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Lack of EC-SOD worsens alveolar and vascular development in a neonatal mouse model of bleomycin-induced bronchopulmonary dysplasia and pulmonary hypertension

BACKGROUND: Pulmonary arterial hypertension (PAH) worsens clinical outcomes in former preterm infants with bronchopulmonary dysplasia (BPD). Oxidant stress disrupts alveolar and vascular development in models of BPD. Bleomycin causes oxidative stress and induces BPD and PAH in neonatal rats. Disrupt...

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Autores principales: Delaney, Cassidy, Wright, Rachel H., Tang, Jen-Ruey, Woods, Crystal, Villegas, Leah, Sherlock, Laurie, Savani, Rashmin C., Abman, Steven H., Nozik-Grayck, Eva
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689645/
https://www.ncbi.nlm.nih.gov/pubmed/26322414
http://dx.doi.org/10.1038/pr.2015.166
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author Delaney, Cassidy
Wright, Rachel H.
Tang, Jen-Ruey
Woods, Crystal
Villegas, Leah
Sherlock, Laurie
Savani, Rashmin C.
Abman, Steven H.
Nozik-Grayck, Eva
author_facet Delaney, Cassidy
Wright, Rachel H.
Tang, Jen-Ruey
Woods, Crystal
Villegas, Leah
Sherlock, Laurie
Savani, Rashmin C.
Abman, Steven H.
Nozik-Grayck, Eva
author_sort Delaney, Cassidy
collection PubMed
description BACKGROUND: Pulmonary arterial hypertension (PAH) worsens clinical outcomes in former preterm infants with bronchopulmonary dysplasia (BPD). Oxidant stress disrupts alveolar and vascular development in models of BPD. Bleomycin causes oxidative stress and induces BPD and PAH in neonatal rats. Disruption in the VEGF and nitric oxide signaling pathways contributes to BPD. We hypothesized that loss of EC-SOD would worsen PAH associated with BPD in a neonatal mouse model of bleomycin-induced BPD by disrupting the VEGF/NO signaling pathway. METHODS: Neonatal wild-type mice (WT), and mice lacking EC-SOD (EC-SOD KO) received intraperitoneal bleomycin (2 units/kg) or PBS three times weekly and were evaluated at week 3 or 4. RESULTS: Lack of EC-SOD impaired alveolar development and resulted in PH (elevated right ventricular systolic pressures, right ventricular hypertrophy (RVH)), decreased vessel density and an increased small vessel muscularization. Exposure to bleomycin further impaired alveolar development, worsened RVH and vascular remodeling. Lack of EC-SOD and bleomycin treatment decreased lung total and phosphorylated VEGFR2 and eNOS protein expression. CONCLUSION: EC-SOD is critical in preserving normal lung development and loss of EC-SOD results in disrupted alveolar development, PAH and vascular remodeling at baseline, which is further worsened with bleomycin and associated with decreased activation of VEGFR2.
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spelling pubmed-46896452016-05-18 Lack of EC-SOD worsens alveolar and vascular development in a neonatal mouse model of bleomycin-induced bronchopulmonary dysplasia and pulmonary hypertension Delaney, Cassidy Wright, Rachel H. Tang, Jen-Ruey Woods, Crystal Villegas, Leah Sherlock, Laurie Savani, Rashmin C. Abman, Steven H. Nozik-Grayck, Eva Pediatr Res Article BACKGROUND: Pulmonary arterial hypertension (PAH) worsens clinical outcomes in former preterm infants with bronchopulmonary dysplasia (BPD). Oxidant stress disrupts alveolar and vascular development in models of BPD. Bleomycin causes oxidative stress and induces BPD and PAH in neonatal rats. Disruption in the VEGF and nitric oxide signaling pathways contributes to BPD. We hypothesized that loss of EC-SOD would worsen PAH associated with BPD in a neonatal mouse model of bleomycin-induced BPD by disrupting the VEGF/NO signaling pathway. METHODS: Neonatal wild-type mice (WT), and mice lacking EC-SOD (EC-SOD KO) received intraperitoneal bleomycin (2 units/kg) or PBS three times weekly and were evaluated at week 3 or 4. RESULTS: Lack of EC-SOD impaired alveolar development and resulted in PH (elevated right ventricular systolic pressures, right ventricular hypertrophy (RVH)), decreased vessel density and an increased small vessel muscularization. Exposure to bleomycin further impaired alveolar development, worsened RVH and vascular remodeling. Lack of EC-SOD and bleomycin treatment decreased lung total and phosphorylated VEGFR2 and eNOS protein expression. CONCLUSION: EC-SOD is critical in preserving normal lung development and loss of EC-SOD results in disrupted alveolar development, PAH and vascular remodeling at baseline, which is further worsened with bleomycin and associated with decreased activation of VEGFR2. 2015-08-31 2015-12 /pmc/articles/PMC4689645/ /pubmed/26322414 http://dx.doi.org/10.1038/pr.2015.166 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Delaney, Cassidy
Wright, Rachel H.
Tang, Jen-Ruey
Woods, Crystal
Villegas, Leah
Sherlock, Laurie
Savani, Rashmin C.
Abman, Steven H.
Nozik-Grayck, Eva
Lack of EC-SOD worsens alveolar and vascular development in a neonatal mouse model of bleomycin-induced bronchopulmonary dysplasia and pulmonary hypertension
title Lack of EC-SOD worsens alveolar and vascular development in a neonatal mouse model of bleomycin-induced bronchopulmonary dysplasia and pulmonary hypertension
title_full Lack of EC-SOD worsens alveolar and vascular development in a neonatal mouse model of bleomycin-induced bronchopulmonary dysplasia and pulmonary hypertension
title_fullStr Lack of EC-SOD worsens alveolar and vascular development in a neonatal mouse model of bleomycin-induced bronchopulmonary dysplasia and pulmonary hypertension
title_full_unstemmed Lack of EC-SOD worsens alveolar and vascular development in a neonatal mouse model of bleomycin-induced bronchopulmonary dysplasia and pulmonary hypertension
title_short Lack of EC-SOD worsens alveolar and vascular development in a neonatal mouse model of bleomycin-induced bronchopulmonary dysplasia and pulmonary hypertension
title_sort lack of ec-sod worsens alveolar and vascular development in a neonatal mouse model of bleomycin-induced bronchopulmonary dysplasia and pulmonary hypertension
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689645/
https://www.ncbi.nlm.nih.gov/pubmed/26322414
http://dx.doi.org/10.1038/pr.2015.166
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