Conditional overexpression of bioactive transforming growth factor-beta1 in neonatal mouse lung: a new model for bronchopulmonary dysplasia?
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)-beta. Unfortunately, commonly utilized murine transgenic models are not optimal to investigate the effects of TGF-beta 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-beta1 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-beta1 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-beta1 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-beta system is a central mediator for the histologic alterations described in association with the disease.
Vicencio
Alfin G
AG
Department of Internal Medicine, Yale University School of Medicine, 1 Gilbert Street, S441 TAC, New Haven, CT 06520-8057, USA. jack.elias@yale.edu
Lee
Chun Geun
CG
Cho
Soo Jung
SJ
Eickelberg
Oliver
O
Chuu
Ying
Y
Haddad
Gabriel G
GG
Elias
Jack A
JA
D000199:Actins / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion; D049109:Cell Proliferation; D004318:Doxycycline / Q000008:administration & dosage / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D007231:Infant, Newborn; D008168:Lung / Q000002:abnormalities / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D019076:Transgenes / Q000235:genetics
D000199:Actins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D004318:Doxycycline