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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...

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Autores principales: Devaney, James, Curley, Gerard F, Hayes, Mairead, Masterson, Claire, Ansari, Bilal, O'Brien, Timothy, O'Toole, Daniel, Laffey, John G
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
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.
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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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