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Published ahead of print on December 23, 2003, doi:10.1164/rccm.200307-964OC
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American Journal of Respiratory and Critical Care Medicine Vol 169. pp. 703-711, (2004)
© 2004 American Thoracic Society

Original Article

Human Bronchial Smooth Muscle Cell Lines Show a Hypertrophic Phenotype Typical of Severe Asthma

Limei Zhou, Jing Li, Adam M. Goldsmith, Dawn C. Newcomb, Diane M. Giannola, Robert G. Vosk, Eva M. Eves, Marsha R. Rosner, Julian Solway and Marc B. Hershenson

Departments of Pediatrics and Communicable Diseases, Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan; Department of Medicine; and Ben May Institute for Cancer Research, University of Chicago, Chicago, Illinois

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

We developed clonal cell lines of human bronchial smooth muscle origin by retroviral transduction of temperature-sensitive simian virus 40 large tumor (T) antigen. These cells show increased growth potential at 33°C, but on shift to the nonpermissive temperature (39°C), they show diminished or arrested growth. In addition to the expected reduction in the level of large T antigen, cells shifted to 39°C show increased expression of the cyclin-dependent kinase inhibitor p21Waf1/Cip1, characteristic of cells arrested in G1 of the cell cycle. Shifted cells undergo a process of cell hypertrophy, as demonstrated by increased time of flight and forward scatter, as well as increased expression of the contractile proteins {alpha}-smooth muscle actin, myosin light chain kinase, and SM22. Changes in contractile protein expression were regulated primarily in a posttranscriptional manner. Phosphatidylinositol 3-kinase activity was increased in shifted cells, and chemical inhibition of phosphatidylinositol 3-kinase attenuated {alpha}-actin and myosin light-chain kinase expression. We have developed clonal cell lines of human bronchial smooth muscle origin that may be useful for the study of airway smooth muscle biology. Furthermore, we demonstrate that arrest of airway smooth muscle cell cycle traversal can induce cellular hypertrophy, which parallels changes observed in the airways of patients with severe asthma.

Key Words: airway • hypertrophy • simian virus 40 • p53 • phosphatidylinositol 3-kinase




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