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S92 Matrix metalloproteinase-1 activation by mast cell tryptase causes airway remodelling and is associated with bronchial hyper-responsiveness in patients with asthma
  1. S Naveed1,
  2. D Clements1,
  3. D Jackson2,
  4. D Shaw1,
  5. S Johnston2,
  6. SR Johnson1
  1. 1University of Nottingham, Nottingham, UK
  2. 2Imperial College, London, UK

Abstract

Introduction Matrix Metalloproteinase-1 (MMP-1) is a collagenase, which is present, in its inactive form, in the airways, lung parenchyma and in broncho-alveolar lavage (BAL) fluid of patients with asthma. We hypothesised that MMP-1 could be activated during asthma exacerbations leading to extra-cellular matrix (ECM) processing which contributes to airway remodelling.

Methods Patients with stable, BTS stage 2/3 asthma, and healthy controls underwent Juniper asthma questionnaire, spirometry, methacholine challenge and bronchoscopy. Bronchial washings were processed for MMP-1 protein and activation. A second cohort of 14 patients with mild and 16 with moderate asthma and 10 controls underwent rhinovirus inoculation and had BAL fluid collected 14 days before and 4 days after inoculation. MMP-1 activity was assessed by fluorescent activity assay. ECM was prepared from decellularised airway smooth muscle (ASM) cultures. Cell proliferation was measured by MTT reduction assay and cell counts. Mast cell supernatants were obtained from cultures of HMC-1 cells activated using Phorbol 12-myristate 13-acetate/Calcium ionophore.

Results Pro-MMP-1 was expressed more strongly in bronchial washings in asthma than controls (P = 0.0003). After rhinovirus inoculation, asthma symptoms increased and lung function fell. BAL MMP-1 activity increased in asthma patients compared with controls (P = 0.047). MMP-1 protein and activity was positively associated with fall in FEV1 (R square = 0.3618) (P = 0.0039) post viral inoculation. Activated, but not control, mast cell supernatants increased both expression of pro- and active MMP-1 by ASM cell cultures. This was blocked almost completely by inhibitors of tryptase but not chymase or MMPs. Recombinant tryptase activated MMP-1 in vitro. ECM obtained from both control and asthma derived ASM cells treated with activated mast cell supernatants during matrix synthesis and ECM treated directly after decellularization with active MMP-1 (10 ng/ml) enhanced subsequent ASM growth by 1.5 fold (P < 0.05).

Conclusions MMP-1 expression and activity in bronchial fluid is enhanced during asthma exacerbations and is associated with increased BHR. MMP-1 activation by mast cell tryptase processes ASM derived ECM to enhance ASM growth in-vitro. Our findings suggest that ASM/mast cell interactions during exacerbations may contribute to airway remodelling by generating a pro-proliferative matrix.

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