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Published on: October 19, 2013
Bone Morphogenetic Protein 9 Protects against Neonatal Hyperoxia-Induced Impairment of Alveolarization and Pulmonary
Xueyu Chen1, Mar Orriols2, Frans J Walther1,3
1Division of Neonatology, Department of Pediatrics, Leiden University Medical CenterLeiden, Netherlands.
Insights
Bone morphogenetic protein 9 (BMP9) shows therapeutic potential for bronchopulmonary dysplasia (BPD) in premature infants. BMP9 treatment improved lung development and reduced inflammation in a rat model of BPD.
Area of Science:
- Biomedical Research
- Pulmonary Medicine
- Neonatology
Background:
- Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature infants with limited effective treatments.
- Bone morphogenetic protein 9 (BMP9), a TGF-β family ligand, interacts with ALK1-BMPR2 receptors and presents a potential therapeutic target for BPD.
Purpose of the Study:
- To investigate the cardiopulmonary effects of BMP9 in a rat model of hyperoxia-induced BPD.
- To evaluate BMP9's potential as a novel therapeutic option for BPD.
Main Methods:
- Neonatal Wistar rats were exposed to hyperoxia to induce BPD.
- BMP9 or saline was administered via subcutaneous injection.
- Morphometric analysis, cytokine profiling, and mRNA expression of BMP9 signaling components were performed.
Main Results:
- Hyperoxia induced differential expression of BMP9 receptor components (ALK1, BMPR2, TMEM100) and reduced TMEM100 expression.
- BMP9 treatment attenuated alveolar enlargement, lung inflammation, and fibrosis in the BPD model.
- BMP9 demonstrated anti-inflammatory effects in vitro and induced TMEM100 expression in endothelial cells.
Conclusions:
- BMP9 treatment protects against neonatal hyperoxia-induced BPD by improving lung development and reducing inflammation.
- BMP9 exhibits therapeutic potential for premature infants suffering from severe BPD.
Abstract:
Aim: Effective treatment of premature infants with bronchopulmonary dysplasia (BPD) is lacking. We hypothesize that bone morphogenetic protein 9 (BMP9), a ligand of the TGF-β family that binds to the activin receptor-like kinase 1 (ALK1)-BMP receptor type 2 (BMPR2) receptor complex, may be a novel therapeutic option for BPD. Therefore, we investigated the cardiopulmonary effects of BMP9 in neonatal Wistar rats with hyperoxia-induced BPD. Methods: Directly after birth Wistar rat pups were exposed to 100% oxygen for 10 days. From day 2 rat pups received BMP9 (2.5 microg/kg, twice a day) or 0.9% NaCl by subcutaneous injection. Beneficial effects of BMP9 on aberrant alveolar development, lung inflammation and fibrosis, and right ventricular hypertrophy (RVH) were investigated by morphometric analysis and cytokine production. In addition, differential mRNA expression of BMP9 and its receptor complex: ALK1, BMPR2, and Endoglin, and of the ALK1 downstream target transmembrane protein 100 (TMEM100) were studied during the development of experimental BPD. Expression of the BMP9 receptor complex and TMEM100 was studied in human endothelial and epithelial cell cultures and the effect of BMP9 on inflammatory cytokine production and TMEM100 expression was studied in endothelial cell cultures. Results:ALK1, ALK2, BMPRII, TMEM100, and Endoglin were differentially expressed in experimental BPD, suggesting a role for BMP9-dependent signaling in the development of (experimental) BPD. TMEM100 was expressed in the wall of blood vessels, showing an elastin-like expression pattern in arterioles. Expression of TMEM100 mRNA and protein was decreased after exposure to hyperoxia. BMP9 treatment of rat pups with hyperoxia-induced experimental BPD reduced alveolar enlargement, lung septal thickness and fibrosis, and prevented inflammation, but did not attenuate vascular remodeling and RVH. The anti-inflammatory effect of BMP9 was confirmed in vitro. Highest expression of ALK1, BMPR2, and TMEM100 was observed in human endothelial cell cultures. Stimulation of human endothelial cell cultures with BMP9 reduced their pro-inflammatory cytokine response and induced TMEM100 expression in pulmonary arterial endothelial cells. Conclusion: BMP9 protects against neonatal hyperoxia-induced BPD by improving aberrant alveolar development, inflammation and fibrosis, demonstrating its therapeutic potential for premature infants with severe BPD.
