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Hayes, M,Curley, GF,Masterson, C,Contreras, M,Ansari, B,Devaney, J,O'Toole, D,Laffey, JG
British Journal Of Anaesthesia
Pulmonary overexpression of inhibitor kappa B alpha decreases the severity of ventilator-induced lung injury in a rat model
WOS: 5 ()
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acute respiratory distress syndrome gene therapy, somatic, ventilation, mechanical nuclear factor kappa-B RESPIRATORY-DISTRESS-SYNDROME HYPERCAPNIC ACIDOSIS TIDAL VOLUME RISK-FACTOR ACTIVATION MICE PNEUMONIA MECHANISM RELEASE SEPSIS
Background. Activation of the nuclear factor-kappa B (NE-kappa B) pathway is central to the pathogenesis of lung injury and inflammation. We determined whether targeted overexpression of inhibitor-kappa B alpha (I kappa B alpha) 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 x 10(10) adeno-associated virus encoding I kappa B alpha (AAV-I kappa B alpha, n=10); (iii) 5 x 10(10) AAV-I kappa B alpha (n=10); and (iv) 1 x 10(10) AAV-Null (n=5). This was followed by 4 h of injurious mechanical ventilation. Subsequent experiments examined the effect of I kappa B alpha overexpression in animals undergoing 'protective' mechanical ventilation.Results. I kappa B alpha 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)]. I kappa B alpha 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)-1 beta and IL-10. The lower I kappa B alpha dose was as effective as the higher dose. I kappa B alpha overexpression had no effect in the setting of protective lung ventilation.Conclusions. Inhibition of pulmonary NE-kappa B activity by I kappa B alpha overexpression reduced the severity of VILI in a rat model.
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