title: Inhibition of pulmonary nuclear factor kappa-B decreases the severity of acute Escherichia coli pneumonia but worsens prolonged pneumonia.
abstract: BACKGROUND
  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.
authors.forename: James
authors.initials: J
authors.lastname: Devaney
authors.forename: Gerard F
authors.initials: GF
authors.lastname: Curley
authors.forename: Mairead
authors.initials: M
authors.lastname: Hayes
authors.forename: Claire
authors.initials: C
authors.lastname: Masterson
authors.forename: Bilal
authors.initials: B
authors.lastname: Ansari
authors.forename: Timothy
authors.initials: T
authors.lastname: O'Brien
authors.forename: Daniel
authors.initials: D
authors.lastname: O'Toole
authors.forename: John G
authors.initials: JG
authors.lastname: Laffey
mesh_terms: D000208:Acute Disease; D000818:Animals; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D005822:Genetic Vectors / Q000008:administration & dosage; D020672:I-kappa B Proteins / Q000008:administration & dosage*; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018410:Pneumonia, Bacterial / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D000072000:NF-KappaB Inhibitor alpha