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

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.; Johnson, Simon R.

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.

Citation

Naveed, S.-U.-N., Clements, D., Jackson, D. J., Philp, C., Billington, C. K., Soomro, I. N., Reynolds, C., Harrison, T. W., Johnston, S. L., Shaw, D. E., & Johnson, S. R. (2017). MMP-1 activation contributes to airway smooth muscle growth and asthma severity. American Journal of Respiratory and Critical Care Medicine, 195(8), 1000-1009. https://doi.org/10.1164/rccm.201604-0822OC

• Journal Article Type: Article
• Acceptance Date: Dec 7, 2016
• Online Publication Date: Dec 14, 2016
• Publication Date: Apr 15, 2017
• Deposit Date: Jan 24, 2017
• Publicly Available Date: Jan 24, 2017
• Journal: American Journal of Respiratory and Critical Care Medicine
• Print ISSN: 1073-449X
• Electronic ISSN: 1535-4970
• Publisher: American Thoracic Society
• Peer Reviewed: Peer Reviewed
• Volume: 195
• Issue: 8
• Pages: 1000-1009
• DOI: https://doi.org/10.1164/rccm.201604-0822OC
• Keywords: Asthma, Extracellular matrix, Airway remodeling, Airway smooth muscle, Mast cells
• Public URL: https://nottingham-repository.worktribe.com/output/856199
• Publisher URL: http://www.atsjournals.org/doi/abs/10.1164/rccm.201604-0822OC?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed
• Contract Date: Jan 24, 2017