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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^*

^* From the Division of Pulmonary and Critical Care Medicine (Drs. Mao, Tashkin, Baratelli, and Roth), David Geffen School of Medicine at UCLA, Los Angeles; and Respiratory Diseases (Dr. Belloni and Ms. Baileyhealy), Roche Biosciences, USA, Palo Alto, CA.

Correspondence to: Jenny T. Mao, MD, Division of Pulmonary and Critical Care Medicine, Department of Medicine, CHS 37-131, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1690; e-mail: jmao{at}mednet.ucla.edu

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.

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.

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.

Conclusion: We conclude that ATRA can modulate protease/antiprotease balance in a manner that may impact on disease pathogenesis.

Key Words: all-trans retinoic acid • COPD • human alveolar macrophage • matrix metalloproteinase-9 • tissue inhibitor of metalloproteinase-1

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