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All-trans retinoic acid modulates the balance of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in patients with emphysema.
- Source :
-
Chest [Chest] 2003 Nov; Vol. 124 (5), pp. 1724-32. - Publication Year :
- 2003
-
Abstract
- Study Objective: The balance between proteases and antiproteases plays an essential role in the pathogenesis of emphysema. This study was designed to evaluate the impact of all-trans retinoic acid (ATRA) on the balance of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in patients with emphysema.<br />Design and Setting: As part of a clinical study, ATRA was administered to 20 patients with emphysema for 12 weeks and evaluated for its effects on plasma levels of MMP-9 and TIMP-1. Plasma MMP-9 levels were also measured in a separate cohort of patients with emphysema and matched control subjects to evaluate the relationship of circulating enzyme levels to lung disease. To further investigate the effects of ATRA on protease activity within the lung microenvironment, alveolar macrophages (AM) recovered from the lungs of active smokers with COPD were cultured with ATRA in vitro.<br />Measurements and Results: Administration of ATRA to patients with emphysema produced a 45 +/- 14% reduction (mean +/- SEM) in plasma MMP-9 by enzyme-linked immunosorbent assay and a similar reduction in MMP-9 enzyme activity, while having little effect on TIMP-1 levels. Baseline MMP-9 levels were higher in patients with emphysema compared to nonsmoking control subjects, suggesting a relationship between plasma levels and the presence of lung disease. In vitro, concentrations of ATRA similar to those achieved in the plasma of study subjects significantly reduced both the production and enzyme activity of MMP-9 by AM. In the same experiments, TIMP-1 levels increased significantly, resulting in a marked reduction in the MMP-9/TIMP-1 molar ratio.<br />Conclusion: We conclude that ATRA can modulate protease/antiprotease balance in a manner that may impact on disease pathogenesis.
- Subjects :
- Aged
Bronchoalveolar Lavage Fluid cytology
Cells, Cultured
Cross-Over Studies
Double-Blind Method
Enzyme-Linked Immunosorbent Assay
Female
Humans
Macrophages, Alveolar metabolism
Male
Middle Aged
Pilot Projects
Pulmonary Emphysema drug therapy
Smoking
Matrix Metalloproteinase 9 blood
Pulmonary Emphysema enzymology
Tissue Inhibitor of Metalloproteinase-1 blood
Tretinoin therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 0012-3692
- Volume :
- 124
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Chest
- Publication Type :
- Academic Journal
- Accession number :
- 14605041
- Full Text :
- https://doi.org/10.1378/chest.124.5.1724