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Published ahead of print on January 13, 2006, doi:10.1165/rcmb.2005-0378OC

Am. J. Respir. Cell Mol. Biol., Volume 34, Number 5, May 2006, 552-560

A more recent version of this article appeared on May 1, 2006
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Submitted on October 7, 2005
Revised on January 10, 2006

Expression of the Reverse Tetracycline-Transactivator Gene Causes Emphysema-like Changes in Mice

Thomas H Sisson1*, Jean M Hansen1, Mitali Shah1, Kerstin E Hanson1, Ming Du2, Tony Ling2, Richard H Simon1, and Paul J Christensen2

1 Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Hospital, Ann Arbor, MI, USA, 2 Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Hospital, Ann Arbor, MI, USA; Veterans Affairs Medical Center, Ann Arbor, MI, USA

* To whom correspondence should be addressed. E-mail: tsisson{at}umich.edu.

The doxycycline-inducible, gene regulatory system allows tight control of transgene expression for the study of organ development and disease pathogenesis. Multiple recent reports have employed this model to investigate various lung diseases including emphysema. For our study, we used this transgenic system to test whether prolonged, lung-specific, over-expression of the serine protease urokinase plasminogen activator (uPA) would result in alveolar wall destruction. Double transgenic mice were generated that possessed: 1) the rat Clara cell secretory protein promoter controlling the reverse tetracycline transactivator gene (CCSP:rtTA) and 2) the tetracycline operator controlling the murine uPA cDNA (tet(O):muPA). Mice were treated with doxycycline beginning at age six weeks to initiate uPA over-expression. Single transgenic and wild-type animals served as controls. A second group of double transgenic and control animals were maintained off of doxycycline. At ages 10, 18, and 30 weeks, the mice underwent measurements of alveolar size, lung compliance, and total lung capacity. We found that, although the uPA over-expressing mice demonstrated an emphysema-phenotype, similar abnormalities occurred in the CCSP-rtTA control animals. These CCSP-rtTA-related alterations occurred even without doxycycline exposure. Evaluation of a second transgenic line possessing the human surfactant protein C promoter controlling rtTA expression also exhibited lung abnormalities consistent with emphysema. These findings indicate that pulmonary epithelial expression of rtTA alone causes an emphysema phenotype in mice. Therefore, when using this system to study emphysema pathogenesis, the inclusion of proper controls is essential for accurate data interpretation.




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