Abstract
ObjectivesBronchiectasis is characterized by an irreversible dilatation of bronchi and is associated with lung fibrosis. MMP-1 polymorphism may alter its transcriptional activity, and differentially modulate bronchial destruction and lung fibrosis.DesignTo investigate the association of MMP-1 polymorphisms with disease severity in non-cystic fibrosis (CF) bronchiectasis patients, 51 normal subjects and 113 patients with bronchiectasis were studied. The associations between MMP-1 polymorphisms, lung function, and disease severity evaluated by high resolution computed tomography (HRCT) were analyzed.ResultsThe frequency of MMP-1(-1607G) allele was significantly higher in patients with bronchiectasis than normal subjects (70.8% vs 45.1%, p<0.01). Forced expiratory volume in 1 second (FEV1) was decreased in bronchiectasis patients with 1G/1G (1.2±0.1 L, n = 14) and 1G/2G (1.3±0.1 L, n = 66) genotypes compared to the 2G/2G genotype (1.7±0.1 L, n = 33, p<0.01). Six minute walking distance was decreased in bronchiectasis patients with 1G/1G and 1G/2G compared to that of 2G/2G genotype. Disease severity evaluated by HRCT score significantly increased in bronchiectasis patients with 1G/1G and 1G/2G genotypes compared to that of 2G/2G genotype. Bronchiectasis patients with at least one MMP-1 (-1607G) allele showed increased tendency for hospitalization. Serum levels of pro-MMP-1, active MMP-1 and TGF-β1 were significantly increased in patients with bronchiectasis with 1G/1G and 1G/2G genotype compared with 2G/2G genotype or normal subjects. Under IL-1β stimulation, peripheral blood monocytes from subjects with 1G/2G or 1G/1G genotype secreted higher levels of TGF-β1compared to subjects with 2G/2G genotype.ConclusionThis is the first report to address the influence of MMP-1 polymorphisms on lung function and airway destruction in non-CF bronchiectasis patients. Bronchiectasis patients with MMP-1(-1607G) polymorphism may be more vulnerable to permanent lung fibrosis or airway destruction due to the enhanced MMP-1 and TGF-β1 activity. Upregulated MMP-1 activity results in proteolytic destruction of matrix, and leads to subsequent fibrosis.
Highlights
Bronchiectasis is a chronic inflammatory lung disease characterized by irreversible dilatation of the bronchi and, in most cases, by persistent production of purulent sputum [1], and associated with chronic cough, hemoptysis, breathlessness, and tiredness in patients [2]
Serum levels of pro-Matrix metalloproteinases (MMPs)-1, active MMP-1 and Transforming growth factor (TGF)-b1 were significantly increased in patients with bronchiectasis with 1G/1G and 1G/2G genotype compared with 2G/2G genotype or normal subjects
This is the first report to address the influence of MMP-1 polymorphisms on lung function and airway destruction in non-cystic fibrosis (CF) bronchiectasis patients
Summary
Bronchiectasis is a chronic inflammatory lung disease characterized by irreversible dilatation of the bronchi and, in most cases, by persistent production of purulent sputum [1], and associated with chronic cough, hemoptysis, breathlessness, and tiredness in patients [2]. Matrix metalloproteinases (MMPs) comprise of more than 20 human zinc-dependent proteolytic enzymes that are associated with degradation of the ECM, contributing to the development of tissue remodeling and lung fibrosis [6], [7]. The interstitial collagenases are key initiators of ECM degradation, and comprises of the fibroblast-type collagenase/ MMP-1 derived from fibroblasts [14], [15], and monocyte/ macrophages [9], [10]. Airway epithelium adjacent to TB granuloma expresses high levels of MMP-1 [17], contributing to the rupture of pulmonary cavity formation and tissue destruction [18], [19]. Changes in the level or activities of these MMPs may play a critical role in the altered collagen metabolism of pulmonary fibrosis and airway remodeling in patients with bronchiectasis
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