title: 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.
authors.affiliation: 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, USA. tsisson@umich.edu
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Sisson
authors.forename: Jean M
authors.initials: JM
authors.lastname: Hansen
authors.forename: Mitali
authors.initials: M
authors.lastname: Shah
authors.forename: Kerstin E
authors.initials: KE
authors.lastname: Hanson
authors.forename: Ming
authors.initials: M
authors.lastname: Du
authors.forename: Tony
authors.initials: T
authors.lastname: Ling
authors.forename: Richard H
authors.initials: RH
authors.lastname: Simon
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Christensen
mesh_terms: D000818:Animals; D001835:Body Weight / Q000235:genetics; D004318:Doxycycline / Q000494:pharmacology; D004646:Emphysema / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects*; D005838:Genotype; D007700:Kinetics; D008170:Lung Compliance / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics; D011650:Pulmonary Alveoli / Q000166:cytology; D037721:Pulmonary Surfactant-Associated Protein C / Q000235:genetics; D013752:Tetracycline / Q000378:metabolism*; D014109:Total Lung Capacity / Q000187:drug effects; D015534:Trans-Activators / Q000235:genetics*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics; D014598:Uteroglobin / Q000235:genetics
chemical_list: D037721:Pulmonary Surfactant-Associated Protein C; C556389:SCGB1A1 protein, human; C556390:Scgb1a1 protein, mouse; C556391:Scgb1a1 protein, rat; D015534:Trans-Activators; D014598:Uteroglobin; D014568:Urokinase-Type Plasminogen Activator; D013752:Tetracycline; D004318:Doxycycline