Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade proteins of the extracellular matrix and the basement membrane. Thus, these enzymes regulate airway remodeling, which is a major pathological feature of chronic obstructive pulmonary disease (COPD). Furthermore, proteolytic destruction in the lungs may lead to loss of elastin and the development of emphysema, which is associated with poor lung function in COPD patients. In this literature review, we describe and appraise evidence from the recent literature regarding the role of different MMPs in COPD, as well as how their activity is regulated by specific tissue inhibitors. Considering the importance of MMPs in COPD pathogenesis, we also discuss MMPs as potential targets for therapeutic intervention in COPD and present evidence from recent clinical trials in this regard.

Background: Acute exacerbations of COPD (AECOPD) are associated with worsening health outcomes and efforts should focus to prompt effective treatment of each episode. Heparan sulfate (HS) is the most abundant glycosaminoglycan in the lung parenchyma that regulates the effect of cytokines and growth factors to maintain an inflammatory microenvironment. Aim: In the present study we aimed to investigate if serum levels of HS can predict the etiology of acute exacerbations of COPD (AECOPD). Methods: 638 COPD patients, GOLD grade II-IV from a discovery cohort (PROMISE study) and 551 COPD patients from a validation cohort (PREVENT study, BASCOP study) where included in the study. HS was measured in serum at stable state, at exacerbations that were stratified according to etiology (no infection, bacterial infection, viral infection, both bacterial and viral infection) and at 4 weeks follow up after the exacerbations. Results: In the discovery cohort, serum HS was higher at moderate AECOPD (p<0.001) and severe AECOPD (p=0.002) compared to stable state and remained higher 4 weeks after AECOPD (p<0.001). In the discovery cohort, HS serum levels were increased from stable state to AECOPD by 1.69 times when there was no infection at AECOPD, by 4.14 time when there was a bacterial infection at AECOPD, by 6.23 times when there was a viral infection at AECOPD and by 8.69 times when there was both bacterial and viral infection at AECOPD. Conclusions: HS serum levels may predict the etiology of AECOPD which is of great importance for prompt effective treatment decisions at each episode.

The dysregulated expression of glucocorticoid receptor (GR) and histone deacetylases (HDACs) has been linked to COPD patients’ response to ICS treatment. This study investigates the potential association between the expression of GR and HDACs in endobronchial biopsies (EBB) of COPD patients and their responsiveness to ICS. Tissue expression of GR (including isoforms GRα and GRβ) and HDAC-2, -3, -5 and -8 was evaluated by immunohistochemistry in EBB from 188 patients with COPD, subjects of the HISTORIC study, a randomized, placebo-controlled, double-blind, investigator-initiated trial that proved the hypothesis that high airway smooth muscle cell area in EBB of COPD patients is associated to responsiveness to ICS. Slides were scanned on a Hamamatsu NanoZoomer and marker expression was quantified by digital image analysis using HALOTM (Indica Labs). Patients’ response to ICS was assessed by FEV1 improvement over 12 months. Patients who responded well to ICS exhibited lower expression of total GR in the stroma (p=0.044) and glandular epithelium (p=0.006), and lower overall tissue expression of GRβ (p=0.043) compared with patients who did not respond to ICS. ICS-responsive patients also exhibited higher overall expression of HDAC-2 (p=0.041) and lower expression of HDAC-5 in areas with squamous metaplasia (p=0.036) and of HDAC8 in glandular epithelium (p=0.028). These results suggest that evaluating GR isoforms and HDAC expression in bronchial tissue may help identify COPD patients who would benefit from ICS treatment, potentially leading to more precise and effective medical interventions with reduced side effects and costs.