Matrix metalloproteinases -8, -9 and -12 in smokers and patients with Stage 0 COPD

Helen Ilumets¹, Paula Rytilä², Ingel Demedts⁵, Guy G Brusselle⁵, Anssi Sovijärvi³, Marjukka Myllärniemi¹, Timo Sorsa⁴, Vuokko L Kinnula¹

Department of Medicine and Divisions of ¹Pulmonary Medicine and ²Allergology, Departments of ³Clinical Physiology and ⁴Oral and Maxillofacial Diseases, University of Helsinki, Biomedicum Helsinki and Helsinki University Central Hospital, Helsinki, Finland, ⁵Department of Respiratory Diseases, Ghent University Hospital, Ghent, Belgium

Abstract: COPD is underdiagnosed and its early assessment is problematic. It has been suggested that symptomatic smokers with normal FEV₁/FVC (Stage 0 COPD, GOLD criteria) can develop COPD in the future. Potential early biomarkers in COPD include the matrix metalloproteinases (MMPs). It is not yet known, whether alterations in MMP expression are associated with smoking alone or with the risk of developing COPD. In this cross-sectional study MMP-8, MMP-9 and MMP-12 were determined from induced sputum and plasma by ELISA, immunocytochemistry, zymography, and/or Western blot in non-smokers (n = 32), smokers with symptoms (Stage 0, GOLD criteria) (n = 23) or without symptoms (n = 23). Only MMP-8 differentiated Stage 0 COPD from non-symptomatic smokers (p = 0.02). MMP-9 levels were significantly elevated in the induced sputum of non-symptomatic smokers and Stage 0 COPD (p = 0.01, p < 0.001) compared to non-smokers, but did not differ between the two subgroups of smokers. MMP-12 was higher only at Stage 0 compared to non-smokers (p = 0.04). MMP-8, MMP-9 and MMP-12 immunoreactivity was localized in macrophages and neutrophils, especially in smokers. MMP-8 levels correlated significantly with the small airway flow parameters (MEF50, MEF25) (p = 0.005 and p = 0.0004) and markers of neutrophil activation (myeloperoxidase, lactoferrin). In conclusion MMP-8 may differentiate Stage 0 from healthy smokers.

Keywords: cigarette smoking, GOLD, COPD, MMP, myeloperoxidase, oxidant, Stage 0