Increased matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1 ratio in smokers with airway hyperresponsiveness and accelerated lung function decline

• Published in: International journal of chronic obstructive pulmonary disease 2018-01, Vol.13, p.1135-1144
• Main Authors: Lo, Chun-Yu, Huang, Hung-Yu, He, Jung-Ru, Huang, Tzu-Ting, Heh, Chih-Chen, Sheng, Te-Fang, Chung, Kian Fan, Kuo, Han-Pin, Wang, Chun-Hua
• Format: Article
• Language: English
• Subjects: Adult; Aged; airway hyperresponsiveness (AHR); Airway management; Airway obstruction; alveolar macrophage (AM); Biomarkers - metabolism; Bronchial Provocation Tests; Bronchitis; Bronchoscopy; Cells, Cultured; Chronic obstructive lung disease; Chronic obstructive pulmonary disease; Cigarettes; Disease Progression; Enzyme-linked immunosorbent assay; Enzymes; extracellular signal-regulated kinase (ERK); Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Forced Expiratory Volume; Growth factors; Humans; Inflammation; Kinases; Lung - drug effects; Lung - enzymology; Lung - physiopathology; Lung volume measurement; Lungs; Macrophages; Macrophages, Alveolar - drug effects; Macrophages, Alveolar - enzymology; Male; Matrix Metalloproteinase 9 - metabolism; matrix metalloproteinase-9 (MMP)-9; Methacholine; Middle Aged; Mitogens; Neutrophils; Original Research; p38 mitogen-activated protein kinase (MAPK); p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Protein Kinase Inhibitors - pharmacology; Protein kinases; Proteins; Pulmonary Disease, Chronic Obstructive - enzymology; Pulmonary Disease, Chronic Obstructive - etiology; Pulmonary Disease, Chronic Obstructive - physiopathology; Respiratory Hypersensitivity - enzymology; Respiratory Hypersensitivity - etiology; Respiratory Hypersensitivity - physiopathology; Smokers; Smoking; Smoking - adverse effects; Smoking - blood; Smoking - physiopathology; Spirometry; Steroids; Time Factors; tissue inhibitor of metalloproteinase-1 (TIMP-1); Tissue Inhibitor of Metalloproteinase-1 - metabolism; Vital Capacity; Young Adult
• ISSN: 1178-2005; 1176-9106; 1178-2005
• DOI: 10.2147/COPD.S161257

Airway hyperresponsiveness (AHR) is associated with airway inflammation and a rapid decline in lung function and is a predictor of future risk of COPD among smokers. Alveolar macrophages (AMs) from patients with COPD release a greater amount of matrix metalloproteinase (MMP)-9. We hypothesized that the imbalance between MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) is related to AHR in smokers. Healthy smokers with AHR (AHR + S) or smokers without AHR (AHR - S; divided according to a methacholine challenge test) and nonsmokers without AHR (AHR - NS) were enrolled. Spirometry was performed during enrollment and repeated after 5 years. Initially, AMs recovered from bronchoalveolar lavage (BAL) fluid were cultured in the presence of p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580), MAPK kinase (MEK) 1/2 (the MEK of extracellular signal-regulated kinase [ERK] inhibitor, PD98059), or medium alone for 24 h. The release of MMP-9 and TIMP-1 in culture supernatants was measured by enzyme-linked immunosorbent assay. A greater reduction in forced expiratory volume in 1 s (FEV )/forced vital capacity (FVC), FEV (as a percentage of the predicted value [%pred]), and maximal mid-expiratory flow (MMEF) was observed among AHR + S in the 5-year period. There was a higher proportion of neutrophils and a lower proportion of AMs in BAL fluid recovered from AHR + S. Compared to AMs from AHR - NS and AHR - S, AMs from nonsmokers with AHR (AHR + NS) released more MMP-9 and less TIMP-1, with an increase in MMP-9/TIMP-1 ratios. The MMP-9/TIMP-1 ratio in smokers was positively correlated with the annual decline in FEV %pred, FVC%pred, and MMEF%pred. Both SB203580 and PD98059 significantly reduced MMP-9, but not TIMP-1, from AMs of smokers. AMs of AHR + NS produce excessive MMP-9 over TIMP-1, which may be a predictor of the development of airway obstruction. Inhibition of p38 MAPK and ERK suppresses the generation of MMP-9 by AMs from smokers.