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EDITORIAL FOCUS
disrupts lung morphogenesis, causing pulmonary disease in adulthood
Divisions of 1Pulmonary Biology and 2Pathology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio 45229; and 3Department of Pediatrics, University of Utah, Salt Lake City, Utah 84132
Submitted 10 March 2004 ; accepted in final form 12 April 2004
Clinical studies have associated increased transforming growth factor (TGF)-
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- are sufficient to disrupt postnatal lung morphogenesis, we utilized neonatal transgenic mice conditionally expressing TGF-. Expression of TGF- 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- 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- mice, with attenuated and occasionally tortuous arterial branching. The ratios of right ventricle weight to left ventricle plus septal weight were increased in TGF- mice, indicating pulmonary hypertension. Electron microscopy showed gaps in the capillary endothelium and extravasation of erythrocytes into the alveolar space of TGF- mice. Hemorrhage and inflammatory cells were seen in distal air spaces at 1 mo of age. In adult TGF- 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- mice. Transient induction of TGF- during early alveologenesis permanently disrupted lung structure and function and caused chronic lung disease.
bronchopulmonary dysplasia; neonatal lung development; epidermal growth factor receptor; pulmonary hypertension; lung remodeling
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