title: Matrix Metalloproteinase-1 Activation Contributes to Airway Smooth Muscle Growth and Asthma Severity.
abstract: Matrix metalloproteinase-1 (MMP-1) and mast cells are present in the airways of people with asthma.
  
  
  
  To investigate whether MMP-1 could be activated by mast cells and increase asthma severity.
  
  
  
  Patients 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.
  
  
  
  Airway 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 FEV1and worsening asthma symptoms.
  
  
  
  MMP-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.
authors.affiliation: 1 Division of Respiratory Medicine and Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Shams-Un-Nisa
authors.initials: SU
authors.lastname: Naveed
authors.affiliation: 1 Division of Respiratory Medicine and Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Debbie
authors.initials: D
authors.lastname: Clements
authors.affiliation: 2 National Heart and Lung Institute, Imperial College London and MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom.|3 Respiratory Medicine, Guy's and St Thomas' NHS Trust, London, United Kingdom; and.
authors.forename: David J
authors.initials: DJ
authors.lastname: Jackson
authors.affiliation: 1 Division of Respiratory Medicine and Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Philp
authors.affiliation: 1 Division of Respiratory Medicine and Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Charlotte K
authors.initials: CK
authors.lastname: Billington
authors.affiliation: 4 Department of Histopathology, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.
authors.forename: Irshad
authors.initials: I
authors.lastname: Soomro
authors.affiliation: 1 Division of Respiratory Medicine and Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Catherine
authors.initials: C
authors.lastname: Reynolds
authors.affiliation: 1 Division of Respiratory Medicine and Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Harrison
authors.affiliation: 2 National Heart and Lung Institute, Imperial College London and MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom.
authors.forename: Sebastian L
authors.initials: SL
authors.lastname: Johnston
authors.affiliation: 1 Division of Respiratory Medicine and Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Dominick E
authors.initials: DE
authors.lastname: Shaw
authors.affiliation: 1 Division of Respiratory Medicine and Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Simon R
authors.initials: SR
authors.lastname: Johnson
mesh_terms: D000328:Adult; D001249:Asthma / Q000378:metabolism* / Q000503:physiopathology*; D001980:Bronchi / Q000378:metabolism* / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000378:metabolism / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D018929:Cell Culture Techniques; D005260:Female; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D009130:Muscle, Smooth / Q000378:metabolism* / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D012720:Severity of Illness Index; D013147:Spirometry
chemical_list: D020781:Matrix Metalloproteinase 1
keywords: airway remodeling; airway smooth muscle; asthma; extracellular matrix; mast cells