airway smooth muscle
mast cells
EXTRACELLULAR-MATRIX
SERINE PROTEASES
CHILDHOOD ASTHMA
MAST-CELLS
IN-VITRO
PROLIFERATION
INFLAMMATION
COLLAGENASE
OBSTRUCTION
BRONCHOCONSTRICTION
Adult
Asthma
Bronchi
Bronchial Hyperreactivity
Bronchial Provocation Tests
Cell Culture Techniques
Female
Humans
Male
Matrix Metalloproteinase 1
Muscle, Smooth
Myocytes, Smooth Muscle
Severity of Illness Index
Spirometry
11 Medical And Health Sciences
Publication Status: Published
Conference Place: United States
Appears in Collections:National Heart and Lung Institute
Faculty of Medicine



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