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Am J Physiol Lung Cell Mol Physiol 293: L314-L327, 2007. First published April 27, 2007; doi:10.1152/ajplung.00354.2006
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Perinatal increases in TGF-{alpha} disrupt the saccular phase of lung morphogenesis and cause remodeling: microarray analysis

Elizabeth L. Kramer,1 Gail H. Deutsch,2 Maureen A. Sartor,3 William D. Hardie,1 Machiko Ikegami,1 Thomas R. Korfhagen,1 and Timothy D. Le Cras1

1Section of Neonatology, Perinatal and Pulmonary Biology and 2Division of Pathology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, and 3Center for Environmental Genetics, Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio

Submitted 11 September 2006 ; accepted in final form 24 April 2007

Transforming growth factor-{alpha} (TGF-{alpha}) and its receptor, the epithelial growth factor receptor (EGFR), have been associated with lung remodeling in premature infants with bronchopulmonary dysplasia (BPD). The goal of this study was to target TGF-{alpha} overexpression to the saccular phase of lung morphogenesis and determine early alterations in gene expression. Conditional lung-specific TGF-{alpha} bitransgenic mice and single-transgene control mice were generated. TGF-{alpha} overexpression was induced by doxycycline (Dox) treatment from embryonic day 16.5 (E16.5) to E18.5. After birth, all bitransgenic pups died by postnatal day 7 (P7). Lung histology at E18.5 and P1 showed abnormal lung morphogenesis in bitransgenic mice, characterized by mesenchymal thickening, vascular remodeling, and poor apposition of capillaries to distal air spaces. Surfactant levels (saturated phosphatidylcholine) were not reduced in bitransgenic mice. Microarray analysis was performed after 1 or 2 days of Dox treatment during the saccular (E17.5, E18.5) and alveolar phases (P4, P5) to identify genes induced by EGFR signaling that were shared or unique to each phase. We found 196 genes to be altered (>1.5-fold change; P < 0.01 for at least 2 time points), with only 32% similarly altered in both saccular and alveolar phases. Western blot analysis and immunostaining showed that five genes selected from the microarrays (egr-1, SP-B, SP-D, S100A4, and pleiotrophin) were also increased at the protein level. Pathological changes in TGF-{alpha}-overexpressing mice bore similarities to premature infants born in the saccular phase who develop BPD, including remodeling of the distal lung septae and arteries.

bronchopulmonary dysplasia; epidermal growth factor receptor; lung remodeling; lung development; transforming growth factor-{alpha}


Address for reprint requests and other correspondence: T. Le Cras, Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229-3039 (e-mail: tim.lecras{at}cchmc.org)




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