Abstract
Chronic asthma is associated with progressive airway remodeling, which may contribute to declining lung function. An increase in matrix metalloproteinases-9 (MMP-9)/tissue inhibitor metalloproteinase-1 (TIMP-1) may indicate airway inflammation and bronchial injury. Bronchial biopsy specimens and alveolar macrophages (AMs) were obtained from patients with asthma under regular treatment with inhaled corticosteroids or combination therapy and normal subjects (n = 10). Asthmatics included those with a slow forced expiratory volume in one second (FEV1) decline (<30 mL/year, n = 13) and those with a fast FEV1 decline (≥30 mL/year, n = 8) in 5-year follow-up. Immunostaining expression of MMP-9 and TIMP-1 was detected in airway tissues. MMP-9 and TIMP-1 was measured from AMs cultured for 24 h. After the 5-year treatment, the methacholine airway hyperresponsiveness of the slow FEV1 decline group was decreased, but that of the fast FEV1 decline group was increased (PC20, provocative concentration causing a 20% decrease in FEV1, 3.12 ± 1.10 to 1.14 ± 0.34 mg/dL, p < 0.05). AMs of asthma with a fast FEV1 decline released a higher level of MMP-9 (8.52 ± 3.53 pg/mL, p < 0.05) than those of a slow FEV1 decline (0.99 ± 0.20 pg/mL). The MMP-9/TIMP ratio in the fast FEV1 decline group (0.089 ± 0.032) was higher than that of the slow FEV1 decline group (0.007 ± 0.001, p < 0.01). The annual FEV1 decline in 5 years was proportional to the level of MMP-9 (r = 57, p < 0.01) and MMP-9/TIMP-1 ratio (r = 0.58, p < 0.01). The airways of asthma with greater yearly decline in FEV1 showed an increased thickness of submucosa and strong expression of MMP-9. An increase in MMP-9 and MMP-9/TIMP-1 in airways or AMs could be indicators of chronic airway inflammation and contribute to a greater decline in lung function of patients with chronic asthma.
Highlights
Asthma is a chronic respiratory disease of airway inflammation that manifests as variable airflow limitation [1]
Our aim was to evaluate whether the ratio of matrix metalloproteinases-9 (MMP-9)/tissue inhibitor metalloproteinase-1 (TIMP-1) released from cultured alveolar macrophages was higher in chronic asthmatic patients who had a fast, yearly decline in FEV1
We reported that the generation of Matrix metalloproteinases (MMPs)-9 from alveolar macrophages and the ratio of MMP-9/tissue inhibitors of matrix metalloproteinase (TIMPs)-1 are strongly associated with the magnitude of FEV1 decline in chronic asthma, which is in agreement with the data of Vignola et al [21]
Summary
Asthma is a chronic respiratory disease of airway inflammation that manifests as variable airflow limitation [1]. Or longer duration of asthma is correlated to airway wall remodeling and contributes to a decline in lung function [4]. The MMPs play an important role in several lung or airway diseases, or even lung cancer [7,8,9,10]. MMP-9-deficient animals could inhibit airway inflammation and the immunoreactivity of MMP-9 has been reported to be correlated with asthma severity [14]. A defensive function of MMP-9 in asthma was reported through a heightened inflammation in MMP9-deficient mice [15,16]. MMP-9 may be an important factor involved in asthma, but the production of MMP-9 in chronic asthma with persistent airway obstruction is still undetermined
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