RESUMEN
Lung inflammation plays a key role in the pathogenesis of bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants. The challenge in BPD management is the lack of effective and safe antiinflammatory agents. Leukadherin-1 (LA1) is a novel agonist of the leukocyte surface integrin CD11b/CD18 that enhances leukocyte adhesion to ligands and vascular endothelium and thus reduces leukocyte transendothelial migration and influx to the injury sites. Its functional significance in preventing hyperoxia-induced neonatal lung injury is unknown. We tested the hypothesis that administration of LA1 is beneficial in preventing hyperoxia-induced neonatal lung injury, an experimental model of BPD. Newborn rats were exposed to normoxia (21% O2) or hyperoxia (85% O2) and received twice-daily intraperitoneal injection of LA1 or placebo for 14 days. Hyperoxia exposure in the presence of the placebo resulted in a drastic increase in the influx of neutrophils and macrophages into the alveolar airspaces. This increased leukocyte influx was accompanied by decreased alveolarization and angiogenesis and increased pulmonary vascular remodeling and pulmonary hypertension (PH), the pathological hallmarks of BPD. However, administration of LA1 decreased macrophage infiltration in the lungs during hyperoxia. Furthermore, treatment with LA1 improved alveolarization and angiogenesis and decreased pulmonary vascular remodeling and PH. These data indicate that leukocyte recruitment plays an important role in the experimental model of BPD induced by hyperoxia. Targeting leukocyte trafficking using LA1, an integrin agonist, is beneficial in preventing lung inflammation and protecting alveolar and vascular structures during hyperoxia. Thus, targeting integrin-mediated leukocyte recruitment and inflammation may provide a novel strategy in preventing and treating BPD in preterm infants.
Asunto(s)
Antiinflamatorios/farmacología , Benzoatos/farmacología , Displasia Broncopulmonar/prevención & control , Hiperoxia/tratamiento farmacológico , Tiohidantoínas/farmacología , Animales , Animales Recién Nacidos , Antiinflamatorios/uso terapéutico , Benzoatos/uso terapéutico , Displasia Broncopulmonar/etiología , Evaluación Preclínica de Medicamentos , Hiperoxia/complicaciones , Hipertensión Pulmonar/tratamiento farmacológico , Pulmón/irrigación sanguínea , Pulmón/efectos de los fármacos , Pulmón/inmunología , Infiltración Neutrófila , Ratas Sprague-Dawley , Tiohidantoínas/uso terapéutico , Resultado del Tratamiento , Remodelación VascularRESUMEN
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.