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/BMP signaling in a mouse model of bronchopulmonary dysplasia
1 Department of Internal Medicine, University of Giessen Lung Center, Giessen, Hessen, Germany
2 Department of Pathology, University of Giessen Lung Center, Giessen, Hessen, Germany
3 Department of Paediatrics, University of Giessen Lung Center, Giessen, Hessen, Germany
4 Department of Biochemistry, University of Giessen Lung Center, Giessen, Hessen, Germany
* To whom correspondence should be addressed. E-mail: rory.morty{at}innere.med.uni-giessen.de.
Prematurely born infants who require oxygen therapy often develop bronchopulmonary dysplasia (BPD), a debilitating disorder characterized by pronounced alveolar hypoplasia. Hyperoxic injury is believed to disrupt critical signaling pathways that direct lung development, causing BPD. We investigated the effects of normobaric hyperoxia on transforming growth factor (TGF)-
and bone morphogenetic protein (BMP) signaling in neonatal C57BL/6J mice exposed to 21% or 85% O2 between days P1 and P28. Growth and respiratory compliance were significantly impaired in pups exposed to 85% O2, which also exhibited a pronounced arrest of alveolarization, accompanied by dysregulated expression and localization of both receptor (ALK-1, ALK-3, ALK-6, and the TGF- type II receptor) and Smad (Smads 1, 3 and 4) proteins. TGF- signaling was potentiated, while BMP signaling was impaired, both in the lungs of pups exposed to 85% O2, as well as in MLE-12 epithelial cells, and NIH/3T3 and primary lung fibroblasts cultured in 85% O2. After exposure to 85% O2, primary alveolar type II cells were more susceptible to TGF--induced apoptosis, while primary pulmonary artery smooth muscle cells were unaffected. Exposure of primary lung fibroblasts to 85% O2 significantly enhanced the TGF--stimulated production of collagen Ialpha1, tissue inhibitor of metalloproteinase-1, tropoelastin and tenascin-C. These data demonstrated that hyperoxia significantly affects TGF-/BMP signaling in the lung, including processes central to septation, and hence, alveolarization. The amenability of these pathways to genetic and pharmacological manipulation may provide alternative avenues for the management of BPD.
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