Transient induction of TGF-alpha disrupts lung morphogenesis, causing pulmonary disease in adulthood.
Clinical studies have associated increased transforming growth factor (TGF)-alpha and EGF receptor with lung remodeling in diseases including bronchopulmonary dysplasia (BPD). BPD is characterized by disrupted alveolar and vascular morphogenesis, inflammation, and remodeling. To determine whether transient increases in TGF-alpha are sufficient to disrupt postnatal lung morphogenesis, we utilized neonatal transgenic mice conditionally expressing TGF-alpha. Expression of TGF-alpha from postnatal days 3 to 5 disrupted postnatal alveologenesis, causing permanent enlargement of distal air spaces in neonatal and adult mice. Lung volume-to-body weight ratios and lung compliance were increased in adult TGF-alpha transgenic mice, whereas tissue and airway elastance were reduced. Elastin fibers in the alveolar septae were fragmented and disorganized. Pulmonary vascular morphogenesis was abnormal in TGF-alpha mice, with attenuated and occasionally tortuous arterial branching. The ratios of right ventricle weight to left ventricle plus septal weight were increased in TGF-alpha mice, indicating pulmonary hypertension. Electron microscopy showed gaps in the capillary endothelium and extravasation of erythrocytes into the alveolar space of TGF-alpha mice. Hemorrhage and inflammatory cells were seen in distal air spaces at 1 mo of age. In adult TGF-alpha mice, alveolar remodeling, nodules, proteinaceous deposits, and inflammatory cells were seen. Immunostaining for pro-surfactant protein C showed that type II cells were abundant in the nodules, as well as neutrophils and macrophages. Trichrome staining showed that pulmonary fibrosis was minimal, apart from areas of nodular remodeling in adult TGF-alpha mice. Transient induction of TGF-alpha during early alveologenesis permanently disrupted lung structure and function and caused chronic lung disease.
Le Cras
T D
TD
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio 45229, USA. tim.lecras@cchmc.org
Hardie
W D
WD
Deutsch
G H
GH
Albertine
K H
KH
Ikegami
M
M
Whitsett
J A
JA
Korfhagen
T R
TR
D000818:Animals; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D008168:Lung / Q000196:embryology / Q000503:physiopathology*; D008171:Lung Diseases / Q000503:physiopathology*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009024:Morphogenesis; D016211:Transforming Growth Factor alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D016211:Transforming Growth Factor alpha