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Published on: February 21, 2011
The role of matrix metalloproteinase-9 in cigarette smoke-induced emphysema
Jeffrey J Atkinson1, Barbara A Lutey, Yoko Suzuki
1Washington University School of Medicine, St. Louis, MO 63110, USA.
Rationale:
Matrix metalloprotease (MMP)-9 is an elastolytic endopeptidase produced by activated macrophages that may be involved in the development of human pulmonary emphysema and could be inhibited with existing compounds. Mouse models have demonstrated that excess MMP-9 production can result in permanent alveolar destruction.
Objectives:
To determine if MMP-9 causes cigarette smoke-induced emphysema using MMP-9 knockout mice and human samples.
Methods:
Mouse lungs were analyzed for inflammation and airspace enlargement using a mainstream smoke-exposure model. Human macrophage mRNA was isolated from subjects with emphysema by laser capture microdissection. Human blood monocyte mRNA was isolated from subjects with greater than 30 pack-year smoking history. Human gene expression was determined by quantitative polymerase chain reaction and compared with emphysema severity determined by automated computed tomography analysis. Plasma Clara cell secretory protein and surfactant protein-D were quantified to measure ongoing lung injury.
Measurements And Main Results:
Mice deficient in MMP-9 develop the same degree of cigarette smoke-induced inflammation and airspace enlargement as strain-matched controls. Macrophages are the predominant source of MMP-9 production in human emphysema specimens and similar quantities of macrophage MMP-9 mRNA is present in areas of lung with and without emphysema. Circulating monocytes produce more MMP-9 in individuals with advanced emphysema severity despite no correlation of MMP-9 with markers of ongoing lung damage.
Conclusions:
These results suggest that MMP-9 in humans who smoke is similar to smoke-exposed mice, where MMP-9 is present in emphysematous lung but not correlated with the emphysema. To the degree that the mechanisms of emphysema in humans who smoke resemble the mouse model, these data suggest specific inhibition of MMP-9 is unlikely to be an effective therapy for cigarette smoke-induced emphysema. Clinical trial registered with www.clinicaltrials.gov (NCT 00757120).
Insights
Matrix metalloprotease (MMP)-9 does not appear to cause cigarette smoke-induced emphysema in mice or humans. Inhibition of MMP-9 is unlikely to be an effective therapy for this condition.
Area of Science:
- Pulmonary Medicine
- Immunology
- Genetics
Background:
- Matrix metalloprotease (MMP)-9 is an enzyme linked to pulmonary emphysema development.
- Mouse models indicate excess MMP-9 can cause alveolar destruction.
Purpose of the Study:
- To investigate the role of MMP-9 in cigarette smoke-induced emphysema.
- Utilized MMP-9 knockout mice and human samples for analysis.
Main Methods:
- Analyzed mouse lungs for inflammation and airspace enlargement using a smoke-exposure model.
- Isolated human macrophage and monocyte mRNA for gene expression analysis.
- Quantified plasma biomarkers to assess ongoing lung injury.
Main Results:
- Mice lacking MMP-9 showed similar smoke-induced lung damage as controls.
- Macrophages are the primary source of MMP-9 in human emphysema.
- MMP-9 levels in circulating monocytes correlated with emphysema severity but not ongoing lung damage.
Conclusions:
- MMP-9 is present in emphysematous lungs but not directly correlated with emphysema severity in smokers.
- Specific MMP-9 inhibition may not be an effective treatment for cigarette smoke-induced emphysema.
- Findings suggest mechanisms in human smokers may differ from mouse models.
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