Aerosol-mediated delivery of AAV2/6-IκBα attenuates lipopolysaccharide-induced acute lung injury in rats.
Inhibition of the proinflammatory transcription factor NF-κB 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-κB 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-κB inhibitor IκBα 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-IκBα demonstrated a significant increase in total IκBα levels in lung tissue relative to null vector-treated animals. Aerosolized rAAV2/6-IκBα 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 IκBα significantly attenuate endotoxin-mediated lung injury and may be a potential therapeutic candidate in the treatment of acute lung injury.
1 Regenerative Medicine Institute (REMEDI), National University of Ireland , Galway, Ireland .
Ronan J
RJ
MacLoughlin
Brendan D
BD
Higgins
James
J
Devaney
Daniel
D
O'Toole
John G
JG
Laffey
Timothy
T
O'Brien
D055371:Acute Lung Injury / Q000209:etiology* / Q000628:therapy*; D000280:Administration, Inhalation; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D000229:Dependovirus / Q000145:classification / Q000235:genetics*; D004195:Disease Models, Animal; D004731:Endotoxins / Q000009:adverse effects; D004847:Epithelial Cells / Q000378:metabolism; D015870:Gene Expression; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D020672:I-kappa B Proteins / Q000235:genetics*; D008070:Lipopolysaccharides / Q000009:adverse effects / Q000276:immunology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D020545:Respiratory Mucosa / Q000378:metabolism; D065288:Serogroup; D014161:Transduction, Genetic; D019076:Transgenes
D016207:Cytokines; D004731:Endotoxins; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides