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DISRUPTS LUNG MORPHOGENESIS CAUSING PULMONARY DISEASE IN ADULTHOOD
1 Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
2 Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
3 Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA
* To whom correspondence should be addressed. E-mail: tim.lecras{at}CCHMC.ORG.
Clinical studies have associated increased TGF-
and EGFR with lung remodeling in a number of 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, neonatal transgenic mice conditionally expressing TGF- were utilized. Expression of TGF- from postnatal days 3 to 5 disrupted postnatal alveologenesis, causing permanent enlargement of distal airspaces in neonatal and adult mice. Lung volume to body weight ratios and lung compliance were increased in adult TGF- transgenic mice, while 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 airspaces at 1 month of age. In adult TGF- mice, alveolar remodeling, nodules, proteinaceous deposits, and inflammatory cells were seen. Immunostaining for pro-SP-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.
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