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Published ahead of print on December 23, 2003, doi:10.1164/rccm.200307-964OC

Am. J. Respir. Crit. Care Med., Volume 169, Number 6, March 2004, 703-711

A more recent version of this article appeared on March 15, 2004
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Submitted on July 16, 2003
Accepted on December 23, 2003

HUMAN BRONCHIAL SMOOTH MUSCLE CELL LINES SHOW A HYPERTROPHIC PHENOTYPE TYPICAL OF SEVERE ASTHMA

Limei Zhou1, Jing Li2, Adam M Goldsmith1, Dawn C Newcomb1, Diane M Giannola1, Robert G Vosk1, Eva M Eves3, Marsha R Rosner3, Julian Solway2, and Marc B Hershenson1*

1 Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USA, 2 Medicine, University of Chicago, Chicago, IL, USA, 3 Ben May Institute for Cancer Research, University of Chicago, Chicago, IL, USA

* To whom correspondence should be addressed. 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 upon shift to the non-permissive temperature (39°C) show diminished or arrested growth. In addition to an 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 post-transcriptional manner. Phosphatidylinositol 3-kinase activity was increased in shifted cells, and chemical inhibition of phosphatidylinositol 3-kinase attenuated {alpha}-actin and MLCK expression. We have developed clonal cell lines of human bronchial smooth muscle origin which may be useful for the study of airway smooth muscle biology. Further, 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, SV40, p53, phosphatidylinositol 3-kinase




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