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Expression of the reverse tetracycline-transactivator gene causes emphysema-like changes in mice.

Abstract：

: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.

journal_name

Am J Respir Cell Mol Biol

journal_title

American journal of respiratory cell and molecular biology

authors

Sisson TH,Hansen JM,Shah M,Hanson KE,Du M,Ling T,Simon RH,Christensen PJ

doi

10.1165/rcmb.2005-0378OC

keywords:

subject

Has Abstract

pub_date

2006-05-01 00:00:00

pages

552-60

issue

eissn

1044-1549

issn

1535-4989

pii

2005-0378OC

journal_volume

pub_type

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Expression of the reverse tetracycline-transactivator gene causes emphysema-like changes in mice.