Aerosol-mediated delivery of aav2/6-iκbα attenuates lipopolysaccharide-induced acute lung injury in rats
MacLoughlin, Ronan J.
Higgins, Brendan D.
Laffey, John G.
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MacLoughlin, Ronan J. Higgins, Brendan D.; Devaney, James; O'Toole, Daniel; Laffey, John G.; O'Brien, Timothy (2015). Aerosol-mediated delivery of aav2/6-iκbα attenuates lipopolysaccharide-induced acute lung injury in rats. Human Gene Therapy 26 (1), 36-46
Inhibition of the proinflammatory transcription factor NF-kappa B has previously been shown to attenuate the inflammatory response in tissue after injury. However, the feasibility and efficacy of aerosolized adeno-associated viral (AAV) vector-delivered transgenes to inhibit the NF-kappa B pathway are less clear. Initial studies optimized the AAV vector for delivery of transgenes to the pulmonary epithelium. The effect of repeated nebulization on the integrity and transduction efficacy of the AAV vector was then examined. Subsequent in vivo studies examined the efficacy of aerosolized rAAV2/6 overexpressing the NF-kappa B inhibitor I kappa B alpha in a rodent endotoxin-induced lung injury model. Initial in vitro investigations indicated that rAAV2/6 was the most effective vector to transduce the lung epithelium, and maintained its integrity and transduction efficacy after repeated nebulization. In our in vivo studies, animals that received aerosolized rAAV2/6-I kappa B alpha demonstrated a significant increase in total I kappa B alpha levels in lung tissue relative to null vector-treated animals. Aerosolized rAAV2/6-I kappa B alpha attenuated endotoxin-induced bronchoalveolar lavage-detected neutrophilia, interleukin-6 and cytokine-induced neutrophil chemoattractant-1 levels, as well as total protein content, and decreased histologic indices of injury. These results demonstrate that aerosolized AAV vectors encoding human I kappa B alpha significantly attenuate endotoxin-mediated lung injury and may be a potential therapeutic candidate in the treatment of acute lung injury.