Increased matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1 ratio in smokers with airway hyperresponsiveness and accelerated lung function decline
| Autor: | Tzu Ting Huang, Chih-Chen Heh, Hung-Yu Huang, Jung-Ru He, Te-Fang Sheng, Han Pin Kuo, Chun-Yu Lo, Kian Fan Chung, Chun Hua Wang |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Male Vital capacity Time Factors Vital Capacity p38 Mitogen-Activated Protein Kinases tissue inhibitor of metalloproteinase-1 Pulmonary Disease Chronic Obstructive 0302 clinical medicine Forced Expiratory Volume Extracellular Signal-Regulated MAP Kinases Lung extracellular signal-regulated kinase Cells Cultured Original Research COPD Smokers medicine.diagnostic_test General Medicine respiratory system Middle Aged medicine.anatomical_structure Matrix Metalloproteinase 9 030220 oncology & carcinogenesis Disease Progression Female Spirometry Adult medicine.medical_specialty International Journal of Chronic Obstructive Pulmonary Disease Bronchial Provocation Tests smoking 03 medical and health sciences FEV1/FVC ratio Young Adult Internal medicine matrix metalloproteinase-9 Macrophages Alveolar medicine Respiratory Hypersensitivity Humans Protein Kinase Inhibitors Aged business.industry airway hyperresponsiveness p38 mitogen-activated protein kinase Tissue inhibitor of metalloproteinase medicine.disease respiratory tract diseases 030104 developmental biology Endocrinology Bronchoalveolar lavage alveolar macrophage business Biomarkers |
| Zdroj: | International Journal of Chronic Obstructive Pulmonary Disease |
| ISSN: | 1178-2005 |
| Popis: | Chun-Yu Lo,1 Hung-Yu Huang,1 Jung-Ru He,1 Tzu-Ting Huang,1 Chih-Chen Heh,1 Te-Fang Sheng,1 Kian Fan Chung,2 Han-Pin Kuo,1 Chun-Hua Wang1 1Department of Thoracic Medicine, Chang Gung Medical Foundation, College of Medicine, Chang Gung University, Taipei, Taiwan; 2Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK Background: 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.Patients and methods: 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 5years. 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 24h. The release of MMP-9 and TIMP-1 in culture supernatants was measured by enzyme-linked immunosorbent assay.Results: A greater reduction in forced expiratory volume in 1s (FEV1)/forced vital capacity (FVC), FEV1 (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 FEV1%pred, FVC%pred, and MMEF%pred. Both SB203580 and PD98059 significantly reduced MMP-9, but not TIMP-1, from AMs of smokers.Conclusion: 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. Keywords: smoking, airway hyperresponsiveness, alveolar macrophage, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, p38 mitogen-activated protein kinase, extracellular signal-regulated kinase |
| Databáze: | OpenAIRE |
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