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

Chun Yu Lo, Hung-Yu Huang, Jung-Ru He, Tzu-Ting Huang, Chih-Chen Heh, Te-Fang Sheng, Kian Fan Chung, Han-Pin Kuo, Chun Hua Wang

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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 (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.
Original languageEnglish
Pages (from-to)1135-1144
Number of pages10
JournalInternational Journal of COPD
Publication statusPublished - Apr 11 2018
Externally publishedYes



  • Airway hyperresponsiveness
  • Alveolar macrophage
  • Extracellular signal-regulated kinase
  • Matrix metalloproteinase-9
  • P38 mitogen-activated protein kinase
  • Smoking
  • Tissue inhibitor of metalloproteinase-1

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Health Policy
  • Public Health, Environmental and Occupational Health

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