Abstract
BackgroundBronchopulmonary dysplasia (BPD) is characterized by alveolar simplification and disordered angiogenesis. Stromal derived factor-1 (SDF-1) is a chemokine which modulates cell migration, proliferation, and angiogenesis. Here we tested the hypothesis that intra-tracheal (IT) administration of a naked plasmid DNA expressing SDF-1 would attenuate neonatal hyperoxia-induced lung injury in an experimental model of BPD, by promoting angiogenesis.Design/methodsNewborn Sprague-Dawley rat pups (n = 18–20/group) exposed to room air (RA) or hyperoxia (85% O2) from postnatal day (P) 1 to 14 were randomly assigned to receive IT a naked plasmid expressing SDF-1, JVS-100 (Juventas Therapeutics, Cleveland, Ohio) or placebo (PL) on P3. Lung alveolarization, angiogenesis, inflammation, vascular remodeling and pulmonary hypertension (PH) were assessed on P14. PH was determined by measuring right ventricular systolic pressure (RVSP) and the weight ratio of the right to left ventricle + septum (RV/LV + S). Capillary tube formation in SDF-1 treated hyperoxia-exposed human pulmonary microvascular endothelial cells (HPMEC) was determined by matrigel assay. Data is expressed as mean ± SD and analyzed by two-way ANOVA.ResultsExposure of neonatal pups to 14 days of hyperoxia decreased lung SDF-1 gene expression. Moreover, whilst hyperoxia exposure inhibited capillary tube formation in HPMEC, SDF-1 treatment increased tube length and branching in HPMEC. PL-treated hyperoxia-exposed pups had decreased alveolarization and lung vascular density. This was accompanied by an increase in RVSP, RV/LV + S, pulmonary vascular remodeling and inflammation. In contrast, IT JVS-100 improved lung structure, reduced inflammation, PH and vascular remodeling.ConclusionsIntratracheal administration of a naked plasmid expressing SDF-1 improves alveolar and vascular structure in an experimental model of BPD. These findings suggest that therapies which modulate lung SDF-1 expression may have beneficial effects in preterm infants with BPD.
Highlights
Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification and disordered angiogenesis
PL-treated hyperoxia-exposed pups had decreased alveolarization and lung vascular density. This was accompanied by an increase in right ventricular systolic pressure (RVSP), right ventricle (RV)/left ventricle (LV) + S, pulmonary vascular remodeling and inflammation
Intratracheal administration of a naked plasmid expressing Stromal derived factor-1 (SDF-1) improves alveolar and vascular structure in an experimental model of BPD. These findings suggest that therapies which modulate lung SDF-1 expression may have beneficial effects in preterm infants with BPD
Summary
Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification and disordered angiogenesis. Stromal derived factor-1 (SDF-1) is a chemokine which modulates cell migration, proliferation, and angiogenesis. Bronchopulmonary dysplasia (BPD) is the leading cause of chronic lung disease in infancy. Stromal derived factor-1 (SDF-1), called chemokine ligand 12 (CXCL12), is a small pleiotropic molecule belonging to the CXC chemokine family. It is encoded by the CXCL12 gene on chromosome 10 and is constitutively expressed by many tissues and cell types [8]. SDF-1 is expressed by several cell types including the epithelium, while its receptors CXCR4 and CXCR7 are expressed on vascular endothelial cells. SDF-1 signaling culminates in a multitude of biological functions including modulation of chemotaxis, proliferation, apoptosis, survival, and differentiation [12, 13]
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