RESUMEN
Bronchopulmonary dysplasia (BPD) is the most common and serious chronic lung disease of preterm infants. The development of pulmonary hypertension (PH) significantly increases the mortality and morbidity of this disease. ß-Catenin signaling plays an important role in tissue development and remodeling. Aberrant ß-catenin signaling is associated with clinical and experiment models of BPD. To test the hypothesis that inhibition of ß-catenin signaling is beneficial in promoting alveolar and vascular development and preventing PH in experimental BPD, we examined the effects of ICG001, a newly developed pharmacological inhibitor of ß-catenin, in preventing hyperoxia-induced BPD in neonatal rats. Newborn rat pups were randomized at postnatal day (P)2 to room air (RA) + DMSO (placebo), RA + ICG001, 90% FiO2 (O2) + DMSO, or O2 + ICG001. ICG001 (10 mg/kg) or DMSO was given by daily intraperitoneal injection for 14 days during continuous exposure to RA or hyperoxia. Primary human pulmonary arterial smooth muscle cells (PASMCs) were cultured in RA or hyperoxia (95% O2) in the presence of DMSO or ICG001 for 24 to 72 hours. Treatment with ICG001 significantly increased alveolarization and reduced pulmonary vascular remodeling and PH during hyperoxia. Furthermore, administering ICG001 decreased PASMC proliferation and expression of extracellular matrix remodeling molecules in vitro under hyperoxia. Finally, these structural, cellular, and molecular effects of ICG001 were associated with down-regulation of multiple ß-catenin target genes. These data indicate that ß-catenin signaling mediates hyperoxia-induced alveolar impairment and PH in neonatal animals. Targeting ß-catenin may provide a novel strategy to alleviate BPD in preterm infants.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Displasia Broncopulmonar/prevención & control , Modelos Animales de Enfermedad , Hiperoxia/prevención & control , Hipertensión Pulmonar/prevención & control , Alveolos Pulmonares/efectos de los fármacos , Pirimidinonas/farmacología , beta Catenina/antagonistas & inhibidores , Animales , Animales Recién Nacidos , Apoptosis/efectos de los fármacos , Western Blotting , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/patología , Proliferación Celular/efectos de los fármacos , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Técnica del Anticuerpo Fluorescente , Humanos , Hiperoxia/metabolismo , Hiperoxia/patología , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Técnicas para Inmunoenzimas , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Alveolos Pulmonares/metabolismo , Alveolos Pulmonares/patología , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
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)-3ß 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/ß-catenin pathways. Aberrant GSK-3ß signaling is linked to BPD. We tested the hypothesis that inhibition of GSK-3ß 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-3ß, for 14 days. Hyperoxia exposure in the presence of the placebo increased GSK-3ß 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-3ß inhibitor also improved alveolarization and angiogenesis, and decreased pulmonary vascular remodeling and PH. These data indicate that GSK-3ß signaling plays an important role in the pathogenesis of hyperoxia-induced neonatal lung injury, and that inhibition of GSK-3ß is beneficial in preventing inflammation and protecting alveolar and vascular structures during hyperoxia. Thus, targeting GSK-3ß signaling may offer a novel strategy to prevent and treat preterm infants with BPD.