Targeting glycogen synthase kinase-3β to prevent hyperoxia-induced lung injury in neonatal rats

Stefanie C. Hummler, Min Rong, Shaoyi Chen, Dorothy Hehre, Deepthi Alapati, Shu Wu

Research output: Contribution to journalArticle

25 Citations (Scopus)

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 signalingpathways, particularly the nuclear transcription factor, NF-κB, and Wnt/β-catenin pathways. Aberrant GSK-3β signaling is linked to BPD.Wetested 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 correlatedwith 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.

Original languageEnglish
Pages (from-to)578-588
Number of pages11
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume48
Issue number5
DOIs
StatePublished - May 1 2013

Fingerprint

Glycogen Synthase Kinase 3
Hyperoxia
Lung Injury
Rats
Bronchopulmonary Dysplasia
Pulmonary Hypertension
Inflammation
Phosphorylation
Premature Infants
Placebos
Catenins
Lung
Pulmonary diseases
Wnt Signaling Pathway
Chemokine CCL2
Cell proliferation
Dimethyl Sulfoxide
Intraperitoneal Injections
Lung Diseases
Embryonic Development

Keywords

  • Bronchopulmonary dysplasia
  • Glycogen synthase kinase-3β
  • Hyperoxia
  • Inflammation
  • Lung injury

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Targeting glycogen synthase kinase-3β to prevent hyperoxia-induced lung injury in neonatal rats. / Hummler, Stefanie C.; Rong, Min; Chen, Shaoyi; Hehre, Dorothy; Alapati, Deepthi; Wu, Shu.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 48, No. 5, 01.05.2013, p. 578-588.

Research output: Contribution to journalArticle

Hummler, Stefanie C. ; Rong, Min ; Chen, Shaoyi ; Hehre, Dorothy ; Alapati, Deepthi ; Wu, Shu. / Targeting glycogen synthase kinase-3β to prevent hyperoxia-induced lung injury in neonatal rats. In: American Journal of Respiratory Cell and Molecular Biology. 2013 ; Vol. 48, No. 5. pp. 578-588.
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