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Published ahead of print on October 20, 2005, doi:10.1165/rcmb.2005-0166OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 34, pp. 247-254, 2006
© 2006 American Thoracic Society
DOI: 10.1165/rcmb.2005-0166OC

Transforming Growth Factor-beta Induces Airway Smooth Muscle Hypertrophy

Adam M. Goldsmith, J. Kelley Bentley, Limei Zhou, Yue Jia, Khalil N. Bitar, Diane C. Fingar and Marc B. Hershenson

Department of Pediatrics and Communicable Diseases, Department of Molecular and Integrative Physiology, Department of Cell and Developmental Biology, and Department of Medicine, University of Michigan, Ann Arbor, Michigan

Correspondence and requests for reprints should be addressed to Marc B. Hershenson, M.D., University of Michigan, 1150 W. Medical Center Dr., Room 3570, MSRBII, Box 0688, Ann Arbor, MI 48109-0688. E mail: mhershen{at}umich.edu

Although smooth muscle hypertrophy is present in asthmatic airways, little is known about the biochemical pathways regulating airway smooth muscle protein synthesis, cell size, or accumulation of contractile apparatus proteins. We sought to develop a model of airway smooth muscle hypertrophy in primary cells using a physiologically relevant stimulus. We hypothesized that transforming growth factor (TGF)-beta induces hypertrophy in primary bronchial smooth muscle cells. Primary human bronchial smooth muscle cells isolated from unacceptable lung donor tissue were studied. Cells were seeded on uncoated plastic dishes at 50% confluence and TGF-beta was added. Experiments were performed in the absence of serum. TGF-beta increased cell size and total protein synthesis, expression of {alpha}-smooth muscle actin and smooth muscle myosin heavy chain, formation of actomyosin filaments, and cell shortening to acetylcholine. Further, TGF-beta increased airway smooth muscle {alpha}-actin synthesis in the presence of the transcriptional inhibitor actinomycin D, evidence that translational control is a physiologically important element of the observed hypertrophy. TGF-beta induced the phosphorylation of eukaryotic translation initiation factor-4E–binding protein, a signaling event specifically involved in translational control. Finally, two inhibitors of 4E-binding protein phosphorylation, the phosphoinositol 3-kinase inhibitor LY294002 and a phosphorylation site mutant of 4E-binding protein-1 that dominantly inhibits eukaryotic initiation factor-4E, each blocked TGF-beta– induced {alpha}-actin expression and cell enlargement. We conclude that TGF-beta induces hypertrophy of primary bronchial smooth muscle cells. Further, phosphorylation of 4E-binding protein is required for the observed hypertrophy.

Key Words: 4E-binding protein • {alpha}-smooth muscle actin • eukaryotic initiation factor-4E • mammalian target of rapamycin (mTOR) • phosphatidylinositol 3-kinase




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