Matrix metalloproteinases in asthma and COPD
Introduction
Matrix metalloproteinases (MMPs) are proteolytic enzymes that are able to degrade extracellular matrix (ECM) components, and thus play a role in cell migration and tissue remodeling. Moreover, they can splice and (in)activate cytokines and chemokines, thereby influencing the recruitment and function of inflammatory cells [1••].
Chronic obstructive pulmonary disease (COPD) and asthma are both chronic lung diseases that share some features, and yet are quite different disease entities. COPD is mainly caused by inhalation of cigarette smoke, resulting in irreversible airflow limitation, whereas asthma is characterized by an allergic reaction in the airways, leading to reversible airflow obstruction.
A common feature of both diseases is the chronic inflammation in the airways (influx of inflammatory cells into the lung) and the development of extensive tissue remodeling during the course of the disease process. In some cases, especially in COPD, this remodeling causes destruction of healthy lung tissue, leading to emphysema. For this reason, there is increased interest in the role of MMPs in asthma and COPD: MMPs probably contribute to the migration of inflammatory cells into the lung, as well as to the remodeling, and sometimes even destruction, of lung tissue.
Here, we describe the most recent data on the role of MMPs in asthma and COPD. We focus on findings from studies on human subjects rather than from animal models, and discuss the possibility of targeting MMPs as a new therapeutic approach in the management of asthma and COPD.
Section snippets
Biology of matrix metalloproteinases
MMPs are part of a large metalloendopeptidase superfamily. They typically consist of a pro-domain and a catalytic domain. The latter contains a zinc ion in the active site, as well as a characteristic methionine turn, which is caused by a conserved methionine residue downstream of the zinc binding site. To date, 24 MMPs have been identified in mammals; cellular sources include inflammatory, stromal and epithelial cells. Some MMPs are anchored to the cell surface, whereas others are secreted
Possible pathogenetic mechanisms
There are many ways in which MMPs are likely to participate in the disease process of both asthma and COPD (Figure 1). MMPs might contribute to the breakdown of ECM, resulting in the destruction of healthy lung parenchyma. During this process, chemotactic fragments are generated from the degraded ECM, attracting inflammatory cells into the damaged tissue. It is also possible that ECM breakdown releases chemokines that are otherwise ‘trapped’ in the ECM. Several MMPs affect the activity of
MMPs and asthma
Patients with asthma have an increased gelatinolytic activity linked to MMP-2 and MMP-9 and higher levels of tissue inhibitor of metalloproteinase-1 (TIMP-1; a natural inhibitor of MMPs) in their sputum [3]. The activated form of MMP-9 (85 kDa) was found in the sputum from 60% of asthmatics, but was absent from that of control subjects. Although less frequently detectable than pro-MMP-9 (pro-MMPs are catalytically inactive and are activated into the active MMP after cleaving of the pro-domain),
MMPs and COPD
Recent studies in human subjects provide increasing evidence for a role of MMPs in COPD. Patients with COPD have an increased gelatinolytic activity in sputum linked to MMP-2 and MMP-9 [3]. The activated form of MMP-9 (85 kDa) was found in the sputum from 85% of COPD patients, but was absent from that of control subjects, whereas pro-MMP-2 (72 kDa) was found in 25% of COPD patients and in only 5% of controls. Levels of TIMP-1 were higher in COPD patients than in controls. These findings were
Inhibitors of MMPs
TIMPs are natural inhibitors of MMPs, which they can inhibit by binding to the catalytic site of MMPs. Four different TIMPs are known today (TIMP-1, -2, -3 and -4), and they inhibit all MMPs tested so far (except for TIMP-1, which fails to inhibit MT1-MMP). However, there are differences in the affinity for specific MMPs (e.g. TIMP-3 is a more potent inhibitor of MMP-9 than other MMPs) [30].
It seems logical to use these endogenous antiproteinases in the treatment of asthma and COPD. Indeed, we
Conclusions
There is increasing evidence that MMPs are involved in the pathogenesis of asthma and COPD. Further exploration of the role of MMPs in these highly prevalent diseases is crucial to identify which are possible therapeutic targets. MMP-9, but perhaps also MMP-1, -2, -8 and -12, seem to be good candidates.
As mentioned previously, MMPs have many diverse functions and it is clear that interference with these functions could not only have beneficial effects (e.g. reduced destruction of lung tissue;
Update
Very recently, Molet et al. [33••] reported enhanced MMP-12 levels in BAL fluid from COPD patients compared with that from controls. Moreover, the number of MMP-12-expressing macrophages in BAL, as well as in tissue sections from bronchial biopsies, was higher in COPD patients. These data underscore the importance of MMP-12 in the development of COPD.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We would like to dedicate this review to the memory of Prof Romain Pauwels, whose scientific and clinical experience was of great inspiration to all of us involved in the field of respiratory medicine and research.
This work was supported by the Fund for Scientific Research in Flanders (FWO Vlaanderen, Research Project G. 30001103 and G.0343.01N), by Project Grant 01251504 from the Concerted Research Initiative of the Ghent University and by the Institute for the promotion of Innovation by
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