Matrix Metalloproteinase-1 Activation Contributes to Airway Smooth Muscle Growth and Asthma Severity

Abstract

Rationale: Matrix metalloproteinase-1 (MMP-1) and mast cells are present in the airways of people with asthma.Objectives: To investigate whether MMP-1 could be activated by mast cells and increase asthma severity.Methods: 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.Measurements and Main Results: 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 FEV 1 and worsening asthma symptoms.Conclusions: 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.

Inflammation‐dependent and independent airway remodelling in asthma

“…The increase in ASM thickness in GA was accompanied by a significant increase in the number of ASM cells per length of airway and cell volume, indices of hyperplasia and hypertrophy, respectively. An association between inflammation and ASM proliferation has been demonstrated in horses with heaves, a naturally occurring animal model of allergic airway disease, and recently in human subjects where activation of airway mast cells during an exacerbation of asthma was associated with increased proliferation of ASM cells in vitro . Compared with proliferation, hypertrophy of ASM cells may follow a different time course, as demonstrated in mice where an acute proliferative phase was followed by hypertrophic growth after chronic allergen challenge …”

“…An association between inflammation and ASM proliferation has been demonstrated in horses with heaves, a naturally occurring animal model of allergic airway disease, 27 and recently in human subjects where activation of airway mast cells during an exacerbation of asthma was associated with increased proliferation of ASM cells in vitro. 28 Compared with proliferation, hypertrophy of ASM cells may follow a different time course, as demonstrated in mice where an acute proliferative phase was followed by hypertrophic growth after chronic allergen challenge. 29 The excessive airway narrowing in asthma is due to shortening of the ASM around the lumen, 30 increased thickness of the airway wall which exaggerates the narrowing effect of the ASM shortening 31 and partial occlusion of the airway lumen with mucus.…”

Mast Cell-Mediated Orchestration of the Immune Responses in Human Allergic Asthma: Current Insights

“…Acts as a profibrogenic cytokine during airway remodeling. [60] heterotypic adhesion with ASM. CADM-1 promotes MC survival and proliferation even in the absence of SCF and is thought to corporate with CD117 in promoting MC survival [57].…”

The Role of Mast Cells in IgE-Independent Lung Diseases

“…Moreover, tryptase and histamine together promote the proliferation of airway smooth muscle (ASM) cells [34]. Interestingly, tryptase released from MCs may also activate the pro-metalloproteinase (MMP)-1 produced by ASM to form active MMP1 [35]. The levels of MMP1 in individuals with asthma correlate with bronchial hyperresponsiveness (BHR) and exacerbation of disease [35].…”

“…This suggests that there is an interplay between stem cell factor, MMP9, and mast cell engagement with tissue matrix. Other MMPs such as MMP10 have been associated with MC activation, airway remodeling, and extracellular matrix (ECM) organization in severe asthma [54], while airway smooth muscle-derived MMP1 was activated by MC tryptase enabling the development of a proliferative ECM that may account for the association with a link to airway responsiveness in severe asthma [35]. Finally, activated MCs in 3D culture resulted in enhanced release of active MMP2 and ASM proliferation [55] and of collagen and MMP2 and MMP3 release and fibroblast contraction [56].…”