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

Abstract

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 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.

Results

A greater reduction in forced expiratory volume in 1 s (FEV ₁)/forced vital capacity (FVC), FEV ₁ (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 ₁%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.

Journal

Journal ID (nlm-ta): Int J Chron Obstruct Pulmon Dis

Journal ID (iso-abbrev): Int J Chron Obstruct Pulmon Dis

Journal ID (publisher-id): International Journal of COPD

Title: International Journal of Chronic Obstructive Pulmonary Disease

Publisher: Dove Medical Press

ISSN (Print): 1176-9106

ISSN (Electronic): 1178-2005

Publication date Collection: 2018

Publication date (Electronic): 11 April 2018

Volume: 13

Pages: 1135-1144

Affiliations

[1 ]Department of Thoracic Medicine, Chang Gung Medical Foundation, College of Medicine, Chang Gung University, Taipei, Taiwan

[2 ]Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK

Author notes

Correspondence: Chun-Hua Wang, Department of Thoracic Medicine, Chang Gung Medical Foundation, Chang Gung University College of Medicine, 199 Tun-Hwa North Road, Taipei, Taiwan, Republic of China, Tel [phone] ext 8467, Email wchunhua@ 123456ms7.hinet.net

Article

Publisher ID: copd-13-1135

DOI: 10.2147/COPD.S161257

PMC ID: 5903494

Copyright statement: © 2018 Lo et al. This work is published and licensed by Dove Medical Press Limited

License:

The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

Categories

Subject: Original Research