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Published on: October 19, 2013
Targeting glycogen synthase kinase-3β to prevent hyperoxia-induced lung injury in neonatal rats
Stefanie C Hummler1, Min Rong, Shaoyi Chen
1Department of Pediatrics, Division of Neonatology, Batchelor Children's Research Institute, University of Miami Miller School of Medicine, Miami, FL 33101, USA.
Insights
Inhibiting Glycogen synthase kinase (GSK)-3β protects against lung injury in premature infants. This targeted approach reduces inflammation and improves lung development, offering a new strategy for bronchopulmonary dysplasia (BPD).
Area of Science:
- Neonatal medicine
- Pulmonary biology
- Pharmacology
Background:
- Bronchopulmonary dysplasia (BPD) in premature infants is characterized by inflammation, impaired alveolarization, and abnormal angiogenesis.
- Pulmonary hypertension (PH) is a severe complication of BPD, increasing morbidity and mortality.
- Glycogen synthase kinase (GSK)-3β signaling is implicated in BPD pathogenesis.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting GSK-3β in a neonatal lung injury model.
- To determine if GSK-3β inhibition can prevent hyperoxia-induced lung damage, a model for BPD.
Main Methods:
- Newborn rats were exposed to normoxia or hyperoxia (90% oxygen) for 14 days.
- Animals received daily intraperitoneal injections of either a placebo (DMSO) or SB216763, a GSK-3β inhibitor.
- Lung injury, inflammation, alveolarization, angiogenesis, and PH were assessed.
Main Results:
- Hyperoxia with placebo increased GSK-3β phosphorylation, inflammation, pulmonary vascular remodeling, and PH, while decreasing alveolarization and angiogenesis.
- SB216763 treatment reduced NF-κB phosphorylation, monocyte chemotactic protein-1 expression, and lung inflammation.
- GSK-3β inhibition improved alveolarization and angiogenesis and attenuated pulmonary vascular remodeling and PH.
Conclusions:
- GSK-3β signaling is crucial in the development of hyperoxia-induced neonatal lung injury.
- Inhibiting GSK-3β demonstrates protective effects against inflammation and structural damage in the lungs.
- Targeting GSK-3β represents a promising novel strategy for preventing and treating BPD in preterm infants.
Abstract:
The pathological hallmarks of bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants, include inflammation, arrested alveolarization, and dysregulated angiogenesis. Severe BPD is often complicated by pulmonary hypertension (PH) that significantly increases morbidity and mortality. Glycogen synthase kinase (GSK)-3β plays a pivotal role in embryonic development, cell proliferation and survival, and inflammation by modulating multiple signaling pathways, particularly the nuclear transcription factor, NF-κB, and Wnt/β-catenin pathways. Aberrant GSK-3β signaling is linked to BPD. We tested the hypothesis that inhibition of GSK-3β is beneficial in preventing hyperoxia-induced neonatal lung injury, an experimental model of BPD. Newborn rats were exposed to normoxia or hyperoxia (90% oxygen), and received daily intraperitoneal injections of placebo (DMSO) or SB216763, a specific pharmacological inhibitor of GSK-3β, for 14 days. Hyperoxia exposure in the presence of the placebo increased GSK-3β phosphorylation, which was correlated with increased inflammation, decreased alveolarization and angiogenesis, and increased pulmonary vascular remodeling and PH. However, treatment with SB216763 decreased phosphorylation of NF-κB p65, expression of monocyte chemotactic protein-1, and lung inflammation during hyperoxia. Furthermore, treatment with the GSK-3β inhibitor also improved alveolarization and angiogenesis, and decreased pulmonary vascular remodeling and PH. These data indicate that GSK-3β signaling plays an important role in the pathogenesis of hyperoxia-induced neonatal lung injury, and that inhibition of GSK-3β is beneficial in preventing inflammation and protecting alveolar and vascular structures during hyperoxia. Thus, targeting GSK-3β signaling may offer a novel strategy to prevent and treat preterm infants with BPD.
