Untangling the protease web in COPD: metalloproteinases in the silent zone
The idea that unregulated protease activity underlies the pathogenesis of COPD has been prominent since the recognition that genetic loss of a1 antitrypsin led to unregulated neutrophil elastase activity and premature emphysema.1 Increased proteolysis by other proteases, particularly the matrix metalloproteinases (MMPs) has since been implicated in COPD. The MMPs are a family of over 20 zinc dependent endopeptidases, initially identified as extracellular matrix (ECM) degrading enzymes and classified according to their ECM substrates. In individual studies, genetic association, overexpression, and in fewer cases, activity of individual proteases have been associated with COPD in humans and smoke induced emphysema in animals. While a number of MMPs and disintegrin and metalloproteinases have been studied in COPD at some level, most interest has focused on MMP 1, MMP 12 and MMP 9. MMP 1 is overexpressed by alveolar macrophages, type II pneumocytes and airway epithelial cells. The protein is induced by cigarette smoke and is capable of degrading collagens I and III, the most abundant lung proteins.2 ,3 MMP 9 expressed by neutrophils and macrophages is overexpressed in COPD although MMP 9 activity, rather than protease expression, is suppressed in stable patients compared with healthy smokers but activated during exacerbations.4 ,5 Although MMP 9 has elastase activity in vitro, its action in COPD may be due to generation of prolyl glycine proline (PGP) a collagen derived neutrophil chemotactic matrikine rather than elastolysis.6 MMP 12 is an elastase associated with the development of COPD by genome wide association study,7 whose presence and activity in sputum are associated airflow obstruction8 and in which single nucleotide polymorphisms that reduce enzyme activity are associated with protection from emphysema in COPD.9 While the 'classical' matrix degrading actions of these proteases can be easily related to the pathogenesis of COPD, unfortunately the reality is not that straightforward.
Thorax