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Retinoic Acid Inhibits Airway Smooth Muscle Cell Migration

Department of Pharmacology, Georgetown University Medical Center, Washington, DC; and Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland

Correspondence and requests for reprints should be addressed to Dr. Yuichiro J. Suzuki, Department of Pharmacology, Georgetown University Medical Center, NW403 Medical-Dental Building, 3900 Reservoir Road NW, Washington, DC 20057. E-mail: ys82{at}georgetown.edu

Airway remodeling in chronic asthma is characterized by increased smooth muscle mass that is associated with the reduction of the bronchial lumen as well as airway hyperresponsiveness. The development of agents that inhibit smooth muscle growth is therefore of interest for therapy to prevent asthma-associated airway remodeling. All-trans retinoic acid (ATRA) suppresses growth of vascular smooth muscle cells (SMCs) from the systemic and pulmonary circulation. The present study investigated the effects of ATRA on human bronchial (airway) SMCs. Human bronchial SMCs were found to express mRNAs for retinoic acid receptor (RAR)-, -, -, and retinoid X receptor (RXR)-, -, but not RXR-. Although ATRA was not effective in inhibiting proliferation or in inducing apoptosis in airway SMCs, we found that ATRA (0.2–2 µM) inhibited the SMC migration in response to platelet-derived growth factor (PDGF), as determined in a modified Boyden chamber assay. Both RAR and RXR agonists also blocked PDGF-induced airway SMC migration. ATRA also inhibited PDGF-induced actin reorganization associated with migration. PDGF-induced actin reorganization and migration were blocked by inhibitors of phosphatidylinositol 3 kinase (PI3K) and Akt. However, migration was blocked by inhibitors of the MEK/ERK pathway, with no effect on cytoskeletal reorganization. ATRA suppressed PDGF-induced Akt activation without influencing ERK activation. RAR was found to form protein–protein interactions with the p85 PI3K subunit. These results suggest that retinoic acid inhibits airway SMC migration through the modulation of the PI3K/Akt pathway.

Key Words: airway • migration • retinoic acid • signal transduction • smooth muscle

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