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

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...

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Veröffentlicht in:British journal of anaesthesia : BJA 2014-12, Vol.113 (6), p.1046-1054
Hauptverfasser: Hayes, M., Curley, G.F., Masterson, C., Contreras, M., Ansari, B., Devaney, J., O'Toole, D., Laffey, J.G.
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Sprache:eng
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Zusammenfassung: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.
ISSN:0007-0912
1471-6771
DOI:10.1093/bja/aeu225