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Isolation of Pulmonary Artery Smooth Muscle Cells from Neonatal Mice
Published on: October 19, 2013
Hyperoxia modulates TGF-beta/BMP signaling in a mouse model of bronchopulmonary dysplasia
Miguel A Alejandre-Alcázar1, Grazyna Kwapiszewska, Irwin Reiss
1Department of Internal Medicine, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany.
Insights
High oxygen levels impair lung development in premature infants, causing bronchopulmonary dysplasia by disrupting TGF-beta and BMP signaling pathways. This study reveals how hyperoxia affects lung cell function and extracellular matrix production, offering potential therapeutic targets for BPD.
Area of Science:
- Pulmonary Medicine
- Developmental Biology
- Cell Signaling
Background:
- Bronchopulmonary dysplasia (BPD) is a common complication in premature infants requiring oxygen therapy.
- Hyperoxic injury during lung development is a primary cause of BPD, leading to alveolar hypoplasia.
- Transforming growth factor-beta (TGF-beta) and bone morphogenetic protein (BMP) signaling pathways are crucial for normal lung development.
Purpose of the Study:
- To investigate the impact of normobaric hyperoxia on TGF-beta and BMP signaling in neonatal mice.
- To elucidate the molecular mechanisms by which hyperoxia disrupts lung development and contributes to BPD.
- To identify potential therapeutic targets for managing BPD by examining the role of TGF-beta/BMP signaling.
Main Methods:
- Neonatal C57BL/6J mice were exposed to 21% or 85% oxygen from postnatal days P1 to P28.
- Lung tissue and cultured cells (MLE-12, NIH/3T3, primary fibroblasts, alveolar type II cells, pulmonary artery smooth muscle cells) were analyzed for receptor and Smad protein expression and localization.
- TGF-beta and BMP signaling pathway activity, apoptosis, and extracellular matrix production were assessed under varying oxygen conditions.
Main Results:
- Exposure to 85% oxygen significantly impaired growth and respiratory compliance in mouse pups, with arrested alveolarization.
- Hyperoxia dysregulated the expression and localization of TGF-beta and BMP receptors and Smad proteins in the lungs.
- TGF-beta signaling was potentiated, while BMP signaling was impaired in hyperoxic lungs and cultured cells.
- Primary alveolar type II cells showed increased susceptibility to TGF-beta-induced apoptosis under hyperoxia.
- Hyperoxia enhanced TGF-beta-stimulated production of collagen, tissue inhibitor of metalloproteinase-1, tropoelastin, and tenascin-C in lung fibroblasts.
Conclusions:
- Normobaric hyperoxia significantly disrupts TGF-beta/BMP signaling pathways in the developing lung.
- These signaling pathway alterations contribute to impaired alveolarization and the pathogenesis of bronchopulmonary dysplasia.
- The identified signaling pathways are potential targets for future genetic or pharmacological interventions to manage BPD.
Abstract:
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)-beta and bone morphogenetic protein (BMP) signaling in neonatal C57BL/6J mice exposed to 21% or 85% O(2) between postnatal days P1 and P28. Growth and respiratory compliance were significantly impaired in pups exposed to 85% O(2), and these pups 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-beta type II receptor) and Smad (Smads 1, 3, and 4) proteins. TGF-beta signaling was potentiated, whereas BMP signaling was impaired both in the lungs of pups exposed to 85% O(2) as well as in MLE-12 mouse lung epithelial cells and NIH/3T3 and primary lung fibroblasts cultured in 85% O(2). After exposure to 85% O(2), primary alveolar type II cells were more susceptible to TGF-beta-induced apoptosis, whereas primary pulmonary artery smooth muscle cells were unaffected. Exposure of primary lung fibroblasts to 85% O(2) significantly enhanced the TGF-beta-stimulated production of the alpha(1) subunit of type I collagen (Ialpha(1)), tissue inhibitor of metalloproteinase-1, tropoelastin, and tenascin-C. These data demonstrated that hyperoxia significantly affects TGF-beta/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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