期刊论文详细信息
Critical Care
Inhibition of pulmonary nuclear factor kappa-B decreases the severity of acute Escherichia coli pneumonia but worsens prolonged pneumonia
John G Laffey1  Daniel O'Toole2  Timothy O'Brien3  Bilal Ansari2  Claire Masterson2  Mairead Hayes2  Gerard F Curley1  James Devaney2 
[1] Department of Anesthesia, Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, ONT, M5B 1W8, Canada;Department of Anaesthesia and Critical Care, School of Medicine, Clinical Sciences Institute, National University of Ireland Galway, University Road, Newcastle, Galway, Ireland;Regenerative Medicine Institute, National University of Ireland Galway, University Road, Newcastle, Galway, Ireland
关键词: gene therapy;    pneumonia;    bacteria;    acute respiratory distress syndrome;    rat;    inhibitory kappa-B alpha;    Acute lung injury;   
Others  :  818158
DOI  :  10.1186/cc12696
 received in 2013-01-17, accepted in 2013-04-27,  发布年份 2013
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【 摘 要 】

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.

【 授权许可】

   
2013 Devaney et al.; licensee BioMed Central Ltd.

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