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Inhibition of pulmonary nuclear factor kappa-B decreases the severity of acute Escherichia coli pneumonia but worsens prolonged pneumonia
INTRODUCTION: Nuclear factor (NF)-κB is central to the pathogenesis of inflammation in acute lung injury, but also to inflammation resolution and repair. We wished to determine whether overexpression of the NF-κB inhibitor IκBα could modulate the severity of acute and prolonged pneumonia-induced lun...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4056114/ https://www.ncbi.nlm.nih.gov/pubmed/23622108 http://dx.doi.org/10.1186/cc12696 |
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author | Devaney, James Curley, Gerard F Hayes, Mairead Masterson, Claire Ansari, Bilal O'Brien, Timothy O'Toole, Daniel Laffey, John G |
author_facet | Devaney, James Curley, Gerard F Hayes, Mairead Masterson, Claire Ansari, Bilal O'Brien, Timothy O'Toole, Daniel Laffey, John G |
author_sort | Devaney, James |
collection | PubMed |
description | INTRODUCTION: Nuclear factor (NF)-κB is central to the pathogenesis of inflammation in acute lung injury, but also to inflammation resolution and repair. We wished to determine whether overexpression of the NF-κB inhibitor IκBα could modulate the severity of acute and prolonged pneumonia-induced lung injury in a series of prospective randomized animal studies. METHODS: Adult male Sprague-Dawley rats were randomized to undergo intratracheal instillation of (a) 5 × 10(9 )adenoassociated virus (AAV) vectors encoding the IκBα transgene (5 × 10(9 )AAV-IκBα); (b) 1 × 10(10 )AAV-IκBα; (c) 5 × 10(10 )AAV-IκBα; or (d) vehicle alone. After intratracheal inoculation with Escherichia coli, the severity of the lung injury was measured in one series over a 4-hour period (acute pneumonia), and in a second series after 72 hours (prolonged pneumonia). Additional experiments examined the effects of IκBα and null-gene overexpression on E. coli-induced and sham pneumonia. RESULTS: In acute pneumonia, IκBα dose-dependently decreased lung injury, improving arterial oxygenation and lung static compliance, reducing alveolar protein leak and histologic injury, and decreasing alveolar IL-1β concentrations. Benefit was maximal at the intermediate (1 × 10(10)) IκBα vector dose; however, efficacy was diminished at the higher (5 × 10(10)) IκBα vector dose. In contrast, IκBα worsened prolonged pneumonia-induced lung injury, increased lung bacterial load, decreased lung compliance, and delayed resolution of the acute inflammatory response. CONCLUSIONS: Inhibition of pulmonary NF-κB activity reduces early pneumonia-induced injury, but worsens injury and bacterial load during prolonged pneumonia. |
format | Online Article Text |
id | pubmed-4056114 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-40561142014-06-14 Inhibition of pulmonary nuclear factor kappa-B decreases the severity of acute Escherichia coli pneumonia but worsens prolonged pneumonia Devaney, James Curley, Gerard F Hayes, Mairead Masterson, Claire Ansari, Bilal O'Brien, Timothy O'Toole, Daniel Laffey, John G Crit Care Research INTRODUCTION: Nuclear factor (NF)-κB is central to the pathogenesis of inflammation in acute lung injury, but also to inflammation resolution and repair. We wished to determine whether overexpression of the NF-κB inhibitor IκBα could modulate the severity of acute and prolonged pneumonia-induced lung injury in a series of prospective randomized animal studies. METHODS: Adult male Sprague-Dawley rats were randomized to undergo intratracheal instillation of (a) 5 × 10(9 )adenoassociated virus (AAV) vectors encoding the IκBα transgene (5 × 10(9 )AAV-IκBα); (b) 1 × 10(10 )AAV-IκBα; (c) 5 × 10(10 )AAV-IκBα; or (d) vehicle alone. After intratracheal inoculation with Escherichia coli, the severity of the lung injury was measured in one series over a 4-hour period (acute pneumonia), and in a second series after 72 hours (prolonged pneumonia). Additional experiments examined the effects of IκBα and null-gene overexpression on E. coli-induced and sham pneumonia. RESULTS: In acute pneumonia, IκBα dose-dependently decreased lung injury, improving arterial oxygenation and lung static compliance, reducing alveolar protein leak and histologic injury, and decreasing alveolar IL-1β concentrations. Benefit was maximal at the intermediate (1 × 10(10)) IκBα vector dose; however, efficacy was diminished at the higher (5 × 10(10)) IκBα vector dose. In contrast, IκBα worsened prolonged pneumonia-induced lung injury, increased lung bacterial load, decreased lung compliance, and delayed resolution of the acute inflammatory response. CONCLUSIONS: Inhibition of pulmonary NF-κB activity reduces early pneumonia-induced injury, but worsens injury and bacterial load during prolonged pneumonia. BioMed Central 2013 2013-04-27 /pmc/articles/PMC4056114/ /pubmed/23622108 http://dx.doi.org/10.1186/cc12696 Text en Copyright © 2013 Devaney et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Devaney, James Curley, Gerard F Hayes, Mairead Masterson, Claire Ansari, Bilal O'Brien, Timothy O'Toole, Daniel Laffey, John G Inhibition of pulmonary nuclear factor kappa-B decreases the severity of acute Escherichia coli pneumonia but worsens prolonged pneumonia |
title | Inhibition of pulmonary nuclear factor kappa-B decreases the severity of acute Escherichia coli pneumonia but worsens prolonged pneumonia |
title_full | Inhibition of pulmonary nuclear factor kappa-B decreases the severity of acute Escherichia coli pneumonia but worsens prolonged pneumonia |
title_fullStr | Inhibition of pulmonary nuclear factor kappa-B decreases the severity of acute Escherichia coli pneumonia but worsens prolonged pneumonia |
title_full_unstemmed | Inhibition of pulmonary nuclear factor kappa-B decreases the severity of acute Escherichia coli pneumonia but worsens prolonged pneumonia |
title_short | Inhibition of pulmonary nuclear factor kappa-B decreases the severity of acute Escherichia coli pneumonia but worsens prolonged pneumonia |
title_sort | inhibition of pulmonary nuclear factor kappa-b decreases the severity of acute escherichia coli pneumonia but worsens prolonged pneumonia |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4056114/ https://www.ncbi.nlm.nih.gov/pubmed/23622108 http://dx.doi.org/10.1186/cc12696 |
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