M Hayes1, G F Curley2, C Masterson1, M Contreras1, B Ansari1, J Devaney1, D O'Toole1, J G Laffey3. 1. 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. 2. 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. 3. 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.
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.
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: Ronan J MacLoughlin; Brendan D Higgins; James Devaney; Daniel O'Toole; John G Laffey; Timothy O'Brien Journal: Hum Gene Ther Date: 2015-01 Impact factor: 5.695