This Article Full Text Full Text (PDF) All Versions of this Article: 2005-0378OCv1 34/5/552    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sisson, T. H. Articles by Christensen, P. J. Search for Related Content PubMed PubMed Citation Articles by Sisson, T. H. Articles by Christensen, P. J.

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

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

Correspondence and requests for reprints should be addressed to Thomas H. Sisson, M.D., Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, 1150 West Medical Center Drive, 6301 MSRB III, Ann Arbor, MI 48109-0642. 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, overexpression 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 6 wk to initiate uPA overexpression. 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 wk, the mice underwent measurements of alveolar size, lung compliance, and total lung capacity. We found that, although the uPA overexpressing 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.

Key Words: alveolar enlargement • human surfactant protein C promoter • rat Clara cell secretory protein promoter • reverse tetracycline transactivator • urokinase

This article has been cited by other articles:

				P. J. Christensen, A. M. Preston, T. Ling, M. Du, W. B. Fields, J. L. Curtis, and J. M. Beck Pneumocystis murina Infection and Cigarette Smoke Exposure Interact To Cause Increased Organism Burden, Development of Airspace Enlargement, and Pulmonary Inflammation in Mice Infect. Immun., August 1, 2008; 76(8): 3481 - 3490. [Abstract] [Full Text] [PDF]

				J. L. Wright, M. Cosio, and A. Churg Animal models of chronic obstructive pulmonary disease Am J Physiol Lung Cell Mol Physiol, July 1, 2008; 295(1): L1 - L15. [Abstract] [Full Text] [PDF]

				L. J. Quinton, M. R. Jones, B. E. Robson, B. T. Simms, J. A. Whitsett, and J. P. Mizgerd Alveolar Epithelial STAT3, IL-6 Family Cytokines, and Host Defense during Escherichia coli Pneumonia Am. J. Respir. Cell Mol. Biol., June 1, 2008; 38(6): 699 - 706. [Abstract] [Full Text] [PDF]

				J. P. Mizgerd and S. J. Skerrett Animal models of human pneumonia Am J Physiol Lung Cell Mol Physiol, March 1, 2008; 294(3): L387 - L398. [Abstract] [Full Text] [PDF]

				I-M. Wang, S. Stepaniants, Y. Boie, J. R. Mortimer, B. Kennedy, M. Elliott, S. Hayashi, L. Loy, S. Coulter, S. Cervino, et al. Gene Expression Profiling in Patients with Chronic Obstructive Pulmonary Disease and Lung Cancer Am. J. Respir. Crit. Care Med., February 15, 2008; 177(4): 402 - 411. [Abstract] [Full Text] [PDF]

				C. F. Kim Paving the road for lung stem cell biology: bronchioalveolar stem cells and other putative distal lung stem cells Am J Physiol Lung Cell Mol Physiol, November 1, 2007; 293(5): L1092 - L1098. [Abstract] [Full Text] [PDF]

				Y. Weng, C. Fang, R. J. Turesky, M. Behr, L. S. Kaminsky, and X. Ding Determination of the Role of Target Tissue Metabolism in Lung Carcinogenesis Using Conditional Cytochrome P450 Reductase-Null Mice Cancer Res., August 15, 2007; 67(16): 7825 - 7832. [Abstract] [Full Text] [PDF]

				K. I. Matthaei Genetically manipulated mice: a powerful tool with unsuspected caveats J. Physiol., July 15, 2007; 582(2): 481 - 488. [Abstract] [Full Text] [PDF]

				T. Hoshino, S. Kato, N. Oka, H. Imaoka, T. Kinoshita, S. Takei, Y. Kitasato, T. Kawayama, T. Imaizumi, K. Yamada, et al. Pulmonary Inflammation and Emphysema: Role of the Cytokines IL-18 and IL-13 Am. J. Respir. Crit. Care Med., July 1, 2007; 176(1): 49 - 62. [Abstract] [Full Text] [PDF]

				K. Bry, J. A. Whitsett, and U. Lappalainen IL-1beta Disrupts Postnatal Lung Morphogenesis in the Mouse Am. J. Respir. Cell Mol. Biol., January 1, 2007; 36(1): 32 - 42. [Abstract] [Full Text] [PDF]

				H. Fehrenbach Animal models of pulmonary emphysema: a stereologist's perspective Eur. Respir. Rev., December 1, 2006; 15(101): 136 - 147. [Abstract] [Full Text] [PDF]

				J. A. Whitsett and A.-K. T. Perl Conditional control of gene expression in the respiratory epithelium: a cautionary note. Am. J. Respir. Cell Mol. Biol., May 1, 2006; 34(5): 519 - 520. [Full Text] [PDF]