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Conditional Overexpression of Bioactive Transforming Growth Factor–ß1 in Neonatal Mouse Lung

A New Model for Bronchopulmonary Dysplasia?

Department of Pediatrics, Albert Einstein College of Medicine and Children's Hospital at Montefiore, Bronx, New York; Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; and Department of Medicine II, Giessen University School of Medicine, Giessen, Germany

Address correspondence to: Jack A. Elias, M.D., Chief, Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, 1 Gilbert Street, S441 TAC, New Haven, CT 06520-8057. E-mail: jack.elias{at}yale.edu

Research interest in bronchopulmonary dysplasia (BPD) has steadily increased, and numerous potential mediators have been implicated in the development of the disease. Among such mediators is transforming growth factor (TGF)-ß. Unfortunately, commonly utilized murine transgenic models are not optimal to investigate the effects of TGF-ß specifically during the 2–3 wk period of alveolar formation, the developmental stage that corresponds histologically to early alveolar development in humans, and the time frame during which BPD develops. In the current study, we utilized a triple-transgenic construct to overexpress bioactive TGF-ß1 in the neonatal mouse lung during the period of alveolar formation. Lungs were then examined by histologic, Western blot, and immunofluorescent methods. We found that overexpression of bioactive TGF-ß1 in neonatal mouse lungs resulted in structural changes that have been described in BPD. Included in those characteristics are abnormal alveolar structure, cellular composition, and vascular development. Our study indicates that TGF-ß1 overexpression in the neonatal mouse lung results in histologic alterations that have striking similarities to pathologic descriptions of BPD. We encourage the use of conditional transgenic models for the study of BPD, and hypothesize that the TGF-ß system is a central mediator for the histologic alterations described in association with the disease.

Abbreviations: bronchopulmonary dysplasia, BPD • constitutive heat shock protein-70, HSC-70 • mean linear intercept, MLI • Postnatal Day, P • phosphate-buffered saline, PBS • proliferating cell nuclear antigen, PCNA • platelet endothelial cell adhesion molecule, PECAM • smooth muscle actin, SMA • tetracycline operator, tet-operator • tetracycline transactivator silencer, tTS • transgene, TG • transforming growth factor, TGF

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