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Resolvin D1 and Lipoxin A(4) Improve Alveolarization and Normalize Septal Wall Thickness in a Neonatal Murine Model of Hyperoxia-Induced Lung Injury
BACKGROUND: The critical fatty acids Docosahexaenoic Acid (DHA) and Arachidonic Acid (AA) decline in preterm infants within the first postnatal week and are associated with neonatal morbidities, including bronchopulmonary dysplasia (BPD). DHA and AA are precursors to downstream metabolites that term...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4043836/ https://www.ncbi.nlm.nih.gov/pubmed/24892762 http://dx.doi.org/10.1371/journal.pone.0098773 |
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author | Martin, Camilia R. Zaman, Munir M. Gilkey, Calvin Salguero, Maria V. Hasturk, Hatice Kantarci, Alpdogan Van Dyke, Thomas E. Freedman, Steven D. |
author_facet | Martin, Camilia R. Zaman, Munir M. Gilkey, Calvin Salguero, Maria V. Hasturk, Hatice Kantarci, Alpdogan Van Dyke, Thomas E. Freedman, Steven D. |
author_sort | Martin, Camilia R. |
collection | PubMed |
description | BACKGROUND: The critical fatty acids Docosahexaenoic Acid (DHA) and Arachidonic Acid (AA) decline in preterm infants within the first postnatal week and are associated with neonatal morbidities, including bronchopulmonary dysplasia (BPD). DHA and AA are precursors to downstream metabolites that terminate the inflammatory response. We hypothesized that treatment with Resolvin D1 and/or Lipoxin A(4) would prevent lung injury in a murine model of BPD. OBJECTIVE: To determine the effect of Resolvin D1 and/or Lipoxin A4 on hyperoxia-induced lung injury. METHODS: C57/BL6 pups were randomized at birth to Room Air, Hyperoxia (>90% oxygen), Hyperoxia + Resolvin D1, Hyperoxia + Lipoxin A(4), or Hyperoxia + Resolvin D1/Lipoxin A(4). Resolvin D1 and/or Lipoxin A(4) (2 ng/g) were given IP on days 0, 3, 6, and 9. On day 10, mice were sacrificed and lungs collected for morphometric analyses including Mean Linear Intercept (MLI), Radial Alveolar Count (RAC), and Septal Thickness (ST); RT-PCR analyses of biomarkers of lung development and inflammation; and ELISA for TGFβ(1) and TGFβ(2). RESULT: The increased ST observed with hyperoxia exposure was normalized by both Resolvin D1 and Lipoxin A(4); while, hyperoxia-induced alveolar simplification was attenuated by Lipoxin A(4). Relative to hyperoxia, Resolvin D1 reduced the gene expression of CXCL2 (2.9 fold), TIMP1 (6.7 fold), and PPARγ (4.8 fold). Treatment with Lipoxin A(4) also led to a reduction of CXCL2 (2.4 fold) while selectively increasing TGFβ(2) (2.1 fold) and Smad3 (1.58 fold). CONCLUSION: The histologic and biochemical changes seen in hyperoxia-induced lung injury in this murine model can be reversed by the addition of DHA and AA fatty acid downstream metabolites that terminate the inflammatory pathways and modulate growth factors. These fatty acids or their metabolites may be novel therapies to prevent or treat lung injury in preterm infants. |
format | Online Article Text |
