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

IntroductionNF-kappaB 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-kappaB inhibitor IBcould 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: (1) 5 x 109 adeno-associated virus (AAV) vectors encoding the IB transgene (5 x 109 AAV-IB); (2) 1 x 1010 AAV-IB; (3) 5 x 1010 AAV-IB; or (4) vehicle alone. Following intra-tracheal inoculation with E. Coli the severity of the lung injury was measured in one series over 4h (Acute Pneumonia), and in a second series after 72h (Prolonged Pneumonia). Additional experiments examined the effects of IB and null gene overexpression on E. coli induced and sham pneumonia. Results: In acute pneumonia, IB dose dependently decreased lung injury, improving arterial oxygenation and lung static compliance, reducing alveolar protein leak and histologic injury, and decreasing alveolar IL-1 concentrations. Benefit was maximal at the intermediate (1 x 1010) IB vector dose; however efficacy was diminished at the higher (5 x 1010) IB vector dose. In contrast IB 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-kappaB activity reduces early pneumonia induced injury, but worsens injury and bacterial load during prolonged pneumonia.



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