Inhibition of pulmonary nuclear factor kappa-b decreases the severity of acute escherichia coli pneumonia but worsens prolonged pneumonia
Curley, Gerard F
Laffey, John G
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Devaney, James; Curley, Gerard F; Hayes, Mairead; Masterson, Claire; Ansari, Bilal; O'Brien, Timothy; O'Toole, Daniel; Laffey, John G (2013). Inhibition of pulmonary nuclear factor kappa-b decreases the severity of acute escherichia coli pneumonia but worsens prolonged pneumonia. Critical Care 17 (2),
Introduction: Nuclear factor (NF)-kappa B 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-kappa B inhibitor I kappa B alpha 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 x 10(9) adenoassociated virus (AAV) vectors encoding the I kappa B alpha transgene (5 x 10(9) AAV-I kappa B alpha); (b) 1 x 10(10) AAV-I kappa B alpha; (c) 5 x 10(10) AAV-I kappa B alpha; 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 I kappa B alpha and null-gene overexpression on E. coli-induced and sham pneumonia. Results: In acute pneumonia, I kappa B alpha dose-dependently decreased lung injury, improving arterial oxygenation and lung static compliance, reducing alveolar protein leak and histologic injury, and decreasing alveolar IL-1 beta concentrations. Benefit was maximal at the intermediate (1 x 10(10)) I kappa B alpha vector dose; however, efficacy was diminished at the higher (5 x 10(10)) I kappa B alpha vector dose. In contrast, I kappa B alpha 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-kappa B activity reduces early pneumonia-induced injury, but worsens injury and bacterial load during prolonged pneumonia.