Pulmonary overexpression of inhibitor κBα decreases the severity of ventilator-induced lung injury in a rat model

• Published in: British journal of anaesthesia : BJA Vol. 113; no. 6; pp. 1046 - 1054
• Main Authors: Hayes, M., Curley, G.F., Masterson, C., Contreras, M., Ansari, B., Devaney, J., O'Toole, D., Laffey, J.G.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-12-2014; Oxford University Press
• Subjects: acute respiratory distress syndrome; Animals; Dependovirus - genetics; Disease Models, Animal; Gene Expression; gene therapy, somatic, ventilation, mechanical; Genetic Therapy - methods; Genetic Vectors; I-kappa B Proteins - biosynthesis; I-kappa B Proteins - genetics; Lung - metabolism; Male; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha; nuclear factor κ-B; Oxygen - blood; Pneumonia - metabolism; Pneumonia - prevention & control; Rats, Sprague-Dawley; Respiration, Artificial - methods; Survival Analysis; Transgenes; Ventilator-Induced Lung Injury - metabolism; Ventilator-Induced Lung Injury - pathology; Ventilator-Induced Lung Injury - prevention & control; nuclear factor κ-B; acute respiratory distress syndrome; gene therapy, somatic, ventilation, mechanical
• ISSN: 0007-0912; 1471-6771
• DOI: 10.1093/bja/aeu225

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).
Anaesthetized adult male Sprague–Dawley rats were randomly allocated to undergo intratracheal instillation of: (i) vehicle alone (surfactant, n=10); (ii) 1×1010 adeno-associated virus encoding IκBα (AAV-IκBα, n=10); (iii) 5×1010 AAV-IκBα (n=10); and (iv) 1×1010 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.
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.
Inhibition of pulmonary NF-κB activity by IκBα overexpression reduced the severity of VILI in a rat model.