Inhibition of pulmonary Nuclear Factor kappa-B decreases the severity of acute E. coli pneumonia but worsens prolonged pneumonia

Hdl Handle:
http://hdl.handle.net/10147/294481
Title:
Inhibition of pulmonary Nuclear Factor kappa-B decreases the severity of acute E. coli pneumonia but worsens prolonged pneumonia
Authors:
Devaney, James; Curley, Gerard F; Hayes, Mairead; Masterson, Claire; Ansari, Bilal; O'Brien, Timothy; O'Toole, Daniel; Laffey, John G
Citation:
Critical Care. 2013 Apr 27;17(2):R82
Issue Date:
27-Apr-2013
URI:
http://dx.doi.org/10.1186/cc12696; http://hdl.handle.net/10147/294481
Abstract:
Abstract 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 × 109 adenoassociated virus (AAV) vectors encoding the IκBα transgene (5 × 109 AAV-IκBα); (b) 1 × 1010 AAV-IκBα; (c) 5 × 1010 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 × 1010) IκBα vector dose; however, efficacy was diminished at the higher (5 × 1010) 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.
Item Type:
Journal Article

Full metadata record

DC FieldValue Language
dc.contributor.authorDevaney, James-
dc.contributor.authorCurley, Gerard F-
dc.contributor.authorHayes, Mairead-
dc.contributor.authorMasterson, Claire-
dc.contributor.authorAnsari, Bilal-
dc.contributor.authorO'Brien, Timothy-
dc.contributor.authorO'Toole, Daniel-
dc.contributor.authorLaffey, John G-
dc.date.accessioned2013-06-24T18:19:06Z-
dc.date.available2013-06-24T18:19:06Z-
dc.date.issued2013-04-27-
dc.identifier.citationCritical Care. 2013 Apr 27;17(2):R82-
dc.identifier.urihttp://dx.doi.org/10.1186/cc12696-
dc.identifier.urihttp://hdl.handle.net/10147/294481-
dc.description.abstractAbstract 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 × 109 adenoassociated virus (AAV) vectors encoding the IκBα transgene (5 × 109 AAV-IκBα); (b) 1 × 1010 AAV-IκBα; (c) 5 × 1010 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 × 1010) IκBα vector dose; however, efficacy was diminished at the higher (5 × 1010) 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.-
dc.titleInhibition of pulmonary Nuclear Factor kappa-B decreases the severity of acute E. coli pneumonia but worsens prolonged pneumonia-
dc.typeJournal Article-
dc.language.rfc3066en-
dc.rights.holderJames Devaney et al.; licensee BioMed Central Ltd.-
dc.description.statusPeer Reviewed-
dc.date.updated2013-06-11T15:11:18Z-
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