title: Pulmonary overexpression of inhibitor κBα decreases the severity of ventilator-induced lung injury in a rat model.
abstract: BACKGROUND
  Activation of the nuclear factor-κB (NF-κB) pathway is central to the pathogenesis of lung injury and inflammation. We determined whether targeted overexpression of inhibitor-κBα (IκBα) in the lung could decrease the severity of ventilator-induced lung injury (VILI).
  
  
  METHODS
  Anaesthetized adult male Sprague-Dawley rats were randomly allocated to undergo intratracheal instillation of: (i) vehicle alone (surfactant, n=10); (ii) 1×10(10) adeno-associated virus encoding IκBα (AAV-IκBα, n=10); (iii) 5×10(10) AAV-IκBα (n=10); and (iv) 1×10(10) AAV-Null (n=5). This was followed by 4 h of injurious mechanical ventilation. Subsequent experiments examined the effect of IκBα overexpression in animals undergoing 'protective' mechanical ventilation.
  
  
  RESULTS
  IκBα overexpression increased survival duration at both the lower [3.8 h (0.4)] and higher [3.6 h (0.7)] doses compared with vehicle [2.7 h (1.0)] or the null transgene [2.2 h (0.8)]. IκBα overexpression reduced the alveolar-arterial oxygen gradient (kPa) at both the lower [53 (21)] and higher [52 (19)] doses compared with vehicle [75 (8.5)] or the null transgene [70 (15)], decreased alveolar neutrophil infiltration, and reduced alveolar concentrations of interleukin (IL)-1β and IL-10. The lower IκBα dose was as effective as the higher dose. IκBα overexpression had no effect in the setting of protective lung ventilation.
  
  
  CONCLUSIONS
  Inhibition of pulmonary NF-κB activity by IκBα overexpression reduced the severity of VILI in a rat model.
authors: Lung Biology Group, Regenerative Medicine Institute, National University of Ireland, Galway, Ireland Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland.
authors: M
authors: M
authors: Hayes
authors: Lung Biology Group, Regenerative Medicine Institute, National University of Ireland, Galway, Ireland Department of Anaesthesia, Keenan Research Centre for Biomedical Science, St Michael's Hospital, University of Toronto, Toronto, Canada.
authors: G F
authors: GF
authors: Curley
authors: Lung Biology Group, Regenerative Medicine Institute, National University of Ireland, Galway, Ireland Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland.
authors: C
authors: C
authors: Masterson
authors: Lung Biology Group, Regenerative Medicine Institute, National University of Ireland, Galway, Ireland Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland.
authors: M
authors: M
authors: Contreras
authors: Lung Biology Group, Regenerative Medicine Institute, National University of Ireland, Galway, Ireland Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland.
authors: B
authors: B
authors: Ansari
authors: Lung Biology Group, Regenerative Medicine Institute, National University of Ireland, Galway, Ireland Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland.
authors: J
authors: J
authors: Devaney
authors: Lung Biology Group, Regenerative Medicine Institute, National University of Ireland, Galway, Ireland Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland.
authors: D
authors: D
authors: O'Toole
authors: Lung Biology Group, Regenerative Medicine Institute, National University of Ireland, Galway, Ireland Department of Anaesthesia, Keenan Research Centre for Biomedical Science, St Michael's Hospital, University of Toronto, Toronto, Canada laffeyj@smh.ca.
authors: J G
authors: JG
authors: Laffey
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D020672:I-kappa B Proteins / Q000096:biosynthesis* / Q000235:genetics; D008168:Lung / Q000378:metabolism*; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010100:Oxygen / Q000097:blood; D011014:Pneumonia / Q000378:metabolism / Q000517:prevention & control; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial / Q000379:methods; D016019:Survival Analysis; D019076:Transgenes; D055397:Ventilator-Induced Lung Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D000072000:NF-KappaB Inhibitor alpha; D010100:Oxygen
keywords: acute respiratory distress syndrome; gene therapy, somatic, ventilation, mechanical; nuclear factor κ-B