This is the first study to report detection of MMP‐12 at the protein level in induced sputum. Although several studies in animal models have suggested a possible role for MMP‐12 in the development of COPD, very few data are available on the role of MMP‐12 in human lung diseases, mainly because of the lack of appropriate diagnostic tools.
The major finding of this study was that the level of MMP‐12 in induced sputum was significantly higher in patients with mild to moderate COPD than in the control groups (never smokers, former smokers, and “healthy” smokers). These findings suggest that MMP‐12 is involved (together with other proteolytic enzymes) in the development of COPD and confirms earlier findings from animal models.10
An interesting finding was the difference in the MMP‐12 level in induced sputum from patients with COPD and “healthy” smokers; MMP‐12 levels were clearly increased in COPD patients but not in smokers without airway obstruction. It therefore appears that MMP‐12 is not induced in all smokers but only in those with COPD.
Importantly, MMP‐12 levels were not only increased in COPD patients who were active smokers but also in those who had quit smoking. These data suggest that MMP‐12 in sputum is not induced by cigarette smoking per se, but by the disease itself. However, while there was no statistically significant difference between COPD patients who had quit smoking and those who were current smokers, the mean MMP‐12 levels were higher in the latter group which suggests an additional effect of cigarette smoking on MMP‐12 levels in induced sputum from patients with COPD. It is important to remember that only patients with mild to moderate COPD were included in this study; patients with severe and very severe COPD (GOLD stage III and IV) were excluded for safety reasons. Thus, in those patients with early stages of COPD, MMP‐12 could be an important biomarker of the disease. However, there is some overlap between the lowest MMP‐12 levels in COPD patients and the MMP‐12 levels in controls. Measurement of MMP‐12 in induced sputum as a screening test for COPD is therefore probably not useful. However, future studies in larger groups of subjects are needed to address this question.
The mechanism by which MMP‐12 is induced in patients with COPD remains unclear. Data from animal models suggest that a local deficiency in transforming growth factor β1
or a rise in interleukin‐13 (IL‐13)19
or interferon‐γ (IFN‐γ)20
leads to overproduction of macrophage MMP‐12. Grumelli et al21
recently showed that, in human subjects, lung macrophages release MMP‐12 in response to interferon inducible protein 10 (IP‐10) and monokine induced by interferon (MIG), two chemokines that are secreted by lung macrophages and lymphocytes from patients with emphysema.
Alveolar macrophages appear to be the principal source of MMP‐12 in the lung.9,13
However, recent data from in vitro studies suggest that MMP‐12 can also be released by human bronchial epithelial cells in response to cigarette smoke.22,23
Moreover, in vitro studies show a strong upregulation of MMP‐12 transcription in immature monocyte derived dendritic cells (DC) during differentiation from monocytes into DC.24
So, whereas macrophages are probably the most important source of MMP‐12, both bronchial epithelial cells and DC might contribute to the total amount of MMP‐12 in human lung. In induced sputum, MMP‐12 levels did not correlate with the absolute number of macrophages. However, as already suggested by other authors,4
it is probably macrophage activation rather than the macrophage number that accounts for the increased total secretion of MMP‐12.
Only a few data are available on the role of MMP‐12 in COPD in human subjects. Montaño and colleagues25
studied MMP activity and expression in alveolar macrophages from patients with COPD; they found increased macrophage elastolytic activity in COPD patients and suggest that this enzymatic activity corresponds to MMP‐12. Recent work from Molet and colleagues13
demonstrated enhanced MMP‐12 expression in BAL fluid and in bronchial biopsies from COPD patients compared with controls (a heterogeneous group of smokers and non‐smokers). As mentioned earlier, Grumelli et al
showed that IP‐10 and MIG, released by lung lymphocytes, upregulated MMP‐12 secretion by lung macrophages and that this is mediated by the CXCR3 chemokine receptor on macrophages. Moreover, they showed by immunohistochemistry that lung macrophages from patients with emphysema express MMP‐12 while lung macrophages from healthy smokers (without emphysema) do not.21
Our results show, for the first time, increased MMP‐12 protein levels and MMP‐12 related enzymatic activity in induced sputum from patients with COPD compared with smokers without obstructive airway disease, former smokers and never smokers. Altogether, these data provide increasing evidence that MMP‐12 is involved in the development of COPD in human subjects, and thus confirm the earlier findings from animal models. It is also clear that MMP‐12 could be an interesting target for new pharmacological treatments for COPD. In mice, a potent synthetic inhibitor of both human and murine MMP‐12 (RS‐113456) prevented progression of emphysema in smoke exposed animals.26
These promising preclinical results, however, need to be confirmed in well designed clinical trials in human patients.