• Shams-Un-Nisa Naveed, Debbie Clements, David J Jackson, Christopher Philp, Charlotte K Billington, Irshad Soomro, Catherine Reynolds, Timothy W Harrison, Sebastian L Johnston, Dominick E Shaw, and Simon R Johnson.
• 1 Division of Respiratory Medicine and Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom.
• Am. J. Respir. Crit. Care Med. 2017 Apr 15; 195 (8): 1000-1009.

RationaleMatrix metalloproteinase-1 (MMP-1) and mast cells are present in the airways of people with asthma.ObjectivesTo investigate whether MMP-1 could be activated by mast cells and increase asthma severity.MethodsPatients with stable asthma and healthy control subjects underwent spirometry, methacholine challenge, and bronchoscopy, and their airway smooth muscle cells were grown in culture. A second asthma group and control subjects had symptom scores, spirometry, and bronchoalveolar lavage before and after rhinovirus-induced asthma exacerbations. Extracellular matrix was prepared from decellularized airway smooth muscle cultures. MMP-1 protein and activity were assessed.Measurements And Main ResultsAirway smooth muscle cells generated pro-MMP-1, which was proteolytically activated by mast cell tryptase. Airway smooth muscle treated with activated mast cell supernatants produced extracellular matrix, which enhanced subsequent airway smooth muscle growth by 1.5-fold (P < 0.05), which was dependent on MMP-1 activation. In asthma, airway pro-MMP-1 was 5.4-fold higher than control subjects (P = 0.002). Mast cell numbers were associated with airway smooth muscle proliferation and MMP-1 protein associated with bronchial hyperresponsiveness. During exacerbations, MMP-1 activity increased and was associated with fall in FEV1 and worsening asthma symptoms.ConclusionsMMP-1 is activated by mast cell tryptase resulting in a proproliferative extracellular matrix. In asthma, mast cells are associated with airway smooth muscle growth, MMP-1 levels are associated with bronchial hyperresponsiveness, and MMP-1 activation are associated with exacerbation severity. Our findings suggest that airway smooth muscle/mast cell interactions contribute to asthma severity by transiently increasing MMP activation, airway smooth muscle growth, and airway responsiveness.

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