id | pubmed-4043836 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-40438362014-06-09 Resolvin D1 and Lipoxin A(4) Improve Alveolarization and Normalize Septal Wall Thickness in a Neonatal Murine Model of Hyperoxia-Induced Lung Injury Martin, Camilia R. Zaman, Munir M. Gilkey, Calvin Salguero, Maria V. Hasturk, Hatice Kantarci, Alpdogan Van Dyke, Thomas E. Freedman, Steven D. PLoS One Research Article BACKGROUND: The critical fatty acids Docosahexaenoic Acid (DHA) and Arachidonic Acid (AA) decline in preterm infants within the first postnatal week and are associated with neonatal morbidities, including bronchopulmonary dysplasia (BPD). DHA and AA are precursors to downstream metabolites that terminate the inflammatory response. We hypothesized that treatment with Resolvin D1 and/or Lipoxin A(4) would prevent lung injury in a murine model of BPD. OBJECTIVE: To determine the effect of Resolvin D1 and/or Lipoxin A4 on hyperoxia-induced lung injury. METHODS: C57/BL6 pups were randomized at birth to Room Air, Hyperoxia (>90% oxygen), Hyperoxia + Resolvin D1, Hyperoxia + Lipoxin A(4), or Hyperoxia + Resolvin D1/Lipoxin A(4). Resolvin D1 and/or Lipoxin A(4) (2 ng/g) were given IP on days 0, 3, 6, and 9. On day 10, mice were sacrificed and lungs collected for morphometric analyses including Mean Linear Intercept (MLI), Radial Alveolar Count (RAC), and Septal Thickness (ST); RT-PCR analyses of biomarkers of lung development and inflammation; and ELISA for TGFβ(1) and TGFβ(2). RESULT: The increased ST observed with hyperoxia exposure was normalized by both Resolvin D1 and Lipoxin A(4); while, hyperoxia-induced alveolar simplification was attenuated by Lipoxin A(4). Relative to hyperoxia, Resolvin D1 reduced the gene expression of CXCL2 (2.9 fold), TIMP1 (6.7 fold), and PPARγ (4.8 fold). Treatment with Lipoxin A(4) also led to a reduction of CXCL2 (2.4 fold) while selectively increasing TGFβ(2) (2.1 fold) and Smad3 (1.58 fold). CONCLUSION: The histologic and biochemical changes seen in hyperoxia-induced lung injury in this murine model can be reversed by the addition of DHA and AA fatty acid downstream metabolites that terminate the inflammatory pathways and modulate growth factors. These fatty acids or their metabolites may be novel therapies to prevent or treat lung injury in preterm infants. Public Library of Science 2014-06-03 /pmc/articles/PMC4043836/ /pubmed/24892762 http://dx.doi.org/10.1371/journal.pone.0098773 Text en © 2014 Martin et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Martin, Camilia R. Zaman, Munir M. Gilkey, Calvin Salguero, Maria V. Hasturk, Hatice Kantarci, Alpdogan Van Dyke, Thomas E. Freedman, Steven D. Resolvin D1 and Lipoxin A(4) Improve Alveolarization and Normalize Septal Wall Thickness in a Neonatal Murine Model of Hyperoxia-Induced Lung Injury |
title | Resolvin D1 and Lipoxin A(4) Improve Alveolarization and Normalize Septal Wall Thickness in a Neonatal Murine Model of Hyperoxia-Induced Lung Injury |
title_full | Resolvin D1 and Lipoxin A(4) Improve Alveolarization and Normalize Septal Wall Thickness in a Neonatal Murine Model of Hyperoxia-Induced Lung Injury |
title_fullStr | Resolvin D1 and Lipoxin A(4) Improve Alveolarization and Normalize Septal Wall Thickness in a Neonatal Murine Model of Hyperoxia-Induced Lung Injury |
title_full_unstemmed | Resolvin D1 and Lipoxin A(4) Improve Alveolarization and Normalize Septal Wall Thickness in a Neonatal Murine Model of Hyperoxia-Induced Lung Injury |
title_short | Resolvin D1 and Lipoxin A(4) Improve Alveolarization and Normalize Septal Wall Thickness in a Neonatal Murine Model of Hyperoxia-Induced Lung Injury |
title_sort | resolvin d1 and lipoxin a(4) improve alveolarization and normalize septal wall thickness in a neonatal murine model of hyperoxia-induced lung injury |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4043836/ https://www.ncbi.nlm.nih.gov/pubmed/24892762 http://dx.doi.org/10.1371/journal.pone.0098773 |
